Tumor Microbiota-derived Signaling in Colon Carcinogenesis and Cancer Treatment

Abstract: One of every 20 Americans develops colorectal cancer (CRC) and, once diagnosed, more than one-third will not survive 5 years. Among adult cancers, CRC is the second most common cause of cancer death. Mounting evidence from metagenomic analyses suggests that gut bacteria may affect CRC directly or indirectly by secreting metabolites, invading tissues, and modulating the host immune response. However, knowledge is scarce on how gut microbiota and its products can be utilized to develop therapeutic agents for CRC. We propose to advance current knowledge with an ultimate goal to identify a novel microbial molecules that inhibit tumorigenesis and invasion of colorectal cancer cells. Our preliminary metagenomic and metabolomics studies determined the increased abundance of microbial genes encoding branched-chain amino acid metabolizing genes and a global gene regulator (ilvE and codY), which regulate the expression of virulence genes and production of acidic metabolites from Streptococcus gallolyticus and Ruminococcus gnavus. The specific objective of this proposal focuses on how microbiota- produced metabolites simultaneously regulate S. gallolyticus’s metabolism, which ultimately modulate the pH-sensing GPR4 during tumorigenesis and colorectal cancer cell invasion. Our central hypothesis is that pH-sensing GPR4 cross-talk with tumor-specific microbiota, which generates metabolites and inhibits tumorigenesis and invasion. In Aim 1, we will determine the role of S. gallolyticus BCAA metabolic pathways and CodY transcriptional regulator in generating acidic metabolites. In Aim 2, we will elucidate the function of proton-sensing GPCR in modulating microbiota-stimulated epithelial cell proliferation and migration. The proposed study will provide insights into the molecular basis of GPR4 and S. gallolyticus’s applications to inhibit epithelial proliferation and migration, two critical hallmarks of CRC. Abstract: One of every 20 Americans develops colorectal cancer (CRC) and, once diagnosed, more than one-third will not survive 5 years. Among adult cancers, CRC is the second most common cause of cancer death. Mounting evidence from metagenomic analyses suggests that gut bacteria may affect CRC directly or indirectly by secreting metabolites, invading tissues, and modulating the host immune response. However, knowledge is scarce on how gut microbiota and its products can be utilized to develop therapeutic agents for CRC. We propose to advance current knowledge with an ultimate goal to identify a novel microbial molecules that inhibit tumorigenesis and invasion of colorectal cancer cells. Our preliminary metagenomic and metabolomics studies determined the increased abundance of microbial genes encoding branched-chain amino acid metabolizing genes and a global gene regulator (ilvE and codY), which regulate the expression of virulence genes and production of acidic metabolites from Streptococcus gallolyticus and Ruminococcus gnavus. The specific objective of this proposal focuses on how microbiota- produced metabolites simultaneously regulate S. gallolyticus’s metabolism, which ultimately modulate the pH-sensing GPR4 during tumorigenesis and colorectal cancer cell invasion. Our central hypothesis is that pH-sensing GPR4 cross-talk with tumor-specific microbiota, which generates metabolites and inhibits tumorigenesis and invasion. In Aim 1, we will determine the role of S. gallolyticus BCAA metabolic pathways and CodY transcriptional regulator in generating acidic metabolites. In Aim 2, we will elucidate the function of proton-sensing GPCR in modulating microbiota-stimulated epithelial cell proliferation and migration. The proposed study will provide insights into the molecular basis of GPR4 and S. gallolyticus’s applications to inhibit epithelial proliferation and migration, two critical hallmarks of CRC.