Hot off the presses! Sep 08 Cancer Cell

The Sep 08 issue of the Cancer Cell is now up on Pubget (About Cancer Cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• The Yin-Yang of Tumor-Associated Neutrophils
  - Cancer Cell 16(3):173-174 (2009)
  Cancer-related inflammation is a key component of the tumor microenvironment. A report in this issue of Cancer Cell now indicates that tumor-associated neutrophils in lung cancer can polarize to either "N1" or "N2" phenotype that inhibits or promotes cancer development, respectively.
• Imatinib Resistance and Progression of CML to Blast Crisis: Somatic Hypermutation AIDing the Way
  - Cancer Cell 16(3):174-176 (2009)
  Very little is known about how acquired oncogenic mutations arise. In this issue of Cancer Cell, Klemm and colleagues present evidence supporting a role for the antibody diversification enzyme activation-induced deaminase (AID) in the generation of mutations associated with disease progression and drug resistance in chronic myeloid leukemia.
• Src Substrate Surprise
  - Cancer Cell 16(3):176-178 (2009)
  In this issue of Cancer Cell, Lowy and colleagues show that the SH2 domain of tensin-3 is regulated by phosphorylation by Src and that this phosphorylation promotes the oncogenic function of tensin-3. Phosphorylation of the SH2 domain represents a novel mechanism for the regulation of SH2 ligand binding.
• A Molecular Link between AKT Regulation and Chemotherapeutic Response
  - Cancer Cell 16(3):178-180 (2009)
  The protein kinase AKT is frequently activated in human cancers and has been implicated in resistance to chemotherapy. In this issue of Cancer Cell, Pei et al. show that FKBP51 negatively regulates AKT through the phosphatase PHLPP. This regulation appears to be a determinant of chemosensitivity in cancer cells.
• SDH5 Mutations and Familial Paraganglioma: Somewhere Warburg is Smiling
  - Cancer Cell 16(3):180-182 (2009)
  Paragangliomas have been linked to mutations affecting the succinate dehydrogenase complex. In a recent issue of Science, Rutter and coworkers showed that SDH5 is required for the flavination of SDHA, which is necessary for SDH assembly and function. Moreover, they detected SDH5 mutations in a large kindred with familial paraganglioma.
• Polarization of Tumor-Associated Neutrophil Phenotype by TGF-β: "N1" versus "N2" TAN
  - Cancer Cell 16(3):183-194 (2009)
  TGF-β blockade significantly slows tumor growth through many mechanisms, including activation of CD8+ T cells and macrophages. Here, we show that TGF-β blockade also increases neutrophil-attracting chemokines, resulting in an influx of CD11b+/Ly6G+ tumor-associated neutrophils (TANs) that are hypersegmented, more cytotoxic to tumor cells, and express higher levels of proinflammatory cytokines. Accordingly, following TGF-β blockade, depletion of these neutrophils significantly blunts antitumor effects of treatment and reduces CD8+ T cell activation. In contrast, in control tumors, neutrophil depletion decreases tumor growth and results in more activated CD8+ T cells intratumorally. Together, these data suggest that TGF-β within the tumor microenvironment induces a population of TAN with a protumor phenotype. TGF-β blockade results in the recruitment and activation of TANs with an antitumor phenotype.
• 14-3-3ζ Cooperates with ErbB2 to Promote Ductal Carcinoma In Situ Progression to Invasive Breast Cancer by Inducing Epithelial-Mesenchymal Transition
  - Cancer Cell 16(3):195-207 (2009)
  ErbB2, a metastasis-promoting oncoprotein, is overexpressed in 25% of invasive/metastatic breast cancers, but in 50%–60% of noninvasive ductal carcinomas in situ (DCIS). It has been puzzling how a subset of ErbB2-overexpressing DCIS develops into invasive breast cancer (IBC). We found that co-overexpression of 14-3-3ζ in ErbB2-overexpressing DCIS conferred a higher risk of progression to IBC. ErbB2 and 14-3-3ζ overexpression, respectively, increased cell migration and decreased cell adhesion, two prerequisites of tumor cell invasion. 14-3-3ζ overexpression reduced cell adhesion by activating the TGF-β/Smads pathway that led to ZFHX1B/SIP-1 upregulation, E-cadherin loss, and epithelial-mesenchymal transition. Importantly, patients whose breast tumors overexpressed both ErbB2 and 14-3-3ζ had higher rates of metastatic recurrence and death than those whose tumors overexpressed only one.
• Colitis-Associated Colorectal Cancer Driven by T-bet Deficiency in Dendritic Cells
  - Cancer Cell 16(3):208-219 (2009)
  We previously described a mouse model of ulcerative colitis linked to T-bet deficiency in the innate immune system. Here, we report that the majority of T-bet−/−RAG2−/− ulcerative colitis (TRUC) mice spontaneously progress to colonic dysplasia and rectal adenocarcinoma solely as a consequence of MyD88-independent intestinal inflammation. Dendritic cells (DCs) are necessary cellular effectors for a proinflammatory program that is carcinogenic. Whereas these malignancies arise in the setting of a complex inflammatory environment, restoration of T-bet selectively in DCs was sufficient to reduce colonic inflammation and prevent the development of neoplasia. TRUC colitis-associated colorectal cancer resembles the human disease and provides ample opportunity to probe how inflammation drives colorectal cancer development and to test preventative and therapeutic strategies preclinically.
• Growth Factor-Antagonized Rexinoid Apoptosis Involves Permissive PPARγ/RXR Heterodimers to Activate the Intrinsic Death Pathway by NO
  - Cancer Cell 16(3):220-231 (2009)
  Growth factor (GF) deprivation and/or blocking of cognate signaling can induce apoptosis and is the basis of several cancer treatment paradigms. We observed that RXR agonists (rexinoids) induce apoptosis of tumor cells when GF support is abrogated. This "rexinoid apoptosis" involves activation of both iNOS and eNOS by RXR-PPARγ and results in production of apoptogenic NO. IGF/EGF-induced IGF receptor 1-mediated MAP kinase blocks rexinoid apoptosis by RXR phosphorylation. Combining rexinoids with the MAPK inhibitor U0126 induced apoptosis in human cancer cells in vitro and ex vivo and blocked xenograft growth in vivo. Our results suggest a regulatory mechanism in which GF signaling antagonizes RXR-PPARγ-mediated default apoptosis to sustain cell life.
• The B Cell Mutator AID Promotes B Lymphoid Blast Crisis and Drug Resistance in Chronic Myeloid Leukemia
  - Cancer Cell 16(3):232-245 (2009)
  Chronic myeloid leukemia (CML) is induced by BCR-ABL1 and can be effectively treated for many years with Imatinib until leukemia cells acquire drug resistance through BCR-ABL1 mutations and progress into fatal B lymphoid blast crisis (LBC). Despite its clinical significance, the mechanism of progression into LBC is unknown. Here, we show that LBC but not CML cells express the B cell-specific mutator enzyme AID. We demonstrate that AID expression in CML cells promotes overall genetic instability by hypermutation of tumor suppressor and DNA repair genes. Importantly, our data uncover a causative role of AID activity in the acquisition of BCR-ABL1 mutations leading to Imatinib resistance, thus providing a rationale for the rapid development of drug resistance and blast crisis progression.
