Abstract 4929: Cooperation between the microbiota and oncogenic mutations leading to the development of colon cancer

Abstract

Abstract Background: The microbiome of the colon has been shown to play a role in colon cancer tumorigenesis. Inflammation is a key step in the formation of tumors, and it is possible that microbiota induce this inflammation, further stimulating tumor growth. The interaction between mutant cells in the colon and the microbiota has been understudied. We hypothesized that eradication of the intestinal microbiota could prevent tumorigenesis in the colon despite the presence of oncogeneic mutations. Methods: We have previously generated a transgenic murine model in which a constitutively active PI3K is expressed in the distal small intestine and colon (FC3K). These mice develop aggressive cancers in the proximal colon via a non-canonical mechanism without loss of APC. In addition, we developed a murine model possessing both PIK3CA mutations and loss of APC (FCAK3K). These mice were treated with vancomycin in their drinking water. Necropsy was performed at specific time-points or at moribund to determine tumor counts and size. Spheroid cultures were also utilized to determine the potential for cytotoxic effects of vancomycin treatment. Results: Treatment with vancomycin in FC3K mice at weaning resulted in a reduction in tumor incidence and growth and prolonged survival, indicated by a 42% tumor frequency and median lifespan of 101 days, compared to 100% frequency and 86.5-day lifespan of control mice (p<0.001). In the tumors that formed there was no difference in the epithelial mesenchymal transition (EMT), Ki67 index, nuclear localization of CTNNB1, or activation of the PI3K/AKT/mTOR signaling pathway. FCAK3K spheroid and mouse models portrayed ineffectiveness of vancomycin through an absent change in spheroid diameter and also 100% frequency of both treated and control mice. Conclusion: The above results indicate that colon cancers induced by PIK3CA mutations are at least partially dependent on the microbiota for tumorigenesis. This dependence appears to be overcome in the setting of both APC and PIK3CA mutations. Citation Format: Dana Van De Hey, Susan Payne, Cheri Pasch, Linda Clipson, Kristina Matkowskyj, Dustin Deming. Cooperation between the microbiota and oncogenic mutations leading to the development of colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4929. doi:10.1158/1538-7445.AM2017-4929