Colon cancer is the 2nd-leading cause of cancer-related deaths in the United States and is one of the best- characterized solid tumors in terms of its common genetic mutations. However, knowledge gaps exist in the basic understanding of these cancers downstream of their genetic profile. For instance, while ~60% of colon cancers follow the typical WNT-driven adenoma-to-carcinoma pathway, approximately 30% follow the ?serrated tumor pathway?- often driven by gain-of-function BRAF mutations. Even though serrated tumors have the worst prognosis of colon cancers, there is a large gap in our understanding of the molecular mechanisms. The proposal?s main objective will focus on the tumor-suppressor gene, SMAD4, which is mutated in approximately 57% of all colon tumors, but for which there is little understanding of its molecular mechanisms in colon cancer. The hypothesis is that SMAD4 plays a critical transcriptional regulatory role in serrated tumor pathway, which promotes cancer development and progression. The rationale for this hypothesis is based on preliminary studies that reveal: 1) SMAD4 loss, when combined with activation of BRAF, can trigger serrated tumor formation as rapidly as 1 month in mice, and 2) that SMAD4 binds to regulatory regions of the genome also bound by -catenin ? the transcriptional effector of the most commonly mutated signaling pathway in colon cancer, the WNT pathway.
Aim 1 will use new mouse models to determine how SMAD4 suppresses BRAF-driven serrated tumorigenesis. The goal is to test the hypothesis that SMAD4 suppresses key signaling pathways that are required for serrated tumor development and progression.
Aim 2 will use epigenomic approaches to characterize the role of SMAD4 as a transcriptional regulator and will map the interaction of SMAD4 with -catenin at the level of DNA-binding, thus detailing the first intersection of these pathways on the colon cancer genome. The proposed studies will test the hypothesis that SMAD4 directly regulates the WNT- signaling pathway by redirecting -catenin to tumor-suppressive gene targets in coordination with RUNX3, thus impacting cancer development. The proposed studies are significant in that they will present a new perspective on an understudied, but more deadly, colon cancer tumor type and also identify the cellular mechanisms of tumor development in a commonly mutated tumor-suppressor gene background. These studies would have broad impacts in the cancer research field, and will reveal new targets to identify and treat patients with serrated tumors. With the co-mentorship of Drs. Michael Verzi and Ronald Hart, this proposal's training plan will prepare me for a path towards independence by 1) bolstering my epigenomics training, and 2) guiding my path from a novice in the cancer research field to that of a budding expert poised to make my own impacts towards diagnosing and treating cancer.
Colorectal Cancer is the 3rd most prominent cancer found in men and women, and is the second leading cause of cancer-related deaths in the United States. My proposed research aims to better understand how colorectal tumors develop and progress. I hope that these studies will translate into new, more effective treatments for cancers.