• The Tensin-3 Protein, Including its SH2 Domain, Is Phosphorylated by Src and Contributes to Tumorigenesis and Metastasis
  - Cancer Cell 16(3):246-258 (2009)
  In cell lines from advanced lung cancer, breast cancer, and melanoma, endogenous tensin-3 contributes to cell migration, anchorage-independent growth, and tumorigenesis. Although SH2 domains have not been reported previously to be phosphorylated, the tensin-3 SH2 domain is a physiologic substrate for Src. Tyrosines in the SH2 domain contribute to the biological activity of tensin-3, and phosphorylation of these tyrosines can regulate ligand binding. In a mouse breast cancer model, tensin-3 tyrosines are phosphorylated in a Src-associated manner in primary tumors, and experimental metastases induced by tumor-derived cell lines depend on endogenous tensin-3. Thus, tensin-3 is implicated as an oncoprotein regulated by Src and possessing an SH2 domain with a previously undescribed mechanism for the regulation of ligand binding.
• FKBP51 Affects Cancer Cell Response to Chemotherapy by Negatively Regulating Akt
  - Cancer Cell 16(3):259-266 (2009)
  Akt is a central regulator of cell growth. Its activity can be negatively regulated by the phosphatase PHLPP that specifically dephosphorylates the hydrophobic motif of Akt (Ser473 in Akt1). However, how PHLPP is targeted to Akt is not clear. Here we show that FKBP51 (FK506-binding protein 51) acts as a scaffolding protein for Akt and PHLPP and promotes dephosphorylation of Akt. Furthermore, FKBP51 is downregulated in pancreatic cancer tissue samples and several cancer cell lines. Decreased FKBP51 expression in cancer cells results in hyperphosphorylation of Akt and decreased cell death following genotoxic stress. Overall, our findings identify FKBP51 as a negative regulator of the Akt pathway, with potentially important implications for cancer etiology and response to chemotherapy.
• Identification of CD15 as a Marker for Tumor-Propagating Cells in a Mouse Model of Medulloblastoma
  - Cancer Cell 16(3):267 (2009)
  

Hot off the presses! Aug 16 Cancer Cell

The Aug 16 issue of the Cancer Cell is now up on Pubget (About Cancer Cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Posterior Fossa Ependymomas: A Tale of Two Subtypes
  - Cancer Cell 20(2):133-134 (2011)
  Ependymomas are common childhood brain tumors, but little is known about their underlying biology. In this issue of Cancer Cell, Witt et al. present that posterior fossa ependymomas comprise two distinct molecular subtypes, each with unique gene expression signatures, different levels of genomic instability, and different prognosis.
• Surprise! HSC Are Aberrant in Chronic Lymphocytic Leukemia
  - Cancer Cell 20(2):135-136 (2011)
  In this issue of Cancer Cell, Kikushige et al. report the surprising finding that, in human chronic lymphocytic leukemia (CLL), hematopoietic stem cells (HSC) aberrantly generate clonal B cells with CLL-like phenotypes, which implicate HSC in the pathogenesis of this mature lymphoid malignancy and has major implications for CLL therapies.
• We Contain Multitudes: The Protean Face of Retinoblastoma
  - Cancer Cell 20(2):137-138 (2011)
  The precise cellular characteristics of retinoblastoma have long been debated. In this issue of Cancer Cell, McEvoy et al. reveal that retinoblastomas are highly homogeneous at the molecular level and coexpress genes characteristic of retinal progenitors and various different mature retinal cell types, while ultrastructurally resembling amacrine cells.
• A TeNaCious Foundation for the Metastatic Niche
  - Cancer Cell 20(2):139-141 (2011)
  In the July issue of Nature Medicine, Massagué and colleagues define a biphasic role for the extracellular matrix protein tenascin C as a metastatic niche component in lung colonization by breast cancer cells. These results provide a rationale for designing therapies targeting metastatic progression by disrupting its very foundations.
• Delineation of Two Clinically and Molecularly Distinct Subgroups of Posterior Fossa Ependymoma
  - Cancer Cell 20(2):143-157 (2011)
  Despite the histological similarity of ependymomas from throughout the neuroaxis, the disease likely comprises multiple independent entities, each with a distinct molecular pathogenesis. Transcriptional profiling of two large independent cohorts of ependymoma reveals the existence of two demographically, transcriptionally, genetically, and clinically distinct groups of posterior fossa (PF) ependymomas. Group A patients are younger, have laterally located tumors with a balanced genome, and are much more likely to exhibit recurrence, metastasis at recurrence, and death compared with Group B patients. Identification and optimization of immunohistochemical (IHC) markers for PF ependymoma subgroups allowed validation of our findings on a third independent cohort, using a human ependymoma tissue microarray, and provides a tool for prospective prognostication and stratification of PF ependymoma patients.
• Neuregulin-1-Mediated Autocrine Signaling Underlies Sensitivity to HER2 Kinase Inhibitors in a Subset of Human Cancers
  - Cancer Cell 20(2):158-172 (2011)
  HER2 kinase inhibitors, such as lapatinib, have demonstrated clinical efficacy in HER2-amplified breast cancers. By profiling nearly 700 human cancer cell lines, we identified a subset of non-HER2 amplified cancer cells with striking sensitivity to HER2 kinase inhibition—particularly from head and neck tumors. These cells were found to depend on a neuregulin-1 (NRG1)-mediated autocrine loop driving HER3 activation, which can be disrupted by lapatinib. Elevated NRG1 expression and activated HER3 are strongly associated with lapatinib sensitivity in vitro, and these biomarkers were enriched in a subset of primary head and neck cancer samples. The findings suggest that patients with NRG1-driven tumors lacking HER2 amplification may derive significant clinical benefit from HER2:HER3-directed therapies.
• Identification of PHLPP1 as a Tumor Suppressor Reveals the Role of Feedback Activation in PTEN-Mutant Prostate Cancer Progression
  - Cancer Cell 20(2):173-186 (2011)
  Hyperactivation of the PI 3-kinase/AKT pathway is a driving force of many cancers. Here we identify the AKT-inactivating phosphatase PHLPP1 as a prostate tumor suppressor. We show that Phlpp1-loss causes neoplasia and, on partial Pten-loss, carcinoma in mouse prostate. This genetic setting initially triggers a growth suppressive response via p53 and the Phlpp2 ortholog, and reveals spontaneous Trp53 inactivation as a condition for full-blown disease. Surprisingly, the codeletion of PTEN and PHLPP1 in patient samples is highly restricted to metastatic disease and tightly correlated to deletion of TP53 and PHLPP2. These data establish a conceptual framework for progression of PTEN mutant prostate cancer to life-threatening disease.
• Coordinated Regulation of Polycomb Group Complexes through microRNAs in Cancer
  - Cancer Cell 20(2):187-199 (2011)
  Polycomb Repressive Complexes (PRC1 and PRC2)-mediated epigenetic regulation is critical for maintaining cellular homeostasis. Members of Polycomb Group (PcG) proteins including EZH2, a PRC2 component, are upregulated in various cancer types, implicating their role in tumorigenesis. Here, we have identified several microRNAs (miRNAs) that are repressed by EZH2. These miRNAs, in turn, regulate the expression of PRC1 proteins BMI1 and RING2. We found that ectopic overexpression of EZH2-regulated miRNAs attenuated cancer cell growth and invasiveness, and abrogated cancer stem cell properties. Importantly, expression analysis revealed an inverse correlation between miRNA and PRC protein levels in cell culture and prostate cancer tissues. Taken together, our data have uncovered a coordinate regulation of PRC1 and PRC2 activities that is mediated by miRNAs.
