000000410 001__ 410
000000410 005__ 20260303145320.0
000000410 0247_ $$2DOI$$a10.6083/M4W66HR9
000000410 037__ $$aETD
000000410 245__ $$aStochastic gene alterations for the study of intestinal homeostasis and cancer
000000410 260__ $$bOregon Health and Science University
000000410 269__ $$a2009
000000410 336__ $$aDissertation
000000410 502__ $$bPh.D.
000000410 520__ $$aColorectal cancer (CRC) is a leading cause of cancer morbidity and mortality, yet the contributions of isolated genetic mutations within specific cell types remain poorly understood. This dissertation uses a novel Pms2cre mouse system that induces stochastic, single‑cell gene alterations at frequencies influenced by DNA mismatch repair status, modeling the random mutation events seen in human cancers. Using this approach, activation of oncogenic k‑Ras was found to give stem cells a competitive advantage, producing expanded mutant cell populations and colonic hyperplasia. In contrast, isolated loss of TgfβrII caused a competitive disadvantage and increased apoptosis along the crypt–villus axis. Additional studies showed that stabilization of c‑Myc accelerates Smad4-driven tumorigenesis, producing more aggressive gastrointestinal adenomas enriched with bone‑marrow–derived cells that may represent tumor‑initiating populations. Together, these findings demonstrate how individual genetic changes in different tissue compartments dynamically shape tumor initiation and progression, offering new insight into CRC biology.
000000410 540__ $$fCC BY
000000410 542__ $$fIn copyright - single owner
000000410 650__ $$aIntestinal Neoplasms$$020955
000000410 650__ $$aGenetics$$019472
000000410 650__ $$aStochastic Processes$$026424
000000410 650__ $$aMice$$036842
000000410 650__ $$aDNA Mismatch Repair$$037646
000000410 650__ $$aMice$$036842
000000410 650__ $$aColorectal Neoplasms$$028197
000000410 691__ $$aSchool of Medicine$$041369
000000410 692__ $$aDepartment of Molecular and Medical Genetics$$041428
000000410 7001_ $$aMiller, Ashleigh$$uOregon Health and Science University$$041354
000000410 7201_ $$aLiskay, R. Michael$$uOregon Health and Science University$$041354$$7Personal$$eAdvisor$$eMentor
000000410 8564_ $$946fa574b-3c3f-479e-97fa-b6d33a264423$$s11339077$$uhttps://digitalcollections.ohsu.edu/record/410/files/411_etd.pdf$$ePublic$$227ab1a37c6cb3a212f356fafe301bbe3$$31
000000410 905__ $$a/rest/prod/44/55/8d/29/44558d29f
000000410 909CO $$ooai:digitalcollections.ohsu.edu:410$$pstudent-work
000000410 956__ $$aGet Accessible Copy$$uhttps://ohsu.libwizard.com/f/requestaccessibledocument
000000410 980__ $$aTheses and Dissertations