Milagre C, Dhomen N, Geyer FC, et al. A mouse model of melanoma driven by oncogenic KRAS. Cancer Res 2010;70:5549–57.

Mutations in RAS genes occur in approximately 25% of melanomas. NRAS is mutated in 22% of human melanomas, whereas KRAS and HRAS are mutated in 2% and 1% of cases, respectively. More than 80% of the NRAS and HRAS mutations involve Q61, whereas 77% of the KRAS mutants involve G12. It is unclear why NRAS mutations predominate in melanoma, whereas in cancers such as pancreatic and colorectal cancers, KRAS mutations predominate. Several transgenic mouse melanoma models driven by RAS genes have been developed, but in the absence of additional events, induction of melanoma in these models is generally inefficient. Thus, constitutive or inducible expression of G12VHRAS only induces tumor formation efficiently when Cdkn2a (p16INK4a) or Tp53 is deleted, or when mice are exposed to UV light. Milagre and colleagues have used Cre-recombinase/LoxP–induced expression of G12VKRAS in melanocytes to induce melanomagenesis and found that mice develop skin hyperpigmentation, nevi, and tumors that bear many of the characteristic histopathologic features and molecular characteristics of human melanoma. De novo tumors invade and destroy underlying muscles, and malignant cells derived from them grow as subcutaneous tumors and colonize lungs of nude mice. These data establish that oncogenic KRAS can be a founder event for melanoma development.

Roesch A, Fukunaga-Kalabis M, Schmidt EC, et al. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 2010;141:583–94.

Conflicting studies in malignant melanoma describe melanoma stem cells as either abundant or rare, raising questions as to whether malignant melanoma tumors arise through an organized hierarchy of stem, progenitor, and differentiated elements or from a situation in which every cell can initiate a tumor. A recent paper by Roesch and colleagues suggests an intermediate view. These investigators identified a rare, slow-cycling population of therapy-resistant cells marked by H3K4 demethylase JARID1B. JARID1B-positive cells were required for tumor maintenance. Although all melanoma cells could form tumors in xenograft models, JARID1B-negative cells can turn on this marker, whereas JARID1B-positive cells can become negative. Thus, JARID1B represents a dynamic marker for tumor maintenance in melanoma.

Nam JM, Onodera Y, Bissell MJ, Park CC. Breast cancer cells in three-dimensional culture display an enhanced radioresponse after coordinate targeting of integrin α5β1 and fibronectin. Cancer Res 2010;70:5238–48.

Carcinoma cells co-opt molecular and cellular programs in their microenvironment to foster their own growth and survival. Among these programs, development of angiogenic vasculature, chronic infiltration of premalignant tissue by activated innate and adaptive immune cells, and extracellular matrix (ECM) remodeling significantly contribute to cancer development. Critical molecules regulating some of these processes have also been found to correlate with disease progression. High-level expression of fibronectin and its receptor α5β1 integrin, for example, are associated with poor prognosis in patients with breast cancer. Nam and colleagues have used a three-dimensional laminin-rich culture model to demonstrate that inhibition of β1 integrin, with a function blocking antibody (AIIB2), induced selective apoptosis and decreased proliferation of human breast carcinoma cells without toxicity to non-tumor normal cells. Moreover, they found that inhibition of α5-integrin/fibronectin interaction with a specific peptide (ATN-161) similarly induced apoptosis but also heightened the apoptotic effects of radiation through an Akt-mediated mechanism. Together, these data support preclinical validation of fibronectin and α5β1 integrin as targets for breast cancer therapy.

Huang GS, Brouwer-Visser J, Ramirez MJ, et al. Insulin-like growth factor 2 expression modulates Taxol resistance and is a candidate biomarker for reduced disease-free survival in ovarian cancer. Clin Cancer Res 2010;16:2999–3010.

Ovarian cancer (OvCa) is associated with high mortality largely due to the chemoresistant nature of recurrent and progressive disease. Thus, elucidating cellular and molecular mechanisms that regulate drug resistance is critical for development of more effective treatment. Taxol as first-line and subsequent therapy for OvCa stabilizes microtubules altering their dynamic properties, thereby perturbing their normal function in spindle assembly, cell division, motility, intracellular trafficking, and signaling. Despite recognition of several cell-intrinsic mechanisms contributing to Taxol resistance in OvCa, therapies overcoming clinical Taxol resistance have not been developed. Huang and colleagues have previously shown that Taxol can activate proliferative and antiapoptotic OvCa pathways mediated in part by AKT. In their most recent work, these researchers examined insulin-like growth factor (IGF) signaling in the response of OvCa cells to Taxol and found that Taxol-induced AKT phosphorylation was dependent on type 1 IGF receptor (IGF1R) activity that was associated with upregulation of IGF2. Taxol-resistant cells exhibited increased IGF2 mRNA, compared with sensitive cells. Blockade of the IGF1R, or IGF2 depletion, restored Taxol sensitivity. Significantly, high IGF2 expression in OvCa was associated with advanced-stage and high-grade disease, and patients with high IGF2 tumor expression exhibited reduced disease-free survival. These novel findings suggest that IGF2 may represent a significant and tractable therapeutic target for OvCa.

Pastor F, Kolonias D, Giangrande PH, Gilboa E. Induction of tumour immunity by targeted inhibition of nonsense-mediated mRNA decay. Nature 2010;465:227–31.

Tumor genomes are highly scrambled and would be expected to produce potent tumor rejection antigens. One reason that tumors are not more immunogenic is that a normal cellular sensor, that for nonsense-mediated decay, detects and degrades mRNAs with premature termination codons prior to translation. Pastor and colleagues used RNAi against the nonsense-mediated decay machinery in tumor cells and demonstrated expression of new antigens that engaged an antitumor immune response that led to significant growth inhibition. Recognition of this target/process represents a clinically feasible approach to enhance tumor immunity.

Li B, Gordon GM, Du CH, Xu J, Du W. Specific killing of Rb mutant cancer cells by inactivating TSC2. Cancer Cell 2010;17:469–80.

The ability to combine mutations in tumor suppressor genes into weapons that kill cancer cells represents an “Achilles heel” or synthetic lethal approach to cancer therapy. Li and colleagues demonstrated in Drosophila that the tumor suppressor genes RB and TSC2 represented a synthetic lethal combination. Extending this result to a number of human RB-mutant cell lines and xenografts, they demonstrate that knockdown of TSC2 leads to increased oxidative stress and decreased ability to scavenge reactive oxygen species, resulting in cell death in vitro and reduced tumor formation in vivo.

Note:Breaking Advances are written by Cancer Research Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.