Colorectal cancer (CRC) is a leading cause of cancer morbidity and mortality, yet the contributions of isolated genetic mutations within specific cell types remain poorly understood. This dissertation uses a novel Pms2cre mouse system that induces stochastic, single‑cell gene alterations at frequencies influenced by DNA mismatch repair status, modeling the random mutation events seen in human cancers. Using this approach, activation of oncogenic k‑Ras was found to give stem cells a competitive advantage, producing expanded mutant cell populations and colonic hyperplasia. In contrast, isolated loss of TgfβrII caused a competitive disadvantage and increased apoptosis along the crypt–villus axis. Additional studies showed that stabilization of c‑Myc accelerates Smad4-driven tumorigenesis, producing more aggressive gastrointestinal adenomas enriched with bone‑marrow–derived cells that may represent tumor‑initiating populations. Together, these findings demonstrate how individual genetic changes in different tissue compartments dynamically shape tumor initiation and progression, offering new insight into CRC biology.
