Thursday, November 21, 2024
11/21/2024
Project Summary Abstract Colorectal cancer (CRC) is among the most common malignancy worldwide and has a high mortality rate. In spite of advances in our understanding of the genetics and immunology of CRC, it remains largely resistant to therapy. Colonization of the large intestine by oral microbes is common among healthy individuals. Many of these commensals have pathophysiological effects in CRC patients. However, their mechanism of action is unclear. Our recent study identified Parvimonas micra as the most enriched oral bacteria in CRC patient stool and colon mucosa relative to healthy individuals. Networks of P. micra and other oral commensal in the stool of CRC patients excluded protective commensals. Changes in DNA methylation of a set of cardinal genes in the colon mucosa and blood of the patients predicted CRC risk. Transfer of CRC stool to germ free mice that were treated with AOM resulted in DNA methylation of the host and formation of aberrant crypt foci, over and above that observed with transfer of microbiota from healthy individuals. We provided preliminary data that P. micra can directly methylate human colon tumor cells when co-cultured together under hypoxic conditions. On the basis of these findings we hypothesize that oral commensals exemplified by Parvimonas alter DNA methylation of host DNA to adapt to tumors and promote CRC. We will address this in two Specific Aims. 1. We will test the hypothesis that in mouse models of spontaneous CRC, P. micra alters DNA methylation and expression of host genes that affect CRC tumor growth and tumor associate immunity. Mice prone to spontaneous CRC will get healthy human microbiota with or without P. micra, or L. acidophilus for comparison. Reduced representation bisulfite sequencing (RRBS), ATACseq, RNAseq, immune assays, and histopathology will determine how changes in DNA methylation impacts, (1) the growth and invasion of CRC tumors, (2) tumor associated inflammation and immune response, (3) microbial community composition of the tumor mucosa and stool. 2. We will test the hypothesis that P. micra and bacterial community networks regulate tumor growth and immune response in CRC by altering DNA methylation of host cells. To test this we will, (1) Identify clusters of fecal and tissue-adherent bacteria in CRC patients and relate these to the DNA hypermethylation of patient colon and blood across different CMS subclasses, (2) determine how altered DNA methylation of tumor and blood relate to mutation load and immune response, (3) distinguish pathogenic versus protective patterns of DNA methylation in colon epithelial organoids, that result from exposure to P. micra, versus L. acidophilus.
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