{"id":{"repo_id":"vt","oai_identifier":"oai:vtechworks.lib.vt.edu:10919/140694"},"canonical_url":"https://search.dev.ndltd.org/etd/vt/oai:vtechworks.lib.vt.edu:10919/140694","repository":{"repo_id":"vt","name":"Virginia Tech","base_url":"https://vtechworks.lib.vt.edu/oai/request"},"display":{"title":"Targeting S1PR3 to mitigate flow-enhanced invasion in the glioblastoma tumor microenvironment","abstract":"Glioblastoma is a devastating disease with few effective treatments, in part owed to the dynamic cellular and biophysical factors that influence tumor progression and therapy response. Emerging evidence has implicated pathological interstitial fluid flow, created by high intratumoral pressure relative to the healthy parenchyma, in enhancing cancer invasion. Multiple targetable molecular pathways have been identified that drive this response, but the specific pathways employed by invasive cells differs between patient glioma cell lines. To this end, we sought to identify additional therapeutic candidates mediating flow-enhanced invasion. Our previous work established a role for the G-protein coupled receptor S1PR3 in enhancing invasion under flow. Interestingly, we found this response to be mediated by the brain parenchymal cells, astrocytes and microglia. In this work, we demonstrate clinical relevance for S1PR3 as both a biomarker and therapeutic target with efficacy across a heterogeneous patient cohort. To inform therapeutic development, we investigate the intercellular mechanisms involved in S1PR3-driven invasion. We find that S1PR3 targeting significantly alters flow dynamics in vivo. We connect astrocytic S1PR3 to flow response, finding correlations with flow in both tumor-bearing and tumor-naïve settings, suggesting redundancy across neuropathologies. We build evidence that astrocytic S1P and S1PR3 mediates the response to fluid shear stress and we imply roles for S1P and flow-sensing. This work has exciting implications suggesting a dual role for S1PR3 in flow-regulation and flow-response, thus it may be a doubly effective target for minimizing flow-enhanced glioma invasion.","abstract_html":"Glioblastoma is a devastating disease with few effective treatments, in part owed to the dynamic cellular and biophysical factors that influence tumor progression and therapy response. Emerging evidence has implicated pathological interstitial fluid flow, created by high intratumoral pressure relative to the healthy parenchyma, in enhancing cancer invasion. Multiple targetable molecular pathways have been identified that drive this response, but the specific pathways employed by invasive cells differs between patient glioma cell lines. To this end, we sought to identify additional therapeutic candidates mediating flow-enhanced invasion. Our previous work established a role for the G-protein coupled receptor S1PR3 in enhancing invasion under flow. Interestingly, we found this response to be mediated by the brain parenchymal cells, astrocytes and microglia. In this work, we demonstrate clinical relevance for S1PR3 as both a biomarker and therapeutic target with efficacy across a heterogeneous patient cohort. To inform therapeutic development, we investigate the intercellular mechanisms involved in S1PR3-driven invasion. We find that S1PR3 targeting significantly alters flow dynamics in vivo. We connect astrocytic S1PR3 to flow response, finding correlations with flow in both tumor-bearing and tumor-naïve settings, suggesting redundancy across neuropathologies. We build evidence that astrocytic S1P and S1PR3 mediates the response to fluid shear stress and we imply roles for S1P and flow-sensing. This work has exciting implications suggesting a dual role for S1PR3 in flow-regulation and flow-response, thus it may be a doubly effective target for minimizing flow-enhanced glioma invasion.","abstract_has_math":false,"creators":["Howerton, Samantha Ann"],"institution":"Virginia Tech","degree_name":"Doctor of Philosophy","degree_level":"doctoral","degree_discipline":"Translational Biology, Medicine and Health","degree_department":"Graduate School","school":null,"contributors":[],"advisors":[],"committee_chairs":["Munson, Jennifer Megan"],"committee_members":["Olsen, Michelle Lynne","Purow, Benjamin","Lamouille, Samy"],"year":2026,"date_issued":"2026-01-08","date_published":"2026-01-08","updated_at":"2026-07-22T22:19:56Z","subjects":["interstitial fluid flow","glioblastoma","tumor microenvironment","transport","astrocytes","microglia","S1PR3"],"languages":["en"],"rights":["In Copyright"],"rights_urls":["http://rightsstatements.org/vocab/InC/1.0/"],"identifier_entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["vt_gsexam:45469"],"render_values":[{"text":"vt_gsexam:45469","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/10919/140694","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.committeechair","label":"Committee Chair","values":["Munson, Jennifer