Hot off the presses! Nov 16 Cancer Cell

The Nov 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:

• Pharmacological Rescue of p53 in Cancer Therapy: Widening the Sensitive Tumor Spectrum by Targeting MDMX
  - Cancer Cells 18(5):399-400 (2010)
  Targeting p53's main negative regulator MDM2 is a promising strategy for treating cancers that retain wild-type p53. Unfortunately, MDM2 inhibitors are largely ineffective against tumors overexpressing MDMX. In this issue of Cancer Cell, Bernal et al. describe a "stapled" peptide that targets MDMX and suppresses the growth of tumors resistant to MDM2 inhibitors.
• Unfavorable Drug Interactions in Targeted Breast Cancer Therapy
  - Cancer Cells 18(5):401-402 (2010)
  Trastuzumab is used to treat HER2-positive breast cancer; erythropoietin (EPO) is used to alleviate chemotherapy-associated side effects. In this issue of Cancer Cell, Liang et al. show that many breast tumors express EPO receptor (EpoR), whose activation by EPO recovers signaling pathways downregulated by trastuzumab, thereby blunting trastuzumab's therapeutic effect.
• Can Antitumor Immunity Help to Explain "Oncogene Addiction"?
  - Cancer Cells 18(5):403-405 (2010)
  "Oncogene addiction" refers to the process of tumor cell death that can occur after inactivation of a single oncogene. In this issue of Cancer Cell, Rakhra et al. argue that complete tumor clearance after molecular targeted therapies requires a functioning immune system, pointing the way toward radically new combination therapies.
• STATistical Power of Clonal Analysis: Differential STAT1 Pathway Activation Downstream of the JAK2V617F Mutation
  - Cancer Cells 18(5):405-406 (2010)
  The biological basis of the phenotypic diversity observed in JAK2V617F-positive myeloproliferative neoplasms is poorly understood. In this issue of Cancer Cell, Chen et al. show that interferon and STAT1 signaling are activated in essential thrombocythemia but not in polycythemia vera. STAT1 promotes megakaryopoiesis and thus contributes to an essential thrombocythemia phenotype.
• Bioinformatic Mining of Gene Expression Datasets Identifies ETV1 as a Critical Regulator of Oncogenesis in Gastrointestinal Stromal Tumors
  - Cancer Cells 18(5):407-408 (2010)
  KIT mutations are the hallmark of gastrointestinal stromal tumors (GISTs). In a paper recently published in Nature, Sawyers and colleagues demonstrate that ETV1 collaborates with oncogenic KIT to initiate a GIST-specific transcriptional program. These results radically alter our view of GIST oncogenesis and have important implications for diagnosis and therapy.
• An Identity Crisis for a Cancer Gene: Subcellular Location Determines ASPP1 Function
  - Cancer Cells 18(5):409-410 (2010)
  Two recent papers in Genes and Development argue that the ASPP1 protein has distinct roles in cell survival, depending upon its subcellular localization, that are determined by a complex interplay with LATS kinase and the YAP transcriptional cofactor.
• A Stapled p53 Helix Overcomes HDMX-Mediated Suppression of p53
  - Cancer Cells 18(5):411-422 (2010)
  Cancer cells neutralize p53 by deletion, mutation, proteasomal degradation, or sequestration to achieve a pathologic survival advantage. Targeting the E3 ubiquitin ligase HDM2 can lead to a therapeutic surge in p53 levels. However, the efficacy of HDM2 inhibition can be compromised by overexpression of HDMX, an HDM2 homolog that binds and sequesters p53. Here, we report that a stapled p53 helix preferentially targets HDMX, blocks the formation of inhibitory p53-HDMX complexes, induces p53-dependent transcriptional upregulation, and thereby overcomes HDMX-mediated cancer resistance in vitro and in vivo. Importantly, our analysis of p53 interaction dynamics provides a blueprint for reactivating the p53 pathway in cancer by matching HDM2, HDMX, or dual inhibitors to the appropriate cellular context.
