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)