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)