• Recombinant Human Erythropoietin Antagonizes Trastuzumab Treatment of Breast Cancer Cells via Jak2-Mediated Src Activation and PTEN Inactivation
  - Cancer Cells 18(5):423-435 (2010)
  We found that the receptor for erythropoietin (EpoR) is coexpressed with human epidermal growth factor receptor-2 (HER2) in a significant percentage of human breast tumor specimens and breast cancer cell lines. Exposure of HER2 and EpoR dual-positive breast cancer cells to recombinant human erythropoietin (rHuEPO) activated cell signaling. Concurrent treatment of the cells with rHuEPO and trastuzumab reduced the cells' response to trastuzumab both in vitro and in vivo. We identified Jak2-mediated activation of Src and inactivation of PTEN as underlying mechanisms through which rHuEPO antagonizes trastuzumab-induced therapeutic effects. Furthermore, we found that compared with administration of trastuzumab alone, concurrent administration of rHuEPO and trastuzumab correlated with shorter progression-free and overall survival in patients with HER2-positive metastatic breast cancer.
• Hdac3 Is Essential for the Maintenance of Chromatin Structure and Genome Stability
  - Cancer Cells 18(5):436-447 (2010)
  Hdac3 is essential for efficient DNA replication and DNA damage control. Deletion of Hdac3 impaired DNA repair and greatly reduced chromatin compaction and heterochromatin content. These defects corresponded to increases in histone H3K9,K14ac; H4K5ac; and H4K12ac in late S phase of the cell cycle, and histone deposition marks were retained in quiescent Hdac3-null cells. Liver-specific deletion of Hdac3 culminated in hepatocellular carcinoma. Whereas HDAC3 expression was downregulated in only a small number of human liver cancers, the mRNA levels of the HDAC3 cofactor NCOR1 were reduced in one-third of these cases. siRNA targeting of NCOR1 and SMRT (NCOR2) increased H4K5ac and caused DNA damage, indicating that the HDAC3/NCOR/SMRT axis is critical for maintaining chromatin structure and genomic stability.
• Oncogenic KRas Suppresses Inflammation-Associated Senescence of Pancreatic Ductal Cells
  - Cancer Cells 18(5):448-458 (2010)
  Mutational activation of KRas is the first and most frequently detected genetic lesion in pancreatic ductal adenocarcinoma (PDAC). However, the precise role of oncogenic KRas in the pathogenesis of PDAC is not fully understood. Here, we report that the endogenous expression of oncogenic KRas suppresses premature senescence in primary pancreatic duct epithelial cells (PDEC). Oncogenic KRas-mediated senescence bypass is conferred by the upregulation of the basic helix-loop-helix transcription factor Twist that in turn abrogates p16INK4A induction. Moreover, the KRas-Twist-p16INK4A senescence bypass pathway is employed in vivo to prevent inflammation-associated senescence of pancreatic ductal epithelium. Our findings indicate that oncogenic KRas could contribute to PDAC initiation by protecting cells from entering a state of permanent growth arrest.
• B55β-Associated PP2A Complex Controls PDK1-Directed Myc Signaling and Modulates Rapamycin Sensitivity in Colorectal Cancer
  - Cancer Cells 18(5):459-471 (2010)
  The PP2A serine/threonine protein phosphatase serves as a critical cellular regulator of cell growth, proliferation, and survival. However, how this pathway is altered in human cancer to confer growth advantage is largely unknown. Here, we show that PPP2R2B, encoding the B55β regulatory subunit of the PP2A complex, is epigenetically inactivated by DNA hypermethylation in colorectal cancer. B55β-associated PP2A interacts with PDK1 and modulates its activity toward Myc phosphorylation. On loss of PPP2R2B, mTORC1 inhibitor rapamycin triggers a compensatory Myc phosphorylation in PDK1-dependent, but PI3K and AKT-independent manner, resulting in resistance. Reexpression of PPP2R2B, genetic ablation of PDK1 or pharmacologic inhibition of PDK1 abrogates the rapamycin-induced Myc phosphorylation, leading to rapamycin sensitization. Thus, PP2A-B55β antagonizes PDK1-Myc signaling and modulates rapamycin sensitivity.
• FoxOs Enforce a Progression Checkpoint to Constrain mTORC1-Activated Renal Tumorigenesis
  - Cancer Cells 18(5):472-484 (2010)
  mTORC1 is a validated therapeutic target for renal cell carcinoma (RCC). Here, analysis of Tsc1-deficient (mTORC1 hyperactivation) mice uncovered a FoxO-dependent negative feedback circuit constraining mTORC1-mediated renal tumorigenesis. We document robust FoxO activation in Tsc1-deficient benign polycystic kidneys and FoxO extinction on progression to murine renal tumors; murine renal tumor progression on genetic deletion of both Tsc1 and FoxOs; and downregulated FoxO expression in most human renal clear cell and papillary carcinomas, yet continued expression in less aggressive RCCs and benign renal tumor subtypes. Mechanistically, integrated analyses revealed that FoxO-mediated block operates via suppression of Myc through upregulation of the Myc antagonists, Mxi1-SRα and mir-145, establishing a FoxO-Mxi1-SRα/mir-145 axis as a major progression block in renal tumor development.