• Dominantly Inherited Constitutional Epigenetic Silencing of MLH1 in a Cancer-Affected Family Is Linked to a Single Nucleotide Variant within the 5′UTR
  - Cancer Cell 20(2):200-213 (2011)
  Constitutional epimutations of tumor suppressor genes manifest as promoter methylation and transcriptional silencing of a single allele in normal somatic tissues, thereby predisposing to cancer. Constitutional MLH1 epimutations occur in individuals with young-onset cancer and demonstrate non-Mendelian inheritance through their reversal in the germline. We report a cancer-affected family showing dominant transmission of soma-wide highly mosaic MLH1 methylation and transcriptional repression linked to a particular genetic haplotype. The epimutation was erased in spermatozoa but reinstated in the somatic cells of the next generation. The affected haplotype harbored two single nucleotide substitutions in tandem; c.-27C > A located near the transcription initiation site and c.85G > T. The c.-27C > A variant significantly reduced transcriptional activity in reporter assays and is the probable cause of this epimutation.
• A Cullin3-KLHL20 Ubiquitin Ligase-Dependent Pathway Targets PML to Potentiate HIF-1 Signaling and Prostate Cancer Progression
  - Cancer Cell 20(2):214-228 (2011)
  Tumor hypoxia is associated with disease progression and treatment failure, but the hypoxia signaling mechanism is not fully understood. Here, we show that KLHL20, a Cullin3 (Cul3) substrate adaptor induced by HIF-1, coordinates with the actions of CDK1/2 and Pin1 to mediate hypoxia-induced PML proteasomal degradation. Furthermore, this PML destruction pathway participates in a feedback mechanism to maximize HIF-1α induction, thereby potentiating multiple tumor hypoxia responses, including metabolic reprogramming, epithelial-mesenchymal transition, migration, tumor growth, angiogenesis, and chemoresistance. In human prostate cancer, overexpression of HIF-1α, KLHL20, and Pin1 correlates with PML down-regulation, and hyperactivation of the PML destruction pathway is associated with disease progression. Our study indicates that the KLHL20-mediated PML degradation and HIF-1α autoregulation play key roles in tumor progression.
• ROCK and JAK1 Signaling Cooperate to Control Actomyosin Contractility in Tumor Cells and Stroma
  - Cancer Cell 20(2):229-245 (2011)
  Proinflammatory cytokines are frequently observed in the tumor microenvironment, and chronic inflammation is involved in cancer initiation and progression. We show that cytokine signaling through the receptor subunit GP130-IL6ST and the kinase JAK1 generates actomyosin contractility through Rho-kinase dependent signaling. This pathway generates contractile force in stromal fibroblasts to remodel the extracellular matrix to create tracks for collective migration of squamous carcinoma cells and provides the high levels of actomyosin contractility required for migration of individual melanoma cells in the rounded, "amoeboid" mode. Thus, cytokine signaling can generate actomyosin contractility in both stroma and tumor cells. Strikingly, actomyosin contractility itself positively modulates activity of the transcription factor STAT3 downstream of JAK1, demonstrating positive feedback within the signaling network.
• Self-Renewing Hematopoietic Stem Cell Is the Primary Target in Pathogenesis of Human Chronic Lymphocytic Leukemia
  - Cancer Cell 20(2):246-259 (2011)
  We report here that in chronic lymphocytic leukemia (CLL), the propensity to generate clonal B cells has been acquired already at the hematopoietic stem cell (HSC) stage. HSCs purified from patients with CLL displayed lymphoid-lineage gene priming and produced a high number of polyclonal B cell progenitors. Strikingly, their maturation into B cells was restricted always to mono- or oligo-clones with CLL-like phenotype in xenogeneic recipients. These B cell clones were independent of the original CLL clones because they had their own immunoglobulin VDJ genes. Furthermore, they used preferentially VH genes frequently used in human CLL, presumably reflecting the role of B cell receptor signaling in clonal selection. These data suggest that HSCs can be involved in leukemogenesis even in mature lymphoid tumors.
• Coexpression of Normally Incompatible Developmental Pathways in Retinoblastoma Genesis
  - Cancer Cell 20(2):260-275 (2011)
  It is widely believed that the molecular and cellular features of a tumor reflect its cell of origin and can thus provide clues about treatment targets. The retinoblastoma cell of origin has been debated for over a century. Here, we report that human and mouse retinoblastomas have molecular, cellular, and neurochemical features of multiple cell classes, principally amacrine/horizontal interneurons, retinal progenitor cells, and photoreceptors. Importantly, single-cell gene expression array analysis showed that these multiple cell type-specific developmental programs are coexpressed in individual retinoblastoma cells, which creates a progenitor/neuronal hybrid cell. Furthermore, neurotransmitter receptors, transporters, and biosynthetic enzymes are expressed in human retinoblastoma, and targeted disruption of these pathways reduces retinoblastoma growth in vivo and in vitro.
• TET2 Inactivation Results in Pleiotropic Hematopoietic Abnormalities in Mouse and Is a Recurrent Event during Human Lymphomagenesis
  - Cancer Cell 20(2):276 (2011)
  
• Proinvasion Metastasis Drivers in Early-Stage Melanoma Are Oncogenes
  - Cancer Cell 20(2):277 (2011)
  

Hot off the presses! Aug 16 Cancer Cell

The Aug 16 issue of the Cancer Cell is now up on Pubget (About Cancer Cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Posterior Fossa Ependymomas: A Tale of Two Subtypes
  - Cancer Cell 20(2):133-134 (2011)
  Ependymomas are common childhood brain tumors, but little is known about their underlying biology. In this issue of Cancer Cell, Witt et al. present that posterior fossa ependymomas comprise two distinct molecular subtypes, each with unique gene expression signatures, different levels of genomic instability, and different prognosis.
• Surprise! HSC Are Aberrant in Chronic Lymphocytic Leukemia
  - Cancer Cell 20(2):135-136 (2011)
  In this issue of Cancer Cell, Kikushige et al. report the surprising finding that, in human chronic lymphocytic leukemia (CLL), hematopoietic stem cells (HSC) aberrantly generate clonal B cells with CLL-like phenotypes, which implicate HSC in the pathogenesis of this mature lymphoid malignancy and has major implications for CLL therapies.
• We Contain Multitudes: The Protean Face of Retinoblastoma
  - Cancer Cell 20(2):137-138 (2011)
  The precise cellular characteristics of retinoblastoma have long been debated. In this issue of Cancer Cell, McEvoy et al. reveal that retinoblastomas are highly homogeneous at the molecular level and coexpress genes characteristic of retinal progenitors and various different mature retinal cell types, while ultrastructurally resembling amacrine cells.
• A TeNaCious Foundation for the Metastatic Niche
  - Cancer Cell 20(2):139-141 (2011)
  In the July issue of Nature Medicine, Massagué and colleagues define a biphasic role for the extracellular matrix protein tenascin C as a metastatic niche component in lung colonization by breast cancer cells. These results provide a rationale for designing therapies targeting metastatic progression by disrupting its very foundations.
• Delineation of Two Clinically and Molecularly Distinct Subgroups of Posterior Fossa Ependymoma
  - Cancer Cell 20(2):143-157 (2011)
  Despite the histological similarity of ependymomas from throughout the neuroaxis, the disease likely comprises multiple independent entities, each with a distinct molecular pathogenesis. Transcriptional profiling of two large independent cohorts of ependymoma reveals the existence of two demographically, transcriptionally, genetically, and clinically distinct groups of posterior fossa (PF) ependymomas. Group A patients are younger, have laterally located tumors with a balanced genome, and are much more likely to exhibit recurrence, metastasis at recurrence, and death compared with Group B patients. Identification and optimization of immunohistochemical (IHC) markers for PF ependymoma subgroups allowed validation of our findings on a third independent cohort, using a human ependymoma tissue microarray, and provides a tool for prospective prognostication and stratification of PF ependymoma patients.
