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Principal Investigator: Neelendu Dey
Organization: FRED HUTCHINSON CANCER CENTER
Fiscal Year: 2024
Award: $1,577,081
Funding agency: National Cancer Institute
SUMMARY
Colorectal cancer (CRC) affects ~145,000 people/year in the US and is the 3rd most common cause of cancer
related deaths. CRC arises from early lesions that are pre-cancerous; these early lesions are colon adenomas
and serrated sessile lesions (SSL). Colon adenomas account for 80-85% of the CRC precancerous lesions and
progress to CRC via an early adenomaàadvanced adenomaàCRC sequence. In light of the well characterized
clinical natural history of adenomas, we plan to study them as early lesions and to determine the mechanisms
involved in the formation and progression of early precancerous lesions. Notably, only a few early adenomas will
progress to advanced adenomas (AA) and even fewer will progress to CRC. Our group and others have shown
that mutations alone are not sufficient to cause adenoma initiation and/or progression in the majority of cases.
There are likely multiple adenoma nonautonomous mechanisms that cooperate with the DNA alterations in the
adenomas to cause progression, and these mechanisms are likely operative in discrete subsets of affected
individuals. We and others have observed alterations, such as tissue senescence, high cancer driver gene
mutation loads, aberrant DNA methylation patterns, and dysbiotic gut microbiomes, in the normal colon of people
with advanced adenomas and CRC patients. We have termed normal colons with these features “primed colons”
and propose that these features are plausible mechanisms that affect adenoma initiation and progression.
Based on these observations and our prior studies, we hypothesize that early lesion progression requires a suite
of hallmark behaviors and that these behaviors are induced by adenoma autonomous factors (e.g. cancer driver
gene mutations) and adenoma nonautonomous factors from the “primed colon” or adenoma microenvironment.
Our proposed studies will integrate basic and translational cancer research Projects to iteratively examine the
direct causal relationships and interactions of adenomas, the colon “primed” microenvironment, and host-
systemic factors as “co-organizers” of adenoma initiation and/or progression. The Specific Aims are:
Aim 1) To determine the adenoma cell autonomous molecular factors that distinguish nonadvanced adenomas
from advanced adenomas and that regulate nonadvanced adenoma progression. (Projects 1 and 2)
Aim 2) To determine the adenoma nonautonomous factors from the “primed” colon and from the adenoma
microenvironment that associate with advanced human colon adenomas and regulate adenoma progression.
These factors will include the following “primed” colon states: 1. senescence state; 2. cancer driver gene mutation
burden; 3. gut microbiome state; 4. colon methylome, and 5. colon immune activity state. (Projects 1-3)
Aim 3)To determine how adenoma autonomous and nonautonomous factors from the adenoma
microenvironment and the “primed” colon cooperate to drive adenoma formation and progression.(Projcts 1-3)
Terms: <Aberrant DNA Methylation><Affect><Architecture><Atlases><Basic Cancer Research><Behavior><Biological Markers><Biology><Body Tissues><CRC prevention><Cancer Cause><Cancer Etiology><Cancer Research Programs><Cancer Research Project><Cancers><Cell Body><Cells><Cessation of life><Clinic><Clinical><Collaborations><Colon><Colonic Adenoma><Colonic Adenomatous Polyp><Colorectal Adenoma><Colorectal Adenomatous Polyp><Colorectal Cancer><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data Set><Death><Engineering / Architecture><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial Cells><Fibroblasts><GI microbiome><Gene Alteration><Gene Mutation><Genetic Alteration><Genetic Change><Genetic defect><Genetic mutation><Goals><History><Human><Immune><Immunes><Individual><Indolent><Investigators><Large Bowel Adenoma><Large Bowel Adenomatous Polyp><Large Intestine Adenoma><Lesion><Light><Malignant Neoplasms><Malignant Tumor><Mission><Modern Man><Molecular><Multiomic Data><Mutation><Natural History><Pathogenesis><Patients><Persons><Photoradiation><Position><Positioning Attribute><Predicting Risk><Recording of previous events><Research Personnel><Researchers><Science><Sequence Alteration><Sessile Lesion><Technology><Testing><Tissues><Translational Research><Translational Science><Translations><Tumor Promotion><adenoma><bio-markers><biologic marker><biomarker><cancer genetics><cancer type><clinical applicability><clinical application><cohort><colon adenoma><colon adenomatous polyp><colon cancer patients><colorectal cancer patients><colorectal cancer prevention><colorectal cancer progression><deep sequencing><digestive tract microbiome><dysbacteriosis><dysbiosis><dysbiotic><enteric microbiome><epigenetically><experience><forecasting risk><gastrointestinal microbiome><genome mutation><genomic alteration><gut microbiome><gut-associated microbiome><histories><human disease><innovate><innovation><innovative><intestinal biome><intestinal microbiome><malignancy><methylation pattern><methylome><microbial imbalance><microbiome><mouse model><multiple omic data><murine model><mutant><neoplasm/cancer><novel><precancer><precancerous><predict risk><predict risks><predicted risk><predicted risks><predicting risks><predictive risk><predicts risk><premalignant><prevent colorectal cancer><risk prediction><risk predictions><senescence><senescent><translation><translation research><translational cancer research><translational investigation>