Abstract C005: APC Mutation-induced Retardation of Tissue Renewal is Fundamental to Colon Tumorigenesis

Abstract Every tissue-type has a specific rate of renewal that maintains its structural integrity throughout life. Our Aim is to understand how changes in the rate of tissue renewal underlie colon cancer development. For colon tumorigenesis, we measured kinetic changes that occur in human and murine intestinal crypts having different APC genotypes. Quantitative histologic mapping showed that transitions between the different cell phenotypes are progressively delayed along the axis of APC mutant crypts. The extent of this delay was greater in homozygous than in heterozygous APC-mutant crypts. In ApcMin/+ mouse intestine, clearance of BrdU from pre-labeled crypts was significantly slower than in wildtype-Apc mice. Kinetic modeling showed that retarded crypt renewal increases the number of cell divisions required for differentiation which causes incomplete differentiation and progressive expansion of the proliferative cell populations. Thus, our findings reveal that APC mutation-induced retardation of tissue renewal is a key driver mechanism in colon tumor initiation and development. Citation Format: Bruce Boman. APC Mutation-induced Retardation of Tissue Renewal is Fundamental to Colon Tumorigenesis abstract. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31 (23Suppl): Abstract nr C005.