Tumor extracellular matrix (ECM) stiffness is correlated with the aggressiveness of breast cancer. Integrin-mediated adhesion and signaling are crucial for mammary tumorigenesis and tumor progression, in which focal adhesion kinase (FAK) - Src family kinases (SFKs) serves as a hub to relay the mechanical cues from the ECM. We have investigated the mechanisms through which integrin signaling controls mammary tumorigenesis and found that integrin-mediated mechanotransduction controls invasive growth of breast cancer cells in stiff matrices through activation of FAK and YAP. Mechanistic studies revealed that integrin signaling induces - via activation SFKs - tyrosine phosphorylation and inactivation of LATS1 and MOB1. The ensuing activation of YAP is necessary for invasive growth of HER2+ breast cancer cells. Engagement of HER2/HER3 with neuregulin impinges on SFKs to amplify activation of YAP in HER2+ breast cancer cells, suggesting that integrin-mediated mechanotransduction functions as a rheostat to regulate HER2 oncogenic signaling. Finally, administration of Dasatinib combined with Lapatinib significantly increases the efficacy of HER2 inhibition in the MMTV-Neu mouse model of HER2+ breast cancer. These findings reveal a major mechanism through which the Hippo tumor suppressive pathway is disabled in breast cancer and suggest that targeting HER2 and SFKs simultaneously may be a rational strategy in selected cases of breast cancer.
","abstract_html":"<p>Tumor extracellular matrix (ECM) stiffness is correlated with the aggressiveness of breast cancer. Integrin-mediated adhesion and signaling are crucial for mammary tumorigenesis and tumor progression, in which focal adhesion kinase (FAK) - Src family kinases (SFKs) serves as a hub to relay the mechanical cues from the ECM. We have investigated the mechanisms through which integrin signaling controls mammary tumorigenesis and found that integrin-mediated mechanotransduction controls invasive growth of breast cancer cells in stiff matrices through activation of FAK and YAP. Mechanistic studies revealed that integrin signaling induces - via activation SFKs - tyrosine phosphorylation and inactivation of LATS1 and MOB1. The ensuing activation of YAP is necessary for invasive growth of HER2+ breast cancer cells. Engagement of HER2/HER3 with neuregulin impinges on SFKs to amplify activation of YAP in HER2+ breast cancer cells, suggesting that integrin-mediated mechanotransduction functions as a rheostat to regulate HER2 oncogenic signaling. Finally, administration of Dasatinib combined with Lapatinib significantly increases the efficacy of HER2 inhibition in the MMTV-Neu mouse model of HER2+ breast cancer. These findings reveal a major mechanism through which the Hippo tumor suppressive pathway is disabled in breast cancer and suggest that targeting HER2 and SFKs simultaneously may be a rational strategy in selected cases of breast cancer.</p>","abstract_has_math":false,"creators":["Wang, Xiaobo",""],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Dissertation (PhD)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Filippo Giancotti","Pierre McCrea","Nicholas Navin"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2022,"date_issued":"2022-08-01T07:00:00Z","date_published":"2022-08-01T07:00:00Z","updated_at":"2026-07-24T05:50:09Z","subjects":["Matrix stiffness","Mechanotransduction","Integrin signaling","FAK","Src","breast cancer","HER2","tumor growth","metastasis","Cancer Biology","Cell Biology"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1199","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Filippo Giancotti","Pierre McCrea","Nicholas Navin"]},{"key":"dc:creator","label":"Author","values":["Wang, Xiaobo",""]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2023-07-29T07:00:00Z"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation (PhD)"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Matrix stiffness","Mechanotransduction","Integrin signaling","FAK","Src","breast cancer","HER2","tumor growth","metastasis","Cancer Biology","Cell Biology"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1199"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Tumor extracellular matrix (ECM) stiffness is correlated with the aggressiveness of breast cancer. Integrin-mediated adhesion and signaling are crucial for mammary tumorigenesis and tumor progression, in which focal adhesion kinase (FAK) - Src family kinases (SFKs) serves as a hub to relay the mechanical cues from the ECM. We have investigated the mechanisms through which integrin signaling controls mammary tumorigenesis and found that integrin-mediated mechanotransduction controls invasive growth of breast cancer cells in stiff matrices through activation of FAK and YAP. Mechanistic studies revealed that integrin signaling induces - via activation SFKs - tyrosine phosphorylation and inactivation of LATS1 and MOB1. The ensuing activation of YAP is necessary for invasive growth of HER2+ breast cancer cells. Engagement of HER2/HER3 with neuregulin impinges on SFKs to amplify activation of YAP in HER2+ breast cancer cells, suggesting that integrin-mediated mechanotransduction functions as a rheostat to regulate HER2 oncogenic signaling. Finally, administration of Dasatinib combined with Lapatinib significantly increases the efficacy of HER2 inhibition in the MMTV-Neu mouse model of HER2+ breast cancer. These findings reveal a major mechanism through which the Hippo tumor suppressive pathway is disabled in breast cancer and suggest that targeting HER2 and SFKs simultaneously may be a rational strategy in selected cases of breast cancer.
"]},{"key":"dc:title","label":"Title","values":["Integrin-Mediated Mechanotransduction Controls Activation of Yap and Invasive Growth of Breast Cancer"]}]}],"canonical_facts":{"dc:contributor":["Filippo Giancotti","Pierre McCrea","Nicholas Navin"],"dc:creator":["Wang, Xiaobo",""],"dc:date.available":["2023-07-29T07:00:00Z"],"dc:description.abstract":["Tumor extracellular matrix (ECM) stiffness is correlated with the aggressiveness of breast cancer. Integrin-mediated adhesion and signaling are crucial for mammary tumorigenesis and tumor progression, in which focal adhesion kinase (FAK) - Src family kinases (SFKs) serves as a hub to relay the mechanical cues from the ECM. We have investigated the mechanisms through which integrin signaling controls mammary tumorigenesis and found that integrin-mediated mechanotransduction controls invasive growth of breast cancer cells in stiff matrices through activation of FAK and YAP. Mechanistic studies revealed that integrin signaling induces - via activation SFKs - tyrosine phosphorylation and inactivation of LATS1 and MOB1. The ensuing activation of YAP is necessary for invasive growth of HER2+ breast cancer cells. Engagement of HER2/HER3 with neuregulin impinges on SFKs to amplify activation of YAP in HER2+ breast cancer cells, suggesting that integrin-mediated mechanotransduction functions as a rheostat to regulate HER2 oncogenic signaling. Finally, administration of Dasatinib combined with Lapatinib significantly increases the efficacy of HER2 inhibition in the MMTV-Neu mouse model of HER2+ breast cancer. These findings reveal a major mechanism through which the Hippo tumor suppressive pathway is disabled in breast cancer and suggest that targeting HER2 and SFKs simultaneously may be a rational strategy in selected cases of breast cancer.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1199"],"dc:subject":["Matrix stiffness","Mechanotransduction","Integrin signaling","FAK","Src","breast cancer","HER2","tumor growth","metastasis","Cancer Biology","Cell Biology"],"dc:title":["Integrin-Mediated Mechanotransduction Controls Activation of Yap and Invasive Growth of Breast Cancer"],"thesis:degree_level":["Dissertation (PhD)"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T05:50:09Z"}