• Neuregulin-1-Mediated Autocrine Signaling Underlies Sensitivity to HER2 Kinase Inhibitors in a Subset of Human Cancers
  - Cancer Cell 20(2):158-172 (2011)
  HER2 kinase inhibitors, such as lapatinib, have demonstrated clinical efficacy in HER2-amplified breast cancers. By profiling nearly 700 human cancer cell lines, we identified a subset of non-HER2 amplified cancer cells with striking sensitivity to HER2 kinase inhibition—particularly from head and neck tumors. These cells were found to depend on a neuregulin-1 (NRG1)-mediated autocrine loop driving HER3 activation, which can be disrupted by lapatinib. Elevated NRG1 expression and activated HER3 are strongly associated with lapatinib sensitivity in vitro, and these biomarkers were enriched in a subset of primary head and neck cancer samples. The findings suggest that patients with NRG1-driven tumors lacking HER2 amplification may derive significant clinical benefit from HER2:HER3-directed therapies.
• Identification of PHLPP1 as a Tumor Suppressor Reveals the Role of Feedback Activation in PTEN-Mutant Prostate Cancer Progression
  - Cancer Cell 20(2):173-186 (2011)
  Hyperactivation of the PI 3-kinase/AKT pathway is a driving force of many cancers. Here we identify the AKT-inactivating phosphatase PHLPP1 as a prostate tumor suppressor. We show that Phlpp1-loss causes neoplasia and, on partial Pten-loss, carcinoma in mouse prostate. This genetic setting initially triggers a growth suppressive response via p53 and the Phlpp2 ortholog, and reveals spontaneous Trp53 inactivation as a condition for full-blown disease. Surprisingly, the codeletion of PTEN and PHLPP1 in patient samples is highly restricted to metastatic disease and tightly correlated to deletion of TP53 and PHLPP2. These data establish a conceptual framework for progression of PTEN mutant prostate cancer to life-threatening disease.
• Coordinated Regulation of Polycomb Group Complexes through microRNAs in Cancer
  - Cancer Cell 20(2):187-199 (2011)
  Polycomb Repressive Complexes (PRC1 and PRC2)-mediated epigenetic regulation is critical for maintaining cellular homeostasis. Members of Polycomb Group (PcG) proteins including EZH2, a PRC2 component, are upregulated in various cancer types, implicating their role in tumorigenesis. Here, we have identified several microRNAs (miRNAs) that are repressed by EZH2. These miRNAs, in turn, regulate the expression of PRC1 proteins BMI1 and RING2. We found that ectopic overexpression of EZH2-regulated miRNAs attenuated cancer cell growth and invasiveness, and abrogated cancer stem cell properties. Importantly, expression analysis revealed an inverse correlation between miRNA and PRC protein levels in cell culture and prostate cancer tissues. Taken together, our data have uncovered a coordinate regulation of PRC1 and PRC2 activities that is mediated by miRNAs.
• Dominantly Inherited Constitutional Epigenetic Silencing of MLH1 in a Cancer-Affected Family Is Linked to a Single Nucleotide Variant within the 5′UTR
  - Cancer Cell 20(2):200-213 (2011)
  Constitutional epimutations of tumor suppressor genes manifest as promoter methylation and transcriptional silencing of a single allele in normal somatic tissues, thereby predisposing to cancer. Constitutional MLH1 epimutations occur in individuals with young-onset cancer and demonstrate non-Mendelian inheritance through their reversal in the germline. We report a cancer-affected family showing dominant transmission of soma-wide highly mosaic MLH1 methylation and transcriptional repression linked to a particular genetic haplotype. The epimutation was erased in spermatozoa but reinstated in the somatic cells of the next generation. The affected haplotype harbored two single nucleotide substitutions in tandem; c.-27C > A located near the transcription initiation site and c.85G > T. The c.-27C > A variant significantly reduced transcriptional activity in reporter assays and is the probable cause of this epimutation.
• A Cullin3-KLHL20 Ubiquitin Ligase-Dependent Pathway Targets PML to Potentiate HIF-1 Signaling and Prostate Cancer Progression
  - Cancer Cell 20(2):214-228 (2011)
  Tumor hypoxia is associated with disease progression and treatment failure, but the hypoxia signaling mechanism is not fully understood. Here, we show that KLHL20, a Cullin3 (Cul3) substrate adaptor induced by HIF-1, coordinates with the actions of CDK1/2 and Pin1 to mediate hypoxia-induced PML proteasomal degradation. Furthermore, this PML destruction pathway participates in a feedback mechanism to maximize HIF-1α induction, thereby potentiating multiple tumor hypoxia responses, including metabolic reprogramming, epithelial-mesenchymal transition, migration, tumor growth, angiogenesis, and chemoresistance. In human prostate cancer, overexpression of HIF-1α, KLHL20, and Pin1 correlates with PML down-regulation, and hyperactivation of the PML destruction pathway is associated with disease progression. Our study indicates that the KLHL20-mediated PML degradation and HIF-1α autoregulation play key roles in tumor progression.
• ROCK and JAK1 Signaling Cooperate to Control Actomyosin Contractility in Tumor Cells and Stroma
  - Cancer Cell 20(2):229-245 (2011)
  Proinflammatory cytokines are frequently observed in the tumor microenvironment, and chronic inflammation is involved in cancer initiation and progression. We show that cytokine signaling through the receptor subunit GP130-IL6ST and the kinase JAK1 generates actomyosin contractility through Rho-kinase dependent signaling. This pathway generates contractile force in stromal fibroblasts to remodel the extracellular matrix to create tracks for collective migration of squamous carcinoma cells and provides the high levels of actomyosin contractility required for migration of individual melanoma cells in the rounded, "amoeboid" mode. Thus, cytokine signaling can generate actomyosin contractility in both stroma and tumor cells. Strikingly, actomyosin contractility itself positively modulates activity of the transcription factor STAT3 downstream of JAK1, demonstrating positive feedback within the signaling network.
• Self-Renewing Hematopoietic Stem Cell Is the Primary Target in Pathogenesis of Human Chronic Lymphocytic Leukemia
  - Cancer Cell 20(2):246-259 (2011)
  We report here that in chronic lymphocytic leukemia (CLL), the propensity to generate clonal B cells has been acquired already at the hematopoietic stem cell (HSC) stage. HSCs purified from patients with CLL displayed lymphoid-lineage gene priming and produced a high number of polyclonal B cell progenitors. Strikingly, their maturation into B cells was restricted always to mono- or oligo-clones with CLL-like phenotype in xenogeneic recipients. These B cell clones were independent of the original CLL clones because they had their own immunoglobulin VDJ genes. Furthermore, they used preferentially VH genes frequently used in human CLL, presumably reflecting the role of B cell receptor signaling in clonal selection. These data suggest that HSCs can be involved in leukemogenesis even in mature lymphoid tumors.
