Translational Science of Gastrointestinal Cancer Initiation and Progression

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SUMMARY: Gastrointestinal tract cancers (GI cancers) account for >70,000 deaths per year. Among GI cancers, colorectal cancer (CRC) is the third most common cancer in the US. Esophageal adenocarcinoma (EAC) is another GI cancer of large concern to US public health and has risen alarmingly with a poor prognosis (20% 5- year survival). There is an unmet need for effective cancer prevention and early detection of CRC and EAC. CRC & EAC arise from precancer lesions: CRC arises from adenomas and EAC from Barrett’s esophagus (BE), which progress to high-grade dysplasia (HGD) and then cancer. This normal precancer lesioncarcinoma sequence of GI tract epithelial cells has been the established paradigm of the cancer initiation and progression process in the GI tract. The polyp-to-cancer paradigm suggests that progression is driven solely by the accumulation of gene mutations and epigenetic alterations in cancer initiating cells. However, emerging evidence suggests that these molecular alterations are insufficient to drive cancer formation and that multiple tumor promoting mechanisms come from surrounding tissue. For example, our previous studies have shown that increased senescent fibroblasts present in the normal colon of advanced adenoma patients can create a pro-tumorigenic microenvironment. Further, molecular changes in the normal colon of patients with advanced lesions may predispose tissue to tumor formation and mediate the carcinogenesis process, such as presence of aberrant DNA methylation pattern, high gene mutation loads and microinflammation. Based on our previous studies, we hypothesize that cancer initiation and progression require both cell-autonomous (e.g., cancer driver gene mutations) and non-autonomous mechanisms from the tissue microenvironment. Discovery of the factors mediating adenoma initiation & progression, and the translation of these findings into novel risk biomarkers or prevention therapy would have a major impact on clinical prevention and management of GI cancers. To overcome technical barriers in prior studies and ensure scientific rigor and reproducibility, the Research Specialist, Dr. Ming Yu, has developed a research plan to achieve the following objectives within the next five years: Objective 1: Determine the role of senescent fibroblasts to promote the survival and clonal expansion of colon cancer initiating cells in ex-vivo & in-vivo model system; Objective 2: Create a precancer atlas of molecular alterations potentially associated with driving adenoma progression in primary clinical samples; Objective 3: Identify and evaluate DNA methylation-based tissue biomarkers as CRC risk markers and BE progression markers. This research plan is an integral part of the NCI-funded research programs led by Unit Director, Dr. William Grady, including the Early Detection Research Network Biomarker Characterization Center and the Translational & Basic Science of Early Lesion Center. Successful completion of this research plan will provide critical support to these research programs and lead to novel insight on the molecular carcinogenesis of GI cancer. Findings will provide a new direction for discovering biomarkers to improve GI cancer management.