Megan"]},{"key":"dc:contributor.committeemember","label":"Committee Member","values":["Olsen, Michelle Lynne","Purow, Benjamin","Lamouille, Samy"]},{"key":"dc:contributor.department","label":"Department","values":["Graduate School"]},{"key":"dc:creator","label":"Author","values":["Howerton, Samantha Ann"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2026-01-09T09:01:32Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2026-01-09T09:01:32Z"]},{"key":"dc:date.issued","label":"Date","values":["2026-01-08"]},{"key":"dc:publisher","label":"Institution","values":["Virginia Tech"]},{"key":"dc:type","label":"Dc Type","values":["Dissertation"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Translational Biology, Medicine and Health"]},{"key":"thesis:degree_level","label":"Degree Level","values":["doctoral"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["Virginia Polytechnic Institute and State University"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["interstitial fluid flow","glioblastoma","tumor microenvironment","transport","astrocytes","microglia","S1PR3"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["In Copyright"]},{"key":"dc:rights.uri","label":"Rights URI","values":["http://rightsstatements.org/vocab/InC/1.0/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.other","label":"Dc Identifier Other","values":["vt_gsexam:45469"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/10919/140694"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Glioblastoma is a devastating disease with few effective treatments, in part owed to the dynamic cellular and biophysical factors that influence tumor progression and therapy response. Emerging evidence has implicated pathological interstitial fluid flow, created by high intratumoral pressure relative to the healthy parenchyma, in enhancing cancer invasion. Multiple targetable molecular pathways have been identified that drive this response, but the specific pathways employed by invasive cells differs between patient glioma cell lines. To this end, we sought to identify additional therapeutic candidates mediating flow-enhanced invasion. Our previous work established a role for the G-protein coupled receptor S1PR3 in enhancing invasion under flow. Interestingly, we found this response to be mediated by the brain parenchymal cells, astrocytes and microglia. In this work, we demonstrate clinical relevance for S1PR3 as both a biomarker and therapeutic target with efficacy across a heterogeneous patient cohort. To inform therapeutic development, we investigate the intercellular mechanisms involved in S1PR3-driven invasion. We find that S1PR3 targeting significantly alters flow dynamics in vivo. We connect astrocytic S1PR3 to flow response, finding correlations with flow in both tumor-bearing and tumor-naïve settings, suggesting redundancy across neuropathologies. We build evidence that astrocytic S1P and S1PR3 mediates the response to fluid shear stress and we imply roles for S1P and flow-sensing. This work has exciting implications suggesting a dual role for S1PR3 in flow-regulation and flow-response, thus it may be a doubly effective target for minimizing flow-enhanced glioma invasion."]},{"key":"dc:description.abstractgeneral","label":"General Abstract","values":["Glioblastoma (GBM) is a devastating disease with few effective treatments, in part owed to the diverse effects of the environment surrounding the tumor on tumor progression and sensitivity to therapeutics. Emerging evidence has described how interstitial fluid flow, or the fluid that surrounds the cells in the tissue, is increased in the tumor-adjacent region and causes tumor cells to spread into the healthy tissue where they can evade surgical removal and seed recurrent tumors. The mechanism by which tumor cells respond to increased interstitial fluid flow are therapeutically targetable, but vary between patients. With the goal of identifying additional targetable mechanisms, we demonstrated an environment-driven mechanism whereby the membrane receptor S1PR3 drives GBM spread as a result of increased tumor-adjacent flow. In this dissertation, we demonstrate that S1PR3 is a clinically relevant target, as it is expressed widely in patient samples, predicts survival, and targeting significantly reduces tumor cell spread in models that replicate the tumor-adjacent environment. To better understand this mechanism to inform therapeutic development, we demonstrate that specific brain-resident cells (astrocytes) appear to be responsible for this effect, and that this is further mediated by the binding partner for S1PR3, S1P. Interestingly, we also demonstrate that S1PR3 also promotes elevated fluid flow, presumably upstream of its effects on tumor cell spread. This work has exciting implications suggesting a dual role for S1PR3 in flow-regulation and flow-response, thus it may be a doubly effective target for minimizing tumor progression due to increased fluid flow."