• CD4+ T Cells Contribute to the Remodeling of the Microenvironment Required for Sustained Tumor Regression upon Oncogene Inactivation
  - Cancer Cells 18(5):485-498 (2010)
  Oncogene addiction is thought to occur cell autonomously. Immune effectors are implicated in the initiation and restraint of tumorigenesis, but their role in oncogene inactivation-mediated tumor regression is unclear. Here, we show that an intact immune system, specifically CD4+ T cells, is required for the induction of cellular senescence, shutdown of angiogenesis, and chemokine expression resulting in sustained tumor regression upon inactivation of the MYC or BCR-ABL oncogenes in mouse models of T cell acute lymphoblastic lymphoma and pro-B cell leukemia, respectively. Moreover, immune effectors knocked out for thrombospondins failed to induce sustained tumor regression. Hence, CD4+ T cells are required for the remodeling of the tumor microenvironment through the expression of chemokines, such as thrombospondins, in order to elicit oncogene addiction.
• Germline Brca2 Heterozygosity Promotes KrasG12D -Driven Carcinogenesis in a Murine Model of Familial Pancreatic Cancer
  - Cancer Cells 18(5):499-509 (2010)
  Inherited heterozygous BRCA2 mutations predispose carriers to tissue-specific cancers, but somatic deletion of the wild-type allele is considered essential for carcinogenesis. We find in a murine model of familial pancreatic cancer that germline heterozygosity for a pathogenic Brca2 truncation suffices to promote pancreatic ductal adenocarcinomas (PDACs) driven by KrasG12D, irrespective of Trp53 status. Unexpectedly, tumor cells retain a functional Brca2 allele. Correspondingly, three out of four PDACs from patients inheriting BRCA2999del5 did not exhibit loss-of-heterozygosity (LOH). Three tumors from these patients displaying LOH were acinar carcinomas, which also developed only in mice with biallelic Brca2 inactivation. We suggest a revised model for tumor suppression by BRCA2 with implications for the therapeutic strategy targeting BRCA2 mutant cancer cells.
• Phenotypic Heterogeneity among Tumorigenic Melanoma Cells from Patients that Is Reversible and Not Hierarchically Organized
  - Cancer Cells 18(5):510-523 (2010)
  We investigated whether melanoma is hierarchically organized into phenotypically distinct subpopulations of tumorigenic and nontumorigenic cells or whether most melanoma cells retain tumorigenic capacity, irrespective of their phenotype. We found 28% of single melanoma cells obtained directly from patients formed tumors in NOD/SCID IL2Rγnull mice. All stage II, III, and IV melanomas obtained directly from patients had common tumorigenic cells. All tumorigenic cells appeared to have unlimited tumorigenic capacity on serial transplantation. We were unable to find any large subpopulation of melanoma cells that lacked tumorigenic potential. None of 22 heterogeneously expressed markers, including CD271 and ABCB5, enriched tumorigenic cells. Some melanomas metastasized in mice, irrespective of whether they arose from CD271− or CD271+ cells. Many markers appeared to be reversibly expressed by tumorigenic melanoma cells.
• Distinct Clinical Phenotypes Associated with JAK2V617F Reflect Differential STAT1 Signaling
  - Cancer Cells 18(5):524-535 (2010)
  The JAK2V617F mutation is associated with distinct myeloproliferative neoplasms, including polycythemia vera (PV) and essential thrombocythemia (ET), but it remains unclear how it generates disparate disorders. By comparing clonally-derived mutant and wild-type cells from individual patients, we demonstrate that the transcriptional consequences of JAK2V617F are subtle, and that JAK2V617F-heterozygous erythroid cells from ET and PV patients exhibit differential interferon signaling and STAT1 phosphorylation. Increased STAT1 activity in normal CD34-positive progenitors produces an ET-like phenotype, whereas downregulation of STAT1 activity in JAK2V617F-heterozygous ET progenitors produces a PV-like phenotype. Our results illustrate the power of clonal analysis, indicate that the consequences of JAK2V617F reflect a balance between STAT5 and STAT1 activation and are relevant for other neoplasms associated with signaling pathway mutations.
• Regulation of the IL-23 and IL-12 Balance by Stat3 Signaling in the Tumor Microenvironment
  - Cancer Cells 18(5):536 (2010)