Microbiome-derived regulators of therapy-resistant colorectal tumors

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PROJECT SUMMARY Colorectal cancer (CRC) is the third most deadly cancer for both men and women in the U.S. Despite effective treatments for early-stage CRC, late-stage solid tumors exhibiting hypoxic and/or poor vascularization are more difficult to treat. To improve the prognosis for these tumors, new treatment regimes for CRC are urgently needed. Intestinal tract bacterial communities (microbiota) present a possible solution. Evidence from our team, as well as others, indicates small molecule metabolites produced via metabolic processes of the microbiota can promote, and in some cases inhibit, CRC tumorigenesis. These findings have suggested the possibility of “Bacterial-derived Metabolite Therapy (BdMT)” as a transformative treatment of resistant CRC tumors. However, our understanding of these tumor-microbe interactions is only in its infancy, and more work is needed to make BdMT a reality. In particular, we lack knowledge on the identity of microbe-derived metabolites that regulate CRC tumors, and also the underlying molecular mechanisms by which these molecules regulate the tumor cells. In order to fill in these gaps, we use a powerful preclinical experimental model system (tumoroids) for assaying physiological effects of microbe-derived metabolites on tumor cells, coupled with cutting-edge multi-omic analysis tools to investigate molecular mechanisms of tumor response and identify their small molecular regulators. Our hypothesis is that CRC tumoroids treated with metabolite fractions obtained from fecal samples of CRC patients and analyzed via multi-omics will reveal microbiome-derived small molecule tumor regulators which can be further leveraged for therapeutic applications. We will test this hypothesis via these Specific Aims: Aim 1. Establish a CRC tumoroid model and test tumor cell response to fecal metabolite fractions. Leveraging the expertise of PI Subramanian, we will establish patient-derived CRC tumoroids, and treat these with metabolite fractions isolated from fecal samples of CRC patients and healthy controls. Tumor cell proliferation will be assayed for each fraction tested; Aim 2. Identify and validate molecular regulators and mechanisms of CRC tumoroid response using multi-omics. For metabolite fractions eliciting proliferative tumor cell response in Aim 1, advanced multi-omic analysis will be performed on the tumor cells to investigate response mechanisms. Metatranscriptomic analysis of fecal samples will identify microbiota functional pathways active in tumor-bearing patients. Tumor response mechanisms and active microbial metabolic pathways will be used to predict potential small molecule regulators active in the fecal fractions. Mass spectrometry-based metabolomics will identify potential small molecule tumor regulators. Enabled by the diverse expertise of our team in cancer microbiology, tumor-microbe interactions and multi-omic analysis, we will identify potential new tumor-regulating metabolites for further investigation, a critical step towards making BdMT a reality for improving outcomes of CRC.