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Doctor of Philosophy"]},{"key":"dc:format.medium","label":"Dc Format Medium","values":["ETD"]},{"key":"dc:title","label":"Title","values":["Targeting S1PR3 to mitigate flow-enhanced invasion in the glioblastoma tumor microenvironment"]}]}],"canonical_facts":{"dc:contributor.committeechair":["Munson, Jennifer Megan"],"dc:contributor.committeemember":["Olsen, Michelle Lynne","Purow, Benjamin","Lamouille, Samy"],"dc:contributor.department":["Graduate School"],"dc:creator":["Howerton, Samantha Ann"],"dc:date.accessioned":["2026-01-09T09:01:32Z"],"dc:date.available":["2026-01-09T09:01:32Z"],"dc:date.issued":["2026-01-08"],"dc:description.abstract":["Glioblastoma is a devastating disease with few effective treatments, in part owed to the dynamic cellular and biophysical factors that influence tumor progression and therapy response. Emerging evidence has implicated pathological interstitial fluid flow, created by high intratumoral pressure relative to the healthy parenchyma, in enhancing cancer invasion. Multiple targetable molecular pathways have been identified that drive this response, but the specific pathways employed by invasive cells differs between patient glioma cell lines. To this end, we sought to identify additional therapeutic candidates mediating flow-enhanced invasion. Our previous work established a role for the G-protein coupled receptor S1PR3 in enhancing invasion under flow. Interestingly, we found this response to be mediated by the brain parenchymal cells, astrocytes and microglia. In this work, we demonstrate clinical relevance for S1PR3 as both a biomarker and therapeutic target with efficacy across a heterogeneous patient cohort. To inform therapeutic development, we investigate the intercellular mechanisms involved in S1PR3-driven invasion. We find that S1PR3 targeting significantly alters flow dynamics in vivo. We connect astrocytic S1PR3 to flow response, finding correlations with flow in both tumor-bearing and tumor-naïve settings, suggesting redundancy across neuropathologies. We build evidence that astrocytic S1P and S1PR3 mediates the response to fluid shear stress and we imply roles for S1P and flow-sensing. This work has exciting implications suggesting a dual role for S1PR3 in flow-regulation and flow-response, thus it may be a doubly effective target for minimizing flow-enhanced glioma invasion."],"dc:description.abstractgeneral":["Glioblastoma (GBM) is a devastating disease with few effective treatments, in part owed to the diverse effects of the environment surrounding the tumor on tumor progression and sensitivity to therapeutics. Emerging evidence has described how interstitial fluid flow, or the fluid that surrounds the cells in the tissue, is increased in the tumor-adjacent region and causes tumor cells to spread into the healthy tissue where they can evade surgical removal and seed recurrent tumors. The mechanism by which tumor cells respond to increased interstitial fluid flow are therapeutically targetable, but vary between patients. With the goal of identifying additional targetable mechanisms, we demonstrated an environment-driven mechanism whereby the membrane receptor S1PR3 drives GBM spread as a result of increased tumor-adjacent flow. In this dissertation, we demonstrate that S1PR3 is a clinically relevant target, as it is expressed widely in patient samples, predicts survival, and targeting significantly reduces tumor cell spread in models that replicate the tumor-adjacent environment. To better understand this mechanism to inform therapeutic development, we demonstrate that specific brain-resident cells (astrocytes) appear to be responsible for this effect, and that this is further mediated by the binding partner for S1PR3, S1P. Interestingly, we also demonstrate that S1PR3 also promotes elevated fluid flow, presumably upstream of its effects on tumor cell spread. This work has exciting implications suggesting a dual role for S1PR3 in flow-regulation and flow-response, thus it may be a doubly effective target for minimizing tumor progression due to increased fluid flow."],"dc:description.degree":["Doctor of Philosophy"],"dc:format.medium":["ETD"],"dc:identifier.other":["vt_gsexam:45469"],"dc:identifier.uri":["https://hdl.handle.net/10919/140694"],"dc:language.iso":["en"],"dc:publisher":["Virginia Tech"],"dc:rights":["In Copyright"],"dc:rights.uri":["http://rightsstatements.org/vocab/InC/1.0/"],"dc:subject":["interstitial fluid flow","glioblastoma","tumor microenvironment","transport","astrocytes","microglia","S1PR3"],"dc:title":["Targeting S1PR3 to mitigate flow-enhanced invasion in the glioblastoma tumor microenvironment"],"dc:type":["Dissertation"],"thesis:degree_discipline":["Translational Biology, Medicine and Health"],"thesis:degree_level":["doctoral"],"thesis:degree_name":["Doctor of Philosophy"],"thesis:institution_name":["Virginia Polytechnic Institute and State University"]},"updated_at":"2026-07-22T22:19:56Z"}