• Coexpression of Normally Incompatible Developmental Pathways in Retinoblastoma Genesis
  - Cancer Cell 20(2):260-275 (2011)
  It is widely believed that the molecular and cellular features of a tumor reflect its cell of origin and can thus provide clues about treatment targets. The retinoblastoma cell of origin has been debated for over a century. Here, we report that human and mouse retinoblastomas have molecular, cellular, and neurochemical features of multiple cell classes, principally amacrine/horizontal interneurons, retinal progenitor cells, and photoreceptors. Importantly, single-cell gene expression array analysis showed that these multiple cell type-specific developmental programs are coexpressed in individual retinoblastoma cells, which creates a progenitor/neuronal hybrid cell. Furthermore, neurotransmitter receptors, transporters, and biosynthetic enzymes are expressed in human retinoblastoma, and targeted disruption of these pathways reduces retinoblastoma growth in vivo and in vitro.
• TET2 Inactivation Results in Pleiotropic Hematopoietic Abnormalities in Mouse and Is a Recurrent Event during Human Lymphomagenesis
  - Cancer Cell 20(2):276 (2011)
  
• Proinvasion Metastasis Drivers in Early-Stage Melanoma Are Oncogenes
  - Cancer Cell 20(2):277 (2011)
  

Hot off the presses! Jun 14 Cancer Cell

The Jun 14 issue of the Cancer Cell is now up on Pubget (About Cancer Cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Oncogene-Induced Mitotic Stress: p53 and pRb Get Mad Too
  - Cancer Cell 19(6):691-692 (2011)
  Oncogenic signaling frequently results in unscheduled overexpression of cell cycle proteins and replicative stress. In this issue of Cancer Cell, Schvartzman et al. show that inactivation of p53 or pRb induces Mad2, and the overexpression of this mitotic checkpoint protein is a necessary event during oncogene-induced mitotic stress.
• A Lipid Kinase Cousin Cooperates to Promote Cancer
  - Cancer Cell 19(6):693-695 (2011)
  Phosphoinositide 3-kinases (PI3Ks) are considered promising drug targets in oncology. In this issue of Cancer Cell, Schmid et al. demonstrate that the PI3Kγ isoform is required for inflammatory myeloid cells to traffic to tumors. Though tumor cells do not express PI3Kγ, selective inhibition of this isoform suppresses tumor growth and angiogenesis.
• ROCK-Driven Actomyosin Contractility Induces Tissue Stiffness and Tumor Growth
  - Cancer Cell 19(6):695-697 (2011)
  The tumor environment consists of tumor-associated cells, such as macrophages, fibroblasts, and extracellular matrix, and has an important impact on tumor progression. In this issue of Cancer Cell, Samuel et al. show that ROCK-driven actomyosin contractility increases tissue stiffness affecting epidermal homeostasis, as well as tumor growth and progression.
• Turning Reciprocal Feedback Regulation into Combination Therapy
  - Cancer Cell 19(6):697-699 (2011)
  Two recent Cancer Cell articles report the discovery of reciprocal feedback regulation between androgenic and PTEN loss/PI3K-AKT signaling in prostate cancer. Both studies link endocrine regulation with a common oncogenic pathway, which led to the development of a combination therapeutic approach with immediate application in prostate cancer.
• Mad2 Is a Critical Mediator of the Chromosome Instability Observed upon Rb and p53 Pathway Inhibition
  - Cancer Cell 19(6):701-714 (2011)
  Multiple mechanisms have been proposed to explain how Rb and p53 tumor suppressor loss lead to chromosome instability (CIN). It was recently shown that Rb pathway inhibition causes overexpression of the mitotic checkpoint gene Mad2, but whether Mad2 overexpression is required to generate CIN in this context is unknown. Here, we show that CIN in cultured cells lacking Rb family proteins requires Mad2 upregulation and that this upregulation is also necessary for CIN and tumor progression in vivo. Mad2 is also repressed by p53 and its upregulation is required for CIN in a p53 mutant tumor model. These results demonstrate that Mad2 overexpression is a critical mediator of the CIN observed upon inactivation of two major tumor suppressor pathways.
• Receptor Tyrosine Kinases and TLR/IL1Rs Unexpectedly Activate Myeloid Cell PI3Kγ, A Single Convergent Point Promoting Tumor Inflammation and Progression
  - Cancer Cell 19(6):715-727 (2011)
  Tumor inflammation promotes angiogenesis, immunosuppression, and tumor growth, but the mechanisms controlling inflammatory cell recruitment to tumors are not well understood. We found that a range of chemoattractants activating G protein-coupled receptors (GPCRs), receptor tyrosine kinases (RTKs) and Toll-like/IL-1 receptors (TLR/IL1Rs) unexpectedly initiate tumor inflammation by activating the PI3-kinase isoform p110γ in Gr1+CD11b+ myeloid cells. Whereas GPCRs activate p110γ in a Ras/p101-dependent manner, RTKs and TLR/IL1Rs directly activate p110γ in a Ras/p87-dependent manner. Once activated, p110γ promotes inside-out activation of a single integrin, α4β1, causing myeloid cell invasion into tumors. Pharmacological or genetic blockade of p110γ suppressed inflammation, growth, and metastasis of implanted and spontaneous tumors, revealing an important therapeutic target in oncology.
• Pancreatitis-Induced Inflammation Contributes to Pancreatic Cancer by Inhibiting Oncogene-Induced Senescence
  - Cancer Cell 19(6):728-739 (2011)
  Pancreatic acinar cells of adult mice (≥P60) are resistant to transformation by some of the most robust oncogenic insults including expression of K-Ras oncogenes and loss of p16Ink4a/p19Arf or Trp53 tumor suppressors. Yet, these acinar cells yield pancreatic intraepithelial neoplasias (mPanIN) and ductal adenocarcinomas (mPDAC) if exposed to limited bouts of non-acute pancreatitis, providing they harbor K-Ras oncogenes. Pancreatitis contributes to tumor progression by abrogating the senescence barrier characteristic of low-grade mPanINs. Attenuation of pancreatitis-induced inflammation also accelerates tissue repair and thwarts mPanIN expansion. Patients with chronic pancreatitis display senescent PanINs, providing they have received antiinflammatory drugs. These results support the concept that antiinflammatory treatment of people diagnosed with pancreatitis may reduce their risk of developing PDAC.
• Loss or Inhibition of Stromal-Derived PlGF Prolongs Survival of Mice with Imatinib-Resistant Bcr-Abl1+ Leukemia
  - Cancer Cell 19(6):740-753 (2011)
  Imatinib has revolutionized the treatment of Bcr-Abl1+ chronic myeloid leukemia (CML), but, in most patients, some leukemia cells persist despite continued therapy, while others become resistant. Here, we report that PlGF levels are elevated in CML and that PlGF produced by bone marrow stromal cells (BMSCs) aggravates disease severity. CML cells foster a soil for their own growth by inducing BMSCs to upregulate PlGF, which not only stimulates BM angiogenesis, but also promotes CML proliferation and metabolism, in part independently of Bcr-Abl1 signaling. Anti-PlGF treatment prolongs survival of imatinib-sensitive and -resistant CML mice and adds to the anti-CML activity of imatinib. These results may warrant further investigation of the therapeutic potential of PlGF inhibition for (imatinib-resistant) CML.
• Cell of Origin of Small Cell Lung Cancer: Inactivation of Trp53 and Rb1 in Distinct Cell Types of Adult Mouse Lung
  - Cancer Cell 19(6):754-764 (2011)
  Small cell lung cancer (SCLC) is one of the most lethal human malignancies. To investigate the cellular origin(s) of this cancer, we assessed the effect of Trp53 and Rb1 inactivation in distinct cell types in the adult lung using adenoviral vectors that target Cre recombinase to Clara, neuroendocrine (NE), and alveolar type 2 (SPC-expressing) cells. Using these cell type-restricted Adeno-Cre viruses, we show that loss of Trp53 and Rb1 can efficiently transform NE and SPC-expressing cells leading to SCLC, albeit SPC-expressing cells at a lesser efficiency. In contrast, Clara cells were largely resistant to transformation. The results indicate that although NE cells serve as the predominant cell of origin of SCLC a subset of SPC-expressing cells are also endowed with this ability.
