Targeting S1PR3 to mitigate flow-enhanced invasion in the glioblastoma tumor microenvironment

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.

Name thesis:degree_name

Doctor of Philosophy

Level thesis:degree_level

doctoral

Discipline thesis:degree_discipline

Translational Biology, Medicine and Health

Department dc:contributor.department

Graduate School

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2026

Author dc:creator

• Howerton, Samantha Ann

Chair dc:contributor.committeechair

• Munson, Jennifer Megan

Committee members dc:contributor.committeemember

• Olsen, Michelle Lynne
• Purow, Benjamin
• Lamouille, Samy

• interstitial fluid flow
• glioblastoma
• tumor microenvironment
• transport
• astrocytes
• microglia
• S1PR3

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

en

Dc Identifier Other

vt_gsexam:45469

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/140694