(69a) Targeting Chemoresistance in Bioengineered 3D Tumor Models: Rationally-Designed Combination Therapies Informed By Physical Stress and Heterocellular Communication

Tumor heterogeneity and drug resistance to conventional therapies remain major causes of treatment failure, recurrence and dismal survival rates for patients with advanced stage cancers. A range of cellular, architectural, and physical cues in the tumor microenvironment influence the intrinsic and acquired resistance mechanisms that lead to treatment failure. These cues include physical forces such as hydrodynamic shear stress