LAUSR

Background: Emerging data shows a rise in CRC incidence in men and women under 55 years of age, with a potential new risk factors including alterations in the microbiome. While recent advances have significantly reduced CRC morbidity and mortality, such as screening and new therapeutic strategies, how the microbiome modulates CRC chemotherapy response remains understudied. This alarming trend presents an urgent need for further understanding of the molecular mechanisms and “signatures” of the gut microbiome in CRC patients. Key driving pathways in CRC include WNT, RAS, RAF, APC and TGF-β signaling. Modulating the gut immune response includes multiple mechanisms, including sensors through carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) that serve as receptors to microbes, and crosstalk with signaling pathways such as TGF-β signaling pathway. Interestingly, disruption of TGF-β leads to increased sensitivity to cisplatin and other DNA cross-linking agents. Hypothesis and Aims: Our hypothesis is that the gut microbiome plays a key role in modulating the TGF-β pathway by CEACAMs binding to specific microbial species, thereby impeding the TGF-β pathway and altering chemotherapy response. Our aims are to explore TCGA genomics, and functional interactions between gut microbiota, CEACAMs, and TGF-β signaling in processing chemotherapy response. Methods and Results: We first analyzed microbiome signatures in normal and CRC patients, and identified a signature pattern. TCGA analyses in 9,125 human cancers reveal alterations of TGF-β with CEACAM members in over 40% of CRC and correlate with a cancer stem cell signature. Mechanistic studies reveal that CEACAMs inhibit TGF-β tumor suppressor signaling by blocking TGFBR1, and promoting invasive CRC. Likewise, our TGF-β signaling-deficient mouse models spontaneously develop CRC, as well as metastases, likely modulated in part by the microbiome. Furthermore, key defects in the TGF-β pathway alter sensitivity to 5-FU and DNA cross-linking agents, such as cisplatin, through disruption of DNA repair pathways. Conclusion: The TGF-β pathway is important in maintaining colon epithelial cell homeostasis potentially through interactions with CEACAMs and gut microbiota. When the pathway is disrupted, epithelial cells are more susceptible to transformation and invasion, potentially identifying specific populations that are more sensitive to chemotherapy such as cisplatin and 5FU. Citation Format: Shuyun Rao, Charles Hadley King, Raja Mazumder, Shoujun Gu, Richard Amdur, Bibhuti Mishra, Lopa Mishra. Identification of chemotherapeutic resistant microbiota profile in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2827.