Features of the early adenoma and adjacent colon that drive progression: the role of mutation burden in normal tissue, senescent cells, and tumor clonal architecture

PROJECT SUMMARY CRC persists as a heavy burden in the United States and throughout the world with over 1.93 million new cases and 0.95 million deaths in 2020. Our study is designed to identify autonomous and non-autonomous attributes of the early adenoma and the surrounding colon that drive adenoma progression to malignancy. In this project, we mimic in mice a primed colon with pre-existing mutant clones (Aim 1) or overloaded with senescent cells (Aim 2) to determine whether these altered states enhance adenoma formation and progression. Such attributes can be detected with modern technology, so individuals could be screened to determine their personal risk of developing CRC. We propose that adenomas emerging from a primed colon can have a multi-ancestral origin being derived from multiple progenitors. Interactions among intermingled clones could alter gene expression in the participating clones in a manner that favors adenoma progression (Aim 3). Such interactions could potentially be disrupted with new chemopreventive agents or repurposed common drugs. Thus, individuals having a primed colon and consequently at a high risk of CRC could be identified, surveilled more frequently, and potentially treated to prevent cancers from forming