Flow-induced Shear Stress Confers Resistance to Carboplatin in an Adherent Three-Dimensional Model for Ovarian Cancer: A Role for EGFR-Targeted Photoimmunotherapy Informed by Physical Stress

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dc.contributor.authorNath, Shubhankar
dc.contributor.authorPigula, Michael
dc.contributor.authorKhan, Amjad P.
dc.contributor.authorHanna, William
dc.contributor.authorRuhi, Mustafa Kemal
dc.contributor.authorDehkordy, Farzaneh Mahmoodpoor
dc.contributor.authorPushpavanam, Karthik
dc.contributor.authorRege, Kaushal
dc.contributor.authorMoore, Kaitlin
dc.contributor.authorTsujita, Yujiro
dc.contributor.authorConrad, Christina
dc.contributor.authorInci, Faith
dc.contributor.authordel Carmen, Marcela G.
dc.contributor.authorFranco, Walfre
dc.contributor.authorCelli, Jonathan P.
dc.contributor.authorDemirci, Utkan
dc.contributor.authorHasan, Tayyaba
dc.contributor.authorHuang, Huang-Chiao
dc.contributor.authorRizvi, Imran
dc.date.accessioned2023-11-09T19:34:37Z
dc.date.available2023-11-09T19:34:37Z
dc.date.issued2020-03-28
dc.description.abstractA key reason for the persistently grim statistics associated with metastatic ovarian cancer is resistance to conventional agents, including platinum-based chemotherapies. A major source of treatment failure is the high degree of genetic and molecular heterogeneity, which results from significant underlying genomic instability, as well as stromal and physical cues in the microenvironment. Ovarian cancer commonly disseminates via transcoelomic routes to distant sites, which is associated with the frequent production of malignant ascites, as well as the poorest prognosis. In addition to providing a cell and protein-rich environment for cancer growth and progression, ascitic fluid also confers physical stress on tumors. An understudied area in ovarian cancer research is the impact of fluid shear stress on treatment failure. Here, we investigate the effect of fluid shear stress on response to platinum-based chemotherapy and the modulation of molecular pathways associated with aggressive disease in a perfusion model for adherent 3D ovarian cancer nodules. Resistance to carboplatin is observed under flow with a concomitant increase in the expression and activation of the epidermal growth factor receptor (EGFR) as well as downstream signaling members mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase (ERK). The uptake of platinum by the 3D ovarian cancer nodules was significantly higher in flow cultures compared to static cultures. A downregulation of phospho-focal adhesion kinase (p-FAK), vinculin, and phospho-paxillin was observed following carboplatin treatment in both flow and static cultures. Interestingly, low-dose anti-EGFR photoimmunotherapy (PIT), a targeted photochemical modality, was found to be equally effective in ovarian tumors grown under flow and static conditions. These findings highlight the need to further develop PIT-based combinations that target the EGFR, and sensitize ovarian cancers to chemotherapy in the context of flow-induced shear stress.
dc.description.urihttps://doi.org/10.3390/jcm9040924
dc.identifierhttps://doi.org/10.13016/dspace/xtvk-bnpk
dc.identifier.citationNath, S.; Pigula, M.; Khan, A.P.; Hanna, W.; Ruhi, M.K.; Dehkordy, F.M.; Pushpavanam, K.; Rege, K.; Moore, K.; Tsujita, Y.; et al. Flow-induced Shear Stress Confers Resistance to Carboplatin in an Adherent Three-Dimensional Model for Ovarian Cancer: A Role for EGFR-Targeted Photoimmunotherapy Informed by Physical Stress. J. Clin. Med. 2020, 9, 924.
dc.identifier.urihttp://hdl.handle.net/1903/31348
dc.language.isoen_US
dc.publisherMDPI
dc.relation.isAvailableAtA. James Clark School of Engineeringen_us
dc.relation.isAvailableAtFischell Department of Bioengineeringen_us
dc.relation.isAvailableAtDigital Repository at the University of Marylanden_us
dc.relation.isAvailableAtUniversity of Maryland (College Park, MD)en_us
dc.subjectovarian cancer
dc.subjectepidermal growth factor receptor (EGFR)
dc.subjectmitogen-activated protein kinase/extracellular signal-regulated kinase (MEK)
dc.subjectextracellular signal-regulated kinase (ERK)
dc.subjectchemoresistance
dc.subjectfluid shear stress
dc.subjectascites
dc.subjectperfusion model
dc.subjectphotoimmunotherapy (PIT)
dc.subjectphotodynamic therapy (PDT)
dc.subjectcarboplatin
dc.titleFlow-induced Shear Stress Confers Resistance to Carboplatin in an Adherent Three-Dimensional Model for Ovarian Cancer: A Role for EGFR-Targeted Photoimmunotherapy Informed by Physical Stress
dc.typeArticle
local.equitableAccessSubmissionNo

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