Colon Cancer Initiation and Progression

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dc.contributor.advisorShay, Jerry W.en
dc.creatorEskiocak, Uguren
dc.date.accessioned2012-07-20T18:56:37Z
dc.date.available2012-07-20T18:56:37Z
dc.date.issued2012-07-20
dc.description.abstractLandmark cancer genome resequencing efforts are leading to the identification of mutated genes in many types of cancer.The extreme diversity of mutations being detected presents significant challenges to subdivide causal from coincidental mutations in order to elucidate how disrupted regulatory networks drive cancer processes. Given that a common early perturbation in solid tumor initiation is bypass of matrix-dependent proliferation restraints we sought to functionally interrogate candidate colorectal cancer genes (CAN-genes) to identify driver tumor-suppressors. We have developed an isogenic human colonic epithelial cell (HCEC) model to identify suppressors of anchorage-independent growth by conducting a soft agar based shRNA screen within the cohort of CAN-genes. Remarkably, depletion of 65 of the 151 CAN-genes tested collaborated with ectopic expression of K-RASV12 and/or TP53 knockdown to promote anchorage-independent proliferation of HCECs. In contrast only 5 out of 362 random shRNAs (1.4%) enhanced soft agar growth. We have identified additional members of an extensive gene network specifying matrix-dependent proliferation, by constructing an interaction map of these confirmed progression suppressors with the ~700 mutated genes that were excluded from CAN-genes, and experimentally verifying soft-agar growth enhancement in response to depletion of a subset of these genes. Collectively, this study revealed a profound diversity of nodes within a fundamental tumor suppressor network that are susceptible to perturbation leading to enhanced cell-autonomous anchorage-independent proliferative fitness. Tumor suppressor network fragility as a paradigm within this and other regulatory systems perturbed in cancer, could in large part, account for the heterogeneity of somatic mutations detected in tumors.en
dc.identifier.oclc809539702
dc.identifier.urihttps://hdl.handle.net/2152.5/1023
dc.language.isoenen
dc.subjectColorectal Neoplasmsen
dc.subjectMutationen
dc.titleColon Cancer Initiation and Progressionen
dc.typeThesisen
dc.type.materialTexten
thesis.date.available2012-01-14
thesis.degree.departmentGraduate School of Biomedical Sciencesen
thesis.degree.disciplineCancer Biologyen
thesis.degree.grantorUT Southwestern Medical Centeren
thesis.degree.levelDoctoralen
thesis.degree.nameDoctor of Philosophyen

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