Hot off the presses! Feb 15 Cancer Cell

The Feb 15 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:

• New Insights into the Origin and the Genetic Basis of Rhabdomyosarcomas
  - Cancer Cells 19(2):157-159 (2011)
  In this issue of Cancer Cell, Rubin et al. (2011) describe using various conditional mouse models to trace the developmental origin and genetic basis of rhabdomyosarcomas. Their work provides a genetic dissection underlying rhabdomyosarcomas development and unveils unexpected relationship between various soft-tissue tumor types.
• One NOTCH Further: Jagged 1 in Bone Metastasis
  - Cancer Cells 19(2):159-161 (2011)
  The outgrowth of metastatic cells to bone depends on the interaction between multiple intrinsic and host factors. In this issue of Cancer Cell, Sethi and colleagues report Notch signaling in bone cells as responsible for promoting this outgrowth and provide evidence for a beneficial treatment effect of NOTCH inhibitors.
• HiJAKing the Methylosome in Myeloproliferative Disorders
  - Cancer Cells 19(2):161-163 (2011)
  JAK2 gain-of-function mutations have been shown to cause myeloproliferative neoplasms. In this issue of Cancer Cell, Liu et al. (2011) demonstrate that these JAK2 mutants, but not wild-type JAK2, directly phosphorylate PRMT5 and inhibit its arginine methyltransferase activity, establishing a link between mutant JAK2 and histone arginine methylation.
• Monoallelic Deletion of NFKBIA in Glioblastoma: When Less Is More
  - Cancer Cells 19(2):163-165 (2011)
  Bredel et al. (2010) recently identified a subset of glioblastomas that harbor monoallelic loss of NFKBIA, which negatively affects patient prognosis. This finding raises new questions as to the role of IκBα and NF-κB in glioblastoma, the relationship between EGFR and NF-κB signaling, and potential therapeutic targets.
• PARP Inhibitors in Cancer Therapy: Promise, Progress, and Puzzles
  - Cancer Cells 19(2):165-167 (2011)
  A recent article in the New England Journal of Medicine by O'Shaughnessy et al. provides evidence that a treatment strategy aimed at inducing DNA damage with chemotherapy while simultaneously disabling repair using a PARP inhibitor might offer hope for patients with a treatment-refractory form of breast cancer.
• NEDD8 Pathways in Cancer, Sine Quibus Non
  - Cancer Cells 19(2):168-176 (2011)
  There are 17 known ubiquitin-like proteins (UBLs) from nine phylogenetically distinct classes (NEDD8, SUMO, ISG15, FUB1, FAT10, Atg8, Atg12, Urm1, and UFM1) that have been identified to conjugate to substrates in a manner analogous to ubiquitin. NEDD8 is one of the most studied UBLs and shares the highest amino acid similarity to ubiquitin. Here, we review the current knowledge of the NEDD8 conjugation cascade derived from functional studies in genetic model organisms, structural insights from crystallographic studies, biochemical studies identifying a growing list of NEDD8 substrates with oncogenic implications, and attempts to pharmacologically target the NEDD8 pathway in cancer.
• Evidence for an Unanticipated Relationship between Undifferentiated Pleomorphic Sarcoma and Embryonal Rhabdomyosarcoma
  - Cancer Cells 19(2):177-191 (2011)
  Embryonal rhabdomyosarcoma (eRMS) shows the most myodifferentiation among sarcomas, yet the precise cell of origin remains undefined. Using Ptch1, p53 and/or Rb1 conditional mouse models and controlling prenatal or postnatal myogenic cell of origin, we demonstrate that eRMS and undifferentiated pleomorphic sarcoma (UPS) lie in a continuum, with satellite cells predisposed to giving rise to UPS. Conversely, p53 loss in maturing myoblasts gives rise to eRMS, which have the highest myodifferentiation potential. Regardless of origin, Rb1 loss modifies tumor phenotype to mimic UPS. In human sarcomas that lack pathognomic chromosomal translocations, p53 loss of function is prevalent, whereas Shh or Rb1 alterations likely act primarily as modifiers. Thus, sarcoma phenotype is strongly influenced by cell of origin and mutational profile.
