Deciphering AXL-Driven Molecular Mechanisms of EMT

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dc.contributor.advisorRaj, Ganesh V.en
dc.contributor.committeeMemberBrekken, Rolf A.en
dc.contributor.committeeMemberCobb, Melanie H.en
dc.contributor.committeeMemberKim, Jamesen
dc.creatorArner, Emily Nicoleen
dc.creator.orcid0000-0003-3589-8829
dc.date.accessioned2024-01-11T20:20:50Z
dc.date.available2024-01-11T20:20:50Z
dc.date.created2021-12
dc.date.issuedDecember 2021
dc.date.submittedDecember 2021
dc.date.updated2024-01-11T20:20:51Z
dc.descriptionPages xviii-xix are misnumbered as pages xix-xx.en
dc.description.abstractCellular plasticity, a feature associated with epithelial-to-mesenchymal transition (EMT), contributes to tumor cell survival, migration, invasion, and therapy resistance. Across human cancer, tumors that are high grade, poorly differentiated, and have undergone EMT carry a worse prognosis with a high likelihood of metastasis and poor outcome. AXL, a receptor tyrosine kinase (RTK), drives EMT and is implicated in tumor progression, metastasis, and therapy resistance in multiple cancer types including pancreatic cancer (PDA) and breast cancer. We investigated the contribution of TANK-binding kinase 1 (TBK1) to PDA progression and report that TBK1 supports the growth and metastasis of KRAS-mutant PDA by driving an epithelial plasticity program in tumor cells that enhances invasive and metastatic capacity. We identified that the receptor tyrosine kinase AXL induces TBK1 activity in a Ras-RalB-dependent manner. Furthermore, we report that AXL activation stimulates TBK1 binding and phosphorylation of the specific AKT isoform, AKT3 at S472. Activation of AKT3 drives the binding of AKT3 to slug/snail, where the complex is translocated into the nucleus. The binding of AKT3 to slug/snail protects the EMT-TFs from proteasomal degradation thus leading to an increase in EMT. These data suggest that the translocation of AKT3 to the nucleus is required for AXL-driven EMT and metastasis. Congruently, nuclear AKT3 expression correlates with worse outcome in aggressive breast. These results suggest that selective AKT3 targeting represents a novel therapeutic avenue for treating aggressive cancer that may avoid toxicity associated with pan-AKT inhibition. Additionally, our findings suggest that interruption of the AXL-TBK1-AKT3 cascade, has potential therapeutic efficacy in AXL positive metastatic cancer.en
dc.format.mimetypeapplication/pdfen
dc.identifier.oclc1417098718
dc.identifier.urihttps://hdl.handle.net/2152.5/10241
dc.language.isoenen
dc.subjectNeoplasmsen
dc.subjectNeoplastic Processesen
dc.subjectProto-Oncogene Proteinsen
dc.subjectReceptor Protein-Tyrosine Kinasesen
dc.titleDeciphering AXL-Driven Molecular Mechanisms of EMTen
dc.typeThesisen
dc.type.materialtexten
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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