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)