{"id":{"repo_id":"queens","oai_identifier":"oai:queensu.scholaris.ca:1974/36268"},"canonical_url":"https://search.dev.ndltd.org/etd/queens/oai:queensu.scholaris.ca:1974/36268","repository":{"repo_id":"queens","name":"Queens University","base_url":"https://qspace.library.queensu.ca/server/oai/request"},"display":{"title":"Roles of PKR in High Grade Serous Ovarian Cancer","abstract":"High-grade serous ovarian carcinoma (HGSC) is characterized by dissemination within the peritoneal cavity, a process that critically depends on dynamic regulation of cell adhesion, migration, and invasion rather than primary tumor growth. Protein kinase R (PKR; EIF2AK2) is classically described as a stress-activated kinase within the integrated stress response (ISR); however, its role in ovarian cancer metastasis remains poorly defined. In this study, we investigated the functional contribution of PKR to HGSC progression using integrated in-vitro, in-vivo, and multi-omics approaches. Genetic depletion of PKR in HGSC cell lines resulted in marked impairment of migratory and invasive capacities, particularly under three-dimensional and extracellular matrix-engaging conditions. In-vivo, PKR-deficient cells exhibited reduced metastatic dissemination and delayed tumor progression in both immunodeficient and syngeneic mouse models. Proteomic analyses of ascites and tumor-derived samples revealed consistent enrichment of adhesion-, focal adhesion-, and extracellular matrix-related pathways, with convergence on integrin signaling, cytoskeletal organization, and matrix remodeling factors across models. Notably, the majority of shared deregulated proteins were adhesion-associated, underscoring a central role for PKR in regulating metastatic mechanics rather than proliferation or survival. Mechanistically, basal PKR phosphorylation and downstream ISR activation were not detected under steady-state conditions, and re-expression of kinase-dead PKR rescued the invasive defects observed in PKR-null cells, indicating that PKR potentially regulates HGSC invasion mostly through kinase-independent mechanisms. These findings suggest a structural or scaffolding role for PKR within adhesion-related signaling networks. Preliminary protein interaction and phosphoproteomic analyses further support the involvement of PKR in multi-protein complexes linked to cytoskeletal dynamics. Collectively, this work identifies PKR as a non-canonical regulator of adhesion-driven metastasis in HGSC and highlights functions of PKR as critical determinants of ovarian cancer dissemination.","abstract_html":"High-grade serous ovarian carcinoma (HGSC) is characterized by dissemination within the peritoneal cavity, a process that critically depends on dynamic regulation of cell adhesion, migration, and invasion rather than primary tumor growth. Protein kinase R (PKR; EIF2AK2) is classically described as a stress-activated kinase within the integrated stress response (ISR); however, its role in ovarian cancer metastasis remains poorly defined. In this study, we investigated the functional contribution of PKR to HGSC progression using integrated in-vitro, in-vivo, and multi-omics approaches. Genetic depletion of PKR in HGSC cell lines resulted in marked impairment of migratory and invasive capacities, particularly under three-dimensional and extracellular matrix-engaging conditions. In-vivo, PKR-deficient cells exhibited reduced metastatic dissemination and delayed tumor progression in both immunodeficient and syngeneic mouse models. Proteomic analyses of ascites and tumor-derived samples revealed consistent enrichment of adhesion-, focal adhesion-, and extracellular matrix-related pathways, with convergence on integrin signaling, cytoskeletal organization, and matrix remodeling factors across models. Notably, the majority of shared deregulated proteins were adhesion-associated, underscoring a central role for PKR in regulating metastatic mechanics rather than proliferation or survival. Mechanistically, basal PKR phosphorylation and downstream ISR activation were not detected under steady-state conditions, and re-expression of kinase-dead PKR rescued the invasive defects observed in PKR-null cells, indicating that PKR potentially regulates HGSC invasion mostly through kinase-independent mechanisms. These findings suggest a structural or scaffolding role for PKR within adhesion-related signaling networks. Preliminary protein interaction and phosphoproteomic analyses further support the involvement of PKR in multi-protein complexes linked to cytoskeletal dynamics. Collectively, this work identifies PKR as a non-canonical regulator of adhesion-driven metastasis in HGSC and highlights functions of PKR as critical determinants of ovarian cancer dissemination.","abstract_has_math":false,"creators":["Afzali, Farzaneh"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":"Biomedical and Molecular Sciences","school":null,"contributors":[],"advisors":["Postovit, Lynne-Marie"],"committee_chairs":[],"committee_members":[],"year":2026,"date_issued":"2026-04-15","date_published":"2026-04-15","updated_at":"2026-07-27T20:35:37Z","subjects":["ovarian_cancer","PKR","metastasis"],"languages":["eng"],"rights":["Attribution-NonCommercial-NoDerivatives 4.0 International"],"rights_urls":["http://creativecommons.org/licenses/by-nc-nd/4.0/"],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/1974/36268","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.department","label":"Department","values":["Biomedical and Molecular Sciences"]},{"key":"dc:contributor.supervisor","label":"Supervisor","values":["Postovit, Lynne-Marie"]},{"key":"dc:creator","label":"Author","values":["Afzali, Farzaneh"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2026-04-15T15:14:32Z"]},{"key":"dc:date.issued","label":"Date","values":["2026-04-15"]},{"key":"dc:type","label":"Dc