• Impairment of Cytoplasmic eIF6 Activity Restricts Lymphomagenesis and Tumor Progression without Affecting Normal Growth
  - Cancer Cell 19(6):765-775 (2011)
  Eukaryotic Initiation Factor 6 (eIF6) controls translation by regulating 80S subunit formation. eIF6 is overexpressed in tumors. Here, we demonstrate that eIF6 inactivation delays tumorigenesis and reduces tumor growth in vivo. eIF6+/− mice resist to Myc-induced lymphomagenesis and have prolonged tumor-free survival and reduced tumor growth. eIF6+/− mice are also protected by p53 loss. Myc-driven lymphomas contain PKCβII and phosphorylated eIF6; eIF6 is phosphorylated by tumor-derived PKCβII, but not by the eIF4F activator mTORC1. Mutation of PKCβII phosphosite of eIF6 reduces tumor growth. Thus, eIF6 is a rate-limiting controller of initiation of translation, able to affect tumorigenesis and tumor growth. Modulation of eIF6 activity, independent from eIF4F complex, may lead to a therapeutical avenue in tumor therapy.
• Actomyosin-Mediated Cellular Tension Drives Increased Tissue Stiffness and β-Catenin Activation to Induce Epidermal Hyperplasia and Tumor Growth
  - Cancer Cell 19(6):776-791 (2011)
  Tumors and associated stroma manifest mechanical properties that promote cancer. Mechanosensation of tissue stiffness activates the Rho/ROCK pathway to increase actomyosin-mediated cellular tension to re-establish force equilibrium. To determine how actomyosin tension affects tissue homeostasis and tumor development, we expressed conditionally active ROCK2 in mouse skin. ROCK activation elevated tissue stiffness via increased collagen. β-catenin, a key element of mechanotranscription pathways, was stabilized by ROCK activation leading to nuclear accumulation, transcriptional activation, and consequent hyperproliferation and skin thickening. Inhibiting actomyosin contractility by blocking LIMK or myosin ATPase attenuated these responses, as did FAK inhibition. Tumor number, growth, and progression were increased by ROCK activation, while ROCK blockade was inhibitory, implicating actomyosin-mediated cellular tension and consequent collagen deposition as significant tumo! r promoters.
• Cell Autonomous Role of PTEN in Regulating Castration-Resistant Prostate Cancer Growth
  - Cancer Cell 19(6):792-804 (2011)
  Alteration of the PTEN/PI3K pathway is associated with late-stage and castrate-resistant prostate cancer (CRPC). However, how PTEN loss is involved in CRPC development is not clear. Here, we show that castration-resistant growth is an intrinsic property of Pten null prostate cancer (CaP) cells, independent of cancer development stage. PTEN loss suppresses androgen-responsive gene expressions by modulating androgen receptor (AR) transcription factor activity. Conditional deletion of Ar in the epithelium promotes the proliferation of Pten null cancer cells, at least in part, by downregulating the androgen-responsive gene Fkbp5 and preventing PHLPP-mediated AKT inhibition. Our findings identify PI3K and AR pathway crosstalk as a mechanism of CRPC development, with potentially important implications for CaP etiology and therapy.
• PI3Kγ Mediates Kaposi's Sarcoma-Associated Herpesvirus vGPCR-Induced Sarcomagenesis
  - Cancer Cell 19(6):805-813 (2011)
  Angioproliferative tumors induced by the Kaposi's sarcoma-associated herpesvirus (KSHV) have been successfully treated with rapamycin, which provided direct evidence of the clinical activity of mTOR inhibitors in human malignancies. However, prolonged mTOR inhibition may raise concerns in immunocompromised patients, including AIDS-Kaposi's sarcoma (KS). Here, we explored whether KSHV oncogenes deploy cell type-specific signaling pathways activating mTOR, which could be exploited to halt KS development while minimizing immune suppressive effects. We found that PI3Kγ, a PI3K isoform exhibiting restricted tissue distribution, is strictly required for signaling from the KSHV-encoded vGPCR oncogene to Akt/mTOR. Indeed, by using an endothelial-specific gene delivery system modeling KS development, we provide genetic and pharmacological evidence that PI3Kγ may represent a suitable molecular target for therapeutic intervention in KS.
• CCL18 from Tumor-Associated Macrophages Promotes Breast Cancer Metastasis via PITPNM3
  - Cancer Cell 19(6):814-816 (2011)
  

Hot off the presses! May 17 Cancer Cell

The May 17 issue of the Cancer Cell is now up on Pubget (About Cancer Cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• ATMIN: A New Tumor Suppressor in Developing B Cells
  - Cancer Cell 19(5):569-570 (2011)
  In the current issue of Cancer Cell, Loizou et al. report that the deletion of ATM Interactor (ATMIN) in developing B cells leads to profound genomic instability and clonal B cell leukemia, revealing a novel tumor suppressor function for ATMIN.
• Identifying the Stroma as a Critical Player in Radiation-Induced Mammary Tumor Development
  - Cancer Cell 19(5):571-572 (2011)
  Tumor development requires facilitative alterations in the stroma. In this issue of Cancer Cell, Nguyen et al. provide evidence that irradiation of mammary stroma drives accelerated development of mammary tumors that are more likely to be estrogen receptor-negative and implicate stromal production of transforming growth factor-β in this process.
• Beyond Hormone Therapy for Prostate Cancer with PARP inhibitors
  - Cancer Cell 19(5):573-574 (2011)
  In this issue of Cancer Cell, Brenner et al. describe that the poly-(ADP) ribose polymerase (PARP) may mediate ERG function and that PARP blockade has antitumor activity in ETS gene-rearranged prostate cancer models. These data support the clinical evaluation of PARP inhibitors for treating ETS gene-rearranged prostate cancers.
• Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer
  - Cancer Cell 19(5):575-586 (2011)
  Prostate cancer is characterized by its dependence on androgen receptor (AR) and frequent activation of PI3K signaling. We find that AR transcriptional output is decreased in human and murine tumors with PTEN deletion and that PI3K pathway inhibition activates AR signaling by relieving feedback inhibition of HER kinases. Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival. However, combined pharmacologic inhibition of PI3K and AR signaling caused near-complete prostate cancer regressions in a Pten-deficient murine prostate cancer model and in human prostate cancer xenografts, indicating that both pathways coordinately support survival.
• ATMIN Is Required for Maintenance of Genomic Stability and Suppression of B Cell Lymphoma
  - Cancer Cell 19(5):587-600 (2011)
  Defective V(D)J rearrangement of immunoglobulin heavy or light chain (IgH or IgL) or class switch recombination (CSR) can initiate chromosomal translocations. The DNA-damage kinase ATM is required for the suppression of chromosomal translocations but ATM regulation is incompletely understood. Here, we show that mice lacking the ATM cofactor ATMIN in B cells (ATMINΔB/ΔB) have impaired ATM signaling and develop B cell lymphomas. Notably, ATMINΔB/ΔB cells exhibited defective peripheral V(D)J rearrangement and CSR, resulting in translocations involving the Igh and Igl loci, indicating that ATMIN is required for efficient repair of DNA breaks generated during somatic recombination. Thus, our results identify a role for ATMIN in regulating the maintenance of genomic stability and tumor suppression in B cells.