• Tumor-Derived Jagged1 Promotes Osteolytic Bone Metastasis of Breast Cancer by Engaging Notch Signaling in Bone Cells
  - Cancer Cells 19(2):192-205 (2011)
  Despite evidence supporting an oncogenic role in breast cancer, the Notch pathway's contribution to metastasis remains unknown. Here, we report that the Notch ligand Jagged1 is a clinically and functionally important mediator of bone metastasis by activating the Notch pathway in bone cells. Jagged1 promotes tumor growth by stimulating IL-6 release from osteoblasts and directly activates osteoclast differentiation. Furthermore, Jagged1 is a potent downstream mediator of the bone metastasis cytokine TGFβ that is released during bone destruction. Importantly, γ-secretase inhibitor treatment reduces Jagged1-mediated bone metastasis by disrupting the Notch pathway in stromal bone cells. These findings elucidate a stroma-dependent mechanism for Notch signaling in breast cancer and provide rationale for using γ-secretase inhibitors for the treatment of bone metastasis.
• Early Relapse in ALL Is Identified by Time to Leukemia in NOD/SCID Mice and Is Characterized by a Gene Signature Involving Survival Pathways
  - Cancer Cells 19(2):206-217 (2011)
  We investigated the engraftment properties and impact on patient outcome of 50 pediatric acute lymphoblastic leukemia (ALL) samples transplanted into NOD/SCID mice. Time to leukemia (TTL) was determined for each patient sample engrafted as weeks from transplant to overt leukemia. Short TTL was strongly associated with high risk for early relapse, identifying an independent prognostic factor. This high-risk phenotype is reflected by a gene signature that upon validation in an independent patient cohort (n = 197) identified a high-risk cluster of patients with early relapse. Furthermore, the signature points to independent pathways, including mTOR, involved in cell growth and apoptosis. The pathways identified can directly be targeted, thereby offering additional treatment approaches for these high-risk patients.
• N-α-Acetyltransferase 10 Protein Suppresses Cancer Cell Metastasis by Binding PIX Proteins and Inhibiting Cdc42/Rac1 Activity
  - Cancer Cells 19(2):218-231 (2011)
  N-α-acetyltransferase 10 protein, Naa10p, is an N-acetyltransferase known to be involved in cell cycle control. We found that Naa10p was expressed lower in varieties of malignancies with lymph node metastasis compared with non-lymph node metastasis. Higher Naa10p expression correlates the survival of lung cancer patients. Naa10p significantly suppressed migration, tumor growth, and metastasis independent of its enzymatic activity. Instead, Naa10p binds to the GIT-binding domain of PIX, thereby preventing the formation of the GIT-PIX-Paxillin complex, resulting in reduced intrinsic Cdc42/Rac1 activity and decreased cell migration. Forced expression of PIX in Naa10-transfected tumor cells restored the migration and metastasis ability. We suggest that Naa10p functions as a tumor metastasis suppressor by disrupting the migratory complex, PIX-GIT- Paxillin, in cancer cells.
• Identification of miRNomes in Human Liver and Hepatocellular Carcinoma Reveals miR-199a/b-3p as Therapeutic Target for Hepatocellular Carcinoma
  - Cancer Cells 19(2):232-243 (2011)
  The full scale of human miRNome in specific cell or tissue, especially in cancers, remains to be determined. An in-depth analysis of miRNomes in human normal liver, hepatitis liver, and hepatocellular carcinoma (HCC) was carried out in this study. We found nine miRNAs accounted for 88.2% of the miRNome in human liver. The third most highly expressed miR-199a/b-3p is consistently decreased in HCC, and its decrement significantly correlates with poor survival of HCC patients. Moreover, miR-199a/b-3p can target tumor-promoting PAK4 to suppress HCC growth through inhibiting PAK4/Raf/MEK/ERK pathway both in vitro and in vivo. Our study provides miRNomes of human liver and HCC and contributes to better understanding of the important deregulated miRNAs in HCC and liver diseases.