Type","values":["thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["ovarian_cancer","PKR","metastasis"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["Attribution-NonCommercial-NoDerivatives 4.0 International"]},{"key":"dc:rights.uri","label":"Rights URI","values":["http://creativecommons.org/licenses/by-nc-nd/4.0/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/1974/36268"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["High-grade serous ovarian carcinoma (HGSC) is characterized by dissemination within the peritoneal cavity, a process that critically depends on dynamic regulation of cell adhesion, migration, and invasion rather than primary tumor growth. Protein kinase R (PKR; EIF2AK2) is classically described as a stress-activated kinase within the integrated stress response (ISR); however, its role in ovarian cancer metastasis remains poorly defined. In this study, we investigated the functional contribution of PKR to HGSC progression using integrated in-vitro, in-vivo, and multi-omics approaches. Genetic depletion of PKR in HGSC cell lines resulted in marked impairment of migratory and invasive capacities, particularly under three-dimensional and extracellular matrix-engaging conditions. In-vivo, PKR-deficient cells exhibited reduced metastatic dissemination and delayed tumor progression in both immunodeficient and syngeneic mouse models. Proteomic analyses of ascites and tumor-derived samples revealed consistent enrichment of adhesion-, focal adhesion-, and extracellular matrix-related pathways, with convergence on integrin signaling, cytoskeletal organization, and matrix remodeling factors across models. Notably, the majority of shared deregulated proteins were adhesion-associated, underscoring a central role for PKR in regulating metastatic mechanics rather than proliferation or survival. Mechanistically, basal PKR phosphorylation and downstream ISR activation were not detected under steady-state conditions, and re-expression of kinase-dead PKR rescued the invasive defects observed in PKR-null cells, indicating that PKR potentially regulates HGSC invasion mostly through kinase-independent mechanisms. These findings suggest a structural or scaffolding role for PKR within adhesion-related signaling networks. Preliminary protein interaction and phosphoproteomic analyses further support the involvement of PKR in multi-protein complexes linked to cytoskeletal dynamics. Collectively, this work identifies PKR as a non-canonical regulator of adhesion-driven metastasis in HGSC and highlights functions of PKR as critical determinants of ovarian cancer dissemination."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["PhD"]},{"key":"dc:title","label":"Title","values":["Roles of PKR in High Grade Serous Ovarian Cancer"]}]}],"canonical_facts":{"dc:contributor.department":["Biomedical and Molecular Sciences"],"dc:contributor.supervisor":["Postovit, Lynne-Marie"],"dc:creator":["Afzali, Farzaneh"],"dc:date.accessioned":["2026-04-15T15:14:32Z"],"dc:date.issued":["2026-04-15"],"dc:description.abstract":["High-grade serous ovarian carcinoma (HGSC) is characterized by dissemination within the peritoneal cavity, a process that critically depends on dynamic regulation of cell adhesion, migration, and invasion rather than primary tumor growth. Protein kinase R (PKR; EIF2AK2) is classically described as a stress-activated kinase within the integrated stress response (ISR); however, its role in ovarian cancer metastasis remains poorly defined. In this study, we investigated the functional contribution of PKR to HGSC progression using integrated in-vitro, in-vivo, and multi-omics approaches. Genetic depletion of PKR in HGSC cell lines resulted in marked impairment of migratory and invasive capacities, particularly under three-dimensional and extracellular matrix-engaging conditions. In-vivo, PKR-deficient cells exhibited reduced metastatic dissemination and delayed tumor progression in both immunodeficient and syngeneic mouse models. Proteomic analyses of ascites and tumor-derived samples revealed consistent enrichment of adhesion-, focal adhesion-, and extracellular matrix-related pathways, with convergence on integrin signaling, cytoskeletal organization, and matrix remodeling factors across models. Notably, the majority of shared deregulated proteins were adhesion-associated, underscoring a central role for PKR in regulating metastatic mechanics rather than proliferation or survival. Mechanistically, basal PKR phosphorylation and downstream ISR activation were not detected under steady-state conditions, and re-expression of kinase-dead PKR rescued the invasive defects observed in PKR-null cells, indicating that PKR potentially regulates HGSC invasion mostly through kinase-independent mechanisms. These findings suggest a structural or scaffolding role for PKR within adhesion-related signaling networks. Preliminary protein interaction and phosphoproteomic analyses further support the involvement of PKR in multi-protein complexes linked to cytoskeletal dynamics. Collectively, this work identifies PKR as a non-canonical regulator of adhesion-driven metastasis in HGSC and highlights functions of PKR as critical determinants of ovarian cancer dissemination."],"dc:description.degree":["PhD"],"dc:identifier.uri":["https://hdl.handle.net/1974/36268"],"dc:language.iso":["eng"],"dc:rights":["Attribution-NonCommercial-NoDerivatives 4.0 International"],"dc:rights.uri":["http://creativecommons.org/licenses/by-nc-nd/4.0/"],"dc:subject":["ovarian_cancer","PKR","metastasis"],"dc:title":["Roles of PKR in High Grade Serous Ovarian Cancer"],"dc:type":["thesis"]},"updated_at":"2026-07-27T20:35:37Z"}