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Principal Investigator: LISA Allyn BOARDMAN
Organization: MAYO CLINIC ARIZONA
Fiscal Year: 2024
Award: $575,706
Funding agency: National Cancer Institute
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.
Terms: <ATAC sequencing><ATAC-seq><ATACseq><Aberrant crypt foci><Ablation><Affect><Age><Antibiotic Therapy><Antibiotic Treatment><Assay for Transposase-Accessible Chromatin using sequencing><B fragilis><B. fragilis><BS-seq><Bacteria><Bacteroides fragilis><Beta Cadherin-Associated Protein><Beta-1 Catenin><Biological><Biological Markers><Bisulfite-based sequencing><Blood><Blood Cells><Blood Reticuloendothelial System><Blood Tests><Blood leukocyte><Body Tissues><Buccal Cavity><Buccal Cavity Head and Neck><C fusiforme><C. fusiforme><CUL-2><Cancers><Carcinogenesis Mechanism><Cavitas Oris><Cell Body><Cells><Chromatin><Co-culture><Cocultivation><Coculture><Coculture Techniques><Colon><Colon Cancer><Colon Carcinoma><Colon Neoplasms><Colon Tumor><Colonic Mass><Colonic Neoplasms><Colonic Tumor><Colorectal Cancer><Community Networks><Corynebacterium fusiforme><DNA><DNA Methylation><DNMT3a><Data><Death Rate><Deoxyribonucleic Acid><Development><Diathesis><Disease susceptibility><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial Cells><Epithelium><Exclusion><Exposure to><F fusiformis><F nucleatum><F nucleatus><F. fusiformis><F. nucleatum><F. nucleatus><Feces><Fusiformis fusiformis><Fusiformis nucleatus><Fusobacterium nucleatum><GI colonization><Gene Expression><Generalized Growth><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Germ-Free><Growth><Hematologic Tests><Hematological Tests><Hematology Testing><Histopathology><Human><Hypermethylation><Hypoxia><Hypoxic><Immune response><Immunity><Immunological response><Immunology><Immunology procedure><Individual><Inflammation><Intestinal><Intestines><Invaded><L acidophilus><L. acidophilus><Lactobacillus acidophilus><Large Intestine><Leukocytes><Leukocytes Reticuloendothelial System><Link><Malignant Neoplasms><Malignant Tumor><Marrow leukocyte><Methylation><Methyltransferase Gene><Mice><Mice Mammals><Microbe><Modern Man><Mouth><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><Mutation><Oral><Oral cavity><Organoids><Oxygen Deficiency><PRO2286><Pathogenicity><Patients><Pattern><Peripheral Blood Cell><Preventative strategy><Prevention strategy><Preventive strategy><Process><Progenitor Cells><RNA Seq><RNA sequencing><RNAseq><Regulator Genes><Reporting><Research Specimen><Risk Factors><Signal Pathway><Specimen><T-Cells><T-Lymphocyte><Testing><Tissue Growth><Tissues><Transcriptional Regulatory Elements><Tumor Cell><Tumor Immunity><Tumor Promotion><Weaning><White Blood Cells><White Cell><ages><anti-tumor immunity><antitumor immunity><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><bacterial community><bacterial disease treatment><bacterial infectious disease treatment><beta catenin><bio-markers><biobank><biologic><biologic marker><biomarker><biorepository><bisulfite sequencing><bisulfite-seq><bowel><cancer immunity><cancer in the colon><colon bacteria><colon cancer patients><colon carcinogenesis><colon neoplasia><colonic bacteria><colorectal cancer patients><colorectal cancer risk><colorectal cancer therapy><colorectal cancer treatment><colorectal carcinogenesis><community microbes><demethylation><developmental><epigenetically><epigenome><fecal microbial community><fecal microbiota><gastrointestinal tract colonization><genome mutation><global gene expression><global transcription profile><gut colonization><hDNA methyltransferase 3a><host response><human flora><human microbial communities><human microbiota><human microflora><human-associated microbial communities><human-associated microbiota><humanized mice><humanized mouse><immune system response><immunologic assay><immunologic assay/test><immunoresponse><improved><indexing><intestinal colonization><intestinal epithelium><large bowel><liability to disease><malignancy><methylome><microbial colonization><microbial community><microbial consortia><microbial flora><microbiome><microbiota><microflora><mortality rate><mortality ratio><mouse model><multispecies consortia><murine model><neoplasm/cancer><neoplastic cell><ontogeny><oral bacteria><oral commensal><oral flora><oral pathogen><pathogen><polymicrobial community><regulatory gene><resistance to therapy><resistant to therapy><risk stratification><stem cells><stool><stratify risk><suckling><therapeutic resistance><therapy resistant><thymus derived lymphocyte><trans acting element><transcriptome><transcriptome sequencing><transcriptomic sequencing><treatment resistance><tumor><tumor growth><white blood cell><white blood corpuscle><β-catenin>