{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/10241"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/10241","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"Deciphering AXL-Driven Molecular Mechanisms of EMT","abstract":"Pages xviii-xix are misnumbered as pages xix-xx.","abstract_html":"Pages xviii-xix are misnumbered as pages xix-xx.","abstract_has_math":false,"creators":["Arner, Emily Nicole"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Raj, Ganesh V.","Brekken, Rolf A.","Cobb, Melanie H.","Kim, James"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-01-11T20:20:50Z","date_published":"2024-01-11T20:20:50Z","updated_at":"2026-07-24T05:52:31Z","subjects":["Neoplasms","Neoplastic Processes","Proto-Oncogene Proteins","Receptor Protein-Tyrosine Kinases"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["1417098718"],"render_values":[{"text":"1417098718","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/10241","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Raj, Ganesh V.","Brekken, Rolf A.","Cobb, Melanie H.","Kim, James"]},{"key":"dc:creator","label":"Author","values":["Arner, Emily Nicole"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2024-01-11T20:20:50Z","2021-12","December 2021","2024-01-11T20:20:51Z"]},{"key":"dc:type","label":"Dc Type","values":["Thesis","text"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Neoplasms","Neoplastic Processes","Proto-Oncogene Proteins","Receptor Protein-Tyrosine Kinases"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2152.5/10241","1417098718"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Pages xviii-xix are misnumbered as pages xix-xx.","Cellular 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."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Deciphering AXL-Driven Molecular Mechanisms of EMT"]}]}],"canonical_facts":{"dc:contributor":["Raj, Ganesh V.","Brekken, Rolf A.","Cobb, Melanie H.","Kim, James"],"dc:creator":["Arner, Emily Nicole"],"dc:date":["2024-01-11T20:20:50Z","2021-12","December 2021","2024-01-11T20:20:51Z"],"dc:description":["Pages xviii-xix are misnumbered as pages xix-xx.","Cellular 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."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2152.5/10241","1417098718"],"dc:language":["en"],"dc:subject":["Neoplasms","Neoplastic Processes","Proto-Oncogene Proteins","Receptor Protein-Tyrosine Kinases"],"dc:title":["Deciphering AXL-Driven Molecular Mechanisms of EMT"],"dc:type":["Thesis","text"]},"updated_at":"2026-07-24T05:52:31Z"}