• High-Frequency Canonical Wnt Activation in Multiple Sarcoma Subtypes Drives Proliferation through a TCF/β-Catenin Target Gene, CDC25A
  - Cancer Cell 19(5):601-612 (2011)
  Wnt canonical signaling is critical for normal development as well as homeostasis of several epithelial tissues, and constitutive activation of this pathway is commonly observed in carcinomas. We show here that 50% of human sarcomas (n = 45) and 65% of sarcoma cell lines (n = 23) of diverse histological subtypes exhibit upregulated autocrine canonical Wnt signaling. Furthermore, in Wnt autocrine cell lines, we identify alterations including overexpression or gene amplification of Wnt ligands and/or LRP5/6 coreceptors and epigenetic silencing of different cell surface Wnt antagonists. Mutations in adenomatous polyposis coli (APC) gene were observed in two nonautocrine Wnt-positive sarcoma cell lines. Finally, downregulation of the activated Wnt pathway inhibited sarcoma cell proliferation both in vitro and in vivo by a mechanism involving the downregulation of CDC25A.
• Defective Regulation of Autophagy upon Leucine Deprivation Reveals a Targetable Liability of Human Melanoma Cells In Vitro and In Vivo
  - Cancer Cell 19(5):613-628 (2011)
  Autophagy is of increasing interest as a target for cancer therapy. We find that leucine deprivation causes the caspase-dependent apoptotic death of melanoma cells because it fails to appropriately activate autophagy. Hyperactivation of the RAS-MEK pathway, which is common in melanoma, prevents leucine deprivation from inhibiting mTORC1, the main repressor of autophagy under nutrient-rich conditions. In an in vivo tumor xenograft model, the combination of a leucine-free diet and an autophagy inhibitor synergistically suppresses the growth of human melanoma tumors and triggers widespread apoptosis of the cancer cells. Together, our study represents proof of principle that anticancer effects can be obtained with a combination of autophagy inhibition and strategies to deprive tumors of leucine.
• Ptpn11/Shp2 Acts as a Tumor Suppressor in Hepatocellular Carcinogenesis
  - Cancer Cell 19(5):629-639 (2011)
  The human gene Ptpn11, which encodes the tyrosine phosphatase Shp2, may act as a proto-oncogene because dominantly activating mutations have been detected in several types of leukemia. Herein we report a tumor-suppressor function of Shp2. Hepatocyte-specific deletion of Shp2 promotes inflammatory signaling through the Stat3 pathway and hepatic inflammation/necrosis, resulting in regenerative hyperplasia and development of tumors in aged mice. Furthermore, Shp2 ablation dramatically enhanced diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) development, which was abolished by concurrent deletion of Shp2 and Stat3 in hepatocytes. Decreased Shp2 expression was detected in a subfraction of human HCC specimens. Thus, in contrast to the leukemogenic effect of dominant-active mutants, Ptpn11/Shp2 has a tumor-suppressor function in liver.
• Radiation Acts on the Microenvironment to Affect Breast Carcinogenesis by Distinct Mechanisms that Decrease Cancer Latency and Affect Tumor Type
  - Cancer Cell 19(5):640-651 (2011)
  Tissue microenvironment is an important determinant of carcinogenesis. We demonstrate that ionizing radiation, a known carcinogen, affects cancer frequency and characteristics by acting on the microenvironment. Using a mammary chimera model in which an irradiated host is transplanted with oncogenic Trp53 null epithelium, we show accelerated development of aggressive tumors whose molecular signatures were distinct from tumors arising in nonirradiated hosts. Molecular and genetic approaches show that TGFβ mediated tumor acceleration. Tumor molecular signatures implicated TGFβ, and genetically reducing TGFβ abrogated the effect on latency. Surprisingly, tumors from irradiated hosts were predominantly estrogen receptor negative. This effect was TGFβ independent and linked to mammary stem cell activity. Thus, the irradiated microenvironment affects latency and clinically relevant features of cancer through distinct and unexpected mechanisms.
• c-Raf, but Not B-Raf, Is Essential for Development of K-Ras Oncogene-Driven Non-Small Cell Lung Carcinoma
  - Cancer Cell 19(5):652-663 (2011)
  We have investigated the role of individual members of the Raf/Mek/Erk cascade in the onset of K-Ras oncogene-driven non-small cell lung carcinoma (NSCLC). Ablation of Erk1 or Erk2 in K-Ras oncogene-expressing lung cells had no significant effect due to compensatory activities. Yet, elimination of both Erk kinases completely blocked tumor development. Similar results were obtained with Mek kinases. Ablation of B-Raf had no significant effect on tumor development. However, c-Raf expression was absolutely essential for the onset of NSCLC. Interestingly, concomitant elimination of c-Raf and B-Raf in adult mice had no deleterious consequences for normal homeostasis. These results indicate that c-Raf plays a unique role in mediating K-Ras signaling and makes it a suitable target for therapeutic intervention.
• CH5424802, a Selective ALK Inhibitor Capable of Blocking the Resistant Gatekeeper Mutant
  - Cancer Cell 19(5):679-690 (2011)
  Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in certain cancers, following gene alterations such as chromosomal translocation, amplification, or point mutation. Here, we identified CH5424802, a potent, selective, and orally available ALK inhibitor with a unique chemical scaffold, showing preferential antitumor activity against cancers with gene alterations of ALK, such as nonsmall cell lung cancer (NSCLC) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion in vitro and in vivo. CH5424802 inhibited ALK L1196M, which corresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors, and blocked EML4-ALK L1196M-driven cell growth. Our results support the potential for clinical evaluation of CH5424802 for the treatment of patients with ALK-driven tumors.
• Mechanistic Rationale for Inhibition of Poly(ADP-Ribose) Polymerase in ETS Gene Fusion-Positive Prostate Cancer
  - Cancer Cell 19(5):664-678 (2011)
  Recurrent fusions of ETS genes are considered driving mutations in a diverse array of cancers, including Ewing's sarcoma, acute myeloid leukemia, and prostate cancer. We investigate the mechanisms by which ETS fusions mediate their effects, and find that the product of the predominant ETS gene fusion, TMPRSS2:ERG, interacts in a DNA-independent manner with the enzyme poly (ADP-ribose) polymerase 1 (PARP1) and the catalytic subunit of DNA protein kinase (DNA-PKcs). ETS gene-mediated transcription and cell invasion require PARP1 and DNA-PKcs expression and activity. Importantly, pharmacological inhibition of PARP1 inhibits ETS-positive, but not ETS-negative, prostate cancer xenograft growth. Finally, overexpression of the TMPRSS2:ERG fusion induces DNA damage, which is potentiated by PARP1 inhibition in a manner similar to that of BRCA1/2 deficiency.

Hot off the presses! Jul 07 Cancer Cell

The Jul 07 issue of the Cancer Cell is now up on Pubget (About Cancer Cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Breast Cancer Src Activity: Bad to the Bone
  Sgroi DC - Cancer Cell 16(1):1-2 (2009)
  Bone metastases are a major cause of breast cancer morbidity and mortality. In this issue of Cancer Cell, Zhang and colleagues identify a Src activation expression signature associated with late-onset breast cancer bone metastases and provide evidence for Src as a key mediator of survival signals in latent bone metastases.