• A Functional Role for Tumor Cell Heterogeneity in a Mouse Model of Small Cell Lung Cancer
  - Cancer Cells 19(2):244-256 (2011)
  Small cell lung cancer (SCLC) is the lung neoplasia with the poorest prognosis, due to its high metastatic potential and chemoresistance upon relapse. Using the previously described mouse model for SCLC, we found that the tumors are often composed of phenotypically different cells with either a neuroendocrine or a mesenchymal marker profile. These cells had a common origin because they shared specific genomic aberrations. The transition from neuroendocrine to mesenchymal phenotype could be achieved by the ectopic expression of oncogenic RasV12. Crosstalk between mesenchymal and neuroendocrine cells strongly influenced their behavior. When engrafted as a mixed population, the mesenchymal cells endowed the neuroendocrine cells with metastatic capacity, illustrating the potential relevance of tumor cell heterogeneity in dictating tumor properties.
• Bone Marrow-Derived Myofibroblasts Contribute to the Mesenchymal Stem Cell Niche and Promote Tumor Growth
  - Cancer Cells 19(2):257-272 (2011)
  Carcinoma-associated fibroblasts (CAFs) that express α-smooth muscle actin (αSMA) contribute to cancer progression, but their precise origin and role are unclear. Using mouse models of inflammation-induced gastric cancer, we show that at least 20% of CAFs originate from bone marrow (BM) and derive from mesenchymal stem cells (MSCs). αSMA+ myofibroblasts (MFs) are niche cells normally present in BM and increase markedly during cancer progression. MSC-derived CAFs that are recruited to the dysplastic stomach express IL-6, Wnt5α and BMP4, show DNA hypomethylation, and promote tumor growth. Moreover, CAFs are generated from MSCs and are recruited to the tumor in a TGF-β- and SDF-1α-dependent manner. Therefore, carcinogenesis involves expansion and relocation of BM-niche cells to the tumor to create a niche to sustain cancer progression.
• TheMDM2 Promoter SNP285C/309G Haplotype Diminishes Sp1 Transcription Factor Binding and Reduces Risk for Breast and Ovarian Cancer in Caucasians
  - Cancer Cells 19(2):273-282 (2011)
  MDM2 plays a key role in modulating p53 function. The MDM2 SNP309T > G promoter polymorphism enhances Sp1 binding and has been linked to cancer risk and young age at diagnosis although with conflicting evidence. We report a second MDM2 promoter polymorphism, SNP285G > C, residing on the SNP309G allele. SNP285C occurs in Caucasians only, where 7.7% (95% CI 7.6%–7.8%) of healthy individuals carry the SNP285C/309G haplotype. In vitro analyses reveals that SNP309G enhances but SNP285C strongly reduces Sp1 promoter binding. Comparing MDM2 promoter status among different cohorts of ovarian (n = 1993) and breast (n = 1973) cancer patients versus healthy controls (n = 3646), SNP285C reduced the risk of both ovarian (OR 0.74; CI 0.58–0.94) and breast cancer (OR 0.79; CI 0.62–1.00) among SNP309G carriers.
• JAK2V617F-Mediated Phosphorylation of PRMT5 Downregulates Its Methyltransferase Activity and Promotes Myeloproliferation
  - Cancer Cells 19(2):283-294 (2011)
  The JAK2V617F constitutively activated tyrosine kinase is found in most patients with myeloproliferative neoplasms. While examining the interaction between JAK2 and PRMT5, an arginine methyltransferase originally identified as JAK-binding protein 1, we found that JAK2V617F (and JAK2K539L) bound PRMT5 more strongly than did wild-type JAK2. These oncogenic kinases also acquired the ability to phosphorylate PRMT5, greatly impairing its ability to methylate its histone substrates, and representing a specific gain-of-function that allows them to regulate chromatin modifications. We readily detected PRMT5 phosphorylation in JAK2V617F-positive patient samples, and when we knocked down PRMT5 in human CD34+ cells using shRNA, we observed increased colony formation and erythroid differentiation. These results indicate that phosphorylation of PRMT5 contributes to the mutant JAK2-induced myeloproliferative phenotype.