Genetic Cooperation in BRAF(V600E)-induced Non-Small Cell Lung Cancer Using Genetically Engineered Mouse Models of Cancer.

摘要

Lung cancer is the most common cause of death due to cancer in the world and the most recent statistics from the CDC reveal that in 2011 in the United States alone, lung cancer accounted for 207,339 patient diagnoses and 156,953 deaths. The largest type of lung cancer, non-small cell lung cancer (NSCLC), accounts for nearly 90% of this disease. Data from both humans and preclinical models have revealed that this disease is driven by sustained activation of the RAS/RAF/MEK/ERK MAPK pathway. However, while a strong initiator of tumorigenesis, BRAFV600E expression on its own is not sufficient to drive lung cancer formation. This is due to the need for cells to acquire the prerequisite "Hallmarks of Cancer" required for tumorigenesis, which oftentimes necessitates the activation of separate, cooperating pathways. Use of genetically engineered mouse models (GEMM) of cancer has provided us valuable insight into these mechanisms of cooperation driving cancer progression. In particular, use of the BrafCA GEMM of cancer has given us a better molecular understanding of the initiation, progression, and therapy of tumors driven by the MAPK pathway in multiple tissues including skin and lung.;Using the BrafCA GEM model of lung cancer and taking a candidate-based approach, I have identified a central role for Wnt/beta-catenin signaling in the initiation and progression of lung cancer. Specifically, my results indicate that Wnt/beta-catenin signaling is both necessary for and sufficient to bypass the proliferative arrest observed in BRAFV600E-driven lung tumors through its ability to regulate c-MYC expression. However, my results also show that the ability of this pathway to drive progression to adenocarcinoma is through downstream effectors independent of c-MYC. Taking an unbiased approach using Sleeping Beauty transposon-mediated mutagenesis I have also identified a number of novel candidate cancer genes in pathways playing a role in driving BRAF V600E-initiated lung cancer progression. Some notable candidates currently being validated and pursued include a number of genes highly mutated in human cancers including Fat1, Stag2, and Arid2, and pathways with potential ties to cancer including axonal guidance.;These studies demonstrate the molecular complexity involved in the initiation and progression of BRAFV600E-driven NSCLC, as well as the potential efficacy of targeting these cooperating pathways to combat this disease.