• Reflections on miR-ing Effects in Metastasis
  Dumont N Tlsty TD - Cancer Cell 16(1):3-4 (2009)
  In a recent issue of Cell, Valastyan et al. demonstrate that miR-31 can regulate multiple steps in the metastatic cascade independent of confounding effects on primary tumor development. These data have potential to provide biomarkers for prognosis and novel targets for intervention in this most lethal aspect of malignancy.
• Actin-Based Protrusions: Promoters or Inhibitors of Cancer Invasion?
  Machesky LM Tang HR - Cancer Cell 16(1):5-7 (2009)
  In a recent issue of Cell, Silva and colleagues reported the identification of CYFIP1, a member of the actin-assembly-promoting Scar/WAVE complex, as an invasion suppressor in epithelial cancers. This study challenges ideas about the role of actin in cancer invasion.
• Pancreatic Cancer—Could It Be that Simple? A Different Context of Vulnerability
  Von Hoff DD Korn R Mousses S - Cancer Cell 16(1):7-8 (2009)
  In a recent issue of Science, Olive and colleagues document that inhibition of Hedgehog (Hh) signaling in a genetically engineered mouse model of pancreatic cancer can enhance the intratumor concentration of certain anticancer drugs. Could this finding provide us with a new method to attack pancreatic cancer?
• EphA2 Mediates Ligand-Dependent Inhibition and Ligand-Independent Promotion of Cell Migration and Invasion via a Reciprocal Regulatory Loop with Akt
  - Cancer Cell 16(1):9-20 (2009)
  Both pro- and antioncogenic properties have been attributed to EphA2 kinase. We report that a possible cause for this apparent paradox is diametrically opposite roles of EphA2 in regulating cell migration and invasion. While activation of EphA2 with its ligand ephrin-A1 inhibited chemotactic migration of glioma and prostate cancer cells, EphA2 overexpression promoted migration in a ligand-independent manner. Surprisingly, the latter effects required phosphorylation of EphA2 on serine 897 by Akt, and S897A mutation abolished ligand-independent promotion of cell motility. Ephrin-A1 stimulation of EphA2 negated Akt activation by growth factors and caused EphA2 dephosphorylation on S897. In human astrocytoma, S897 phosphorylation was correlated with tumor grades and Akt activation, suggesting that the Akt-EphA2 crosstalk may contribute to brain tumor progression.
• AKT-Independent Signaling Downstream of Oncogenic PIK3CA Mutations in Human Cancer
  - Cancer Cell 16(1):21-32 (2009)
  Dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway occurs frequently in human cancer. PTEN tumor suppressor or PIK3CA oncogene mutations both direct PI3K-dependent tumorigenesis largely through activation of the AKT/PKB kinase. However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth. Instead, these cells retain robust PDK1 activation and membrane localization and exhibit dependency on the PDK1 substrate SGK3. SGK3 undergoes PI3K- and PDK1-dependent activation in PIK3CA mutant cancer cells. Thus, PI3K may promote cancer through both AKT-dependent and AKT-independent mechanisms. Knowledge of differential PI3K/PDK1 signaling could inform rational therapeutics in cancers harboring PIK3CA mutations.
• Increased Radioresistance and Accelerated B Cell Lymphomas in Mice with Mdmx Mutations that Prevent Modifications by DNA-Damage-Activated Kinases
  Wang YV Leblanc M Wade M Jochemsen AG Wahl GM - Cancer Cell 16(1):33-43 (2009)
  Mdmx is a critical negative regulator of the p53 pathway that is stoichiometrically limiting in some tissues. Posttranslational modification and degradation of Mdmx after DNA damage have been proposed to be essential for p53 activation. We tested this model in vivo, where critical stoichiometric relationships are preserved. We generated an Mdmx mutant mouse in which three conserved serines (S341, S367, S402) targeted by DNA-damage-activated kinases were replaced by alanines to investigate whether modifications of these residues are important for Mdmx degradation and p53 activation. The mutant mice were remarkably resistant to radiation, and very susceptible to Myc-induced lymphomagenesis. These data demonstrate that Mdmx downregulation is crucial for effective p53-mediated radiation responses and tumor suppression in vivo.
• Proteasomal and Genetic Inactivation of the NF1 Tumor Suppressor in Gliomagenesis
  McGillicuddy LT Fromm JA Hollstein PE Kubek S Beroukhim R De Raedt T Johnson BW Williams SM Nghiemphu P Liau LM Cloughesy TF Mischel PS Parret A Seiler J Moldenhauer G Scheffzek K Stemmer-Rachamimov AO Sawyers CL Brennan C Messiaen L Mellinghoff IK Cichowski K - Cancer Cell 16(1):44-54 (2009)
  Loss-of-function mutations in the NF1 tumor suppressor result in deregulated Ras signaling and drive tumorigenesis in the familial cancer syndrome neurofibromatosis type I. However, the extent to which NF1 inactivation promotes sporadic tumorigenesis is unknown. Here we report that NF1 is inactivated in sporadic gliomas via two mechanisms: excessive proteasomal degradation and genetic loss. NF1 protein destabilization is triggered by the hyperactivation of protein kinase C (PKC) and confers sensitivity to PKC inhibitors. However, complete genetic loss, which only occurs when p53 is inactivated, mediates sensitivity to mTOR inhibitors. These studies reveal an expanding role for NF1 inactivation in sporadic gliomagenesis and illustrate how different mechanisms of inactivation are utilized in genetically distinct tumors, which consequently impacts therapeutic sensitivity.
• Epidermal Notch1 Loss Promotes Skin Tumorigenesis by Impacting the Stromal Microenvironment
  Demehri S Turkoz A Kopan R - Cancer Cell 16(1):55-66 (2009)
  Notch1 is a proto-oncogene in several organs. In the skin, however, Notch1 deletion leads to tumor formation, suggesting that Notch1 is a "tumor suppressor" within this context. Here we demonstrate that, unlike classical tumor suppressors, Notch1 loss in epidermal keratinocytes promotes tumorigenesis non-cell autonomously by impairing skin-barrier integrity and creating a wound-like microenvironment in the skin. Using mice with a chimeric pattern of Notch1 deletion, we determined that Notch1-expressing keratinocytes in this microenvironment readily formed papillomas, showing that Notch1 was insufficient to suppress this tumor-promoting effect. Accordingly, loss of other Notch paralogues that impaired the skin barrier also predisposed Notch1-expressing skin to tumorigenesis, demonstrating that the tumor-promoting effect of Notch1 loss involves a crosstalk between barrier-defective epidermis and its stroma.
• Latent Bone Metastasis in Breast Cancer Tied to Src-Dependent Survival Signals
  Zhang XH Wang Q Gerald W Hudis CA Norton L Smid M Foekens JA Massagué J - Cancer Cell 16(1):67-78 (2009)
  Metastasis may arise years after removal of a primary tumor. The mechanisms allowing latent disseminated cancer cells to survive are unknown. We report that a gene expression signature of Src activation is associated with late-onset bone metastasis in breast cancer. This link is independent of hormone receptor status or breast cancer subtype. In breast cancer cells, Src is dispensable for homing to the bones or lungs but is critical for the survival and outgrowth of these cells in the bone marrow. Src mediates AKT regulation and cancer cell survival responses to CXCL12 and TNF-related apoptosis-inducing ligand (TRAIL), factors that are distinctively expressed in the bone metastasis microenvironment. Breast cancer cells that lodge in the bone marrow succumb in this environment when deprived of Src activity.
• MDM2-Dependent Downregulation of p21 and hnRNP K Provides a Switch between Apoptosis and Growth Arrest Induced by Pharmacologically Activated p53
  - Cancer Cell 16(1):79 (2009)