Transforming growth factor fi receptor type II (TGFBR2) is a tumor suppressor gene that is commonly mutated in colon cancer, and its inactivation plays an important and potentially paradoxical role in colon carcinogenesis. TGFBR2 is an essential component of the TGF-fi receptor complex, which mediates the effects of the multi-functional cytokine, TGF-fi. TGF-fi and TGFBR2 regulate a variety of cell functions including cell growth, senescence, differentiation;extracellular matrix remodeling, and genomic stability. Thus, TGFBR2 inactivation likely affects tumor formation through a variety of mechanisms, including excess cell proliferation, increased cell invasiveness, regulation of genomic stability, etc.. Interestingly, unlike classical hormones whose actions are few and specific, TGF-IJ can cause these myriad effects on a cell because TGF-fi's effects depend on the type and state of the cell, termed the 'cellular context'. Our preliminary data demonstrates that the cellular context dependence of TGF-fi's effects dictates the consequences of the loss of TGF-fi signaling in colon cancer and that those consequences are a result of cooperation of TGFBR2 inactivation with other genes commonly mutated in colon cancer. We now propose to study the effects of TGFBR2 inactivation in the context of known genetic events that occur in colon cancer (e.g. ARC, KRAS2, and TRP53 mutations). We will employ novel model systems to determine how TGFBR2 inactivation affects tumor cell behavior, especially in the context of mutant APC, KRAS2, and TP53 . Of note, these studies have yielded novel genetic models for the classic adenoma-cancer pathway and an unprecedented model for the hyperplastic polyp-cancer path.
The Specific Aims are as follows:
Aim 1) To determine the effect of TGF-fi signaling pathway inactivation in the setting of Ape mutation and Wnt signaling activation on intestinal cancer formation.
Aim 2) To determine if TGF-fi signaling pathway inactivation cooperates with Kras2 mutation and Ras-Raf pathway activation in intestinal cancer formation.
Aim 3) To determine the in vivo consequences of TGFBR2 inactivation on colon cancer initiation and progression using novel mouse models of intestinal cancer that genetically recapitulate human colon cancer, Apc1638N;LSL-Kras2G12D;Tgfbr2IEKO, and Apc1638N;LSL-Trp53R172H;Tgfbr2IEKO mice
|Bosch, Linda J W; Luo, Yanxin; Lao, Victoria V et al. (2016) WRN Promoter CpG Island Hypermethylation Does Not Predict More Favorable Outcomes for Patients with Metastatic Colorectal Cancer Treated with Irinotecan-Based Therapy. Clin Cancer Res 22:4612-22|
|Cohen, Stacey A; Wu, Chen; Yu, Ming et al. (2016) Evaluation of CpG Island Methylator Phenotype as a Biomarker in Colorectal Cancer Treated With Adjuvant Oxaliplatin. Clin Colorectal Cancer 15:164-9|
|Okugawa, Yoshinaga; Grady, William M; Goel, Ajay (2015) Epigenetic Alterations in Colorectal Cancer: EmergingÂ Biomarkers. Gastroenterology 149:1204-1225.e12|
|Shiovitz, Stacey; Grady, William M (2015) Molecular markers predictive of chemotherapy response in colorectal cancer. Curr Gastroenterol Rep 17:431|
|Kaz, Andrew M; Grady, William M; Stachler, Matthew D et al. (2015) Genetic and Epigenetic Alterations in Barrett's Esophagus and Esophageal Adenocarcinoma. Gastroenterol Clin North Am 44:473-89|
|Dickinson, Brandon T; Kisiel, John; Ahlquist, David A et al. (2015) Molecular markers for colorectal cancer screening. Gut 64:1485-94|
|Shiovitz, Stacey; Bertagnolli, Monica M; Renfro, Lindsay A et al. (2014) CpG island methylator phenotype is associated with response to adjuvant irinotecan-based therapy for stage III colon cancer. Gastroenterology 147:637-45|
|Yu, M; Trobridge, P; Wang, Y et al. (2014) Inactivation of TGF-* signaling and loss of PTEN cooperate to induce colon cancer in vivo. Oncogene 33:1538-47|
|Luo, Yanxin; Wong, Chao-Jen; Kaz, Andrew M et al. (2014) Differences in DNA methylation signatures reveal multiple pathways of progression from adenoma to colorectal cancer. Gastroenterology 147:418-29.e8|
|Khatayevich, Dmitriy; Page, Tamon; Gresswell, Carolyn et al. (2014) Selective detection of target proteins by peptide-enabled graphene biosensor. Small 10:1505-13, 1504|
Showing the most recent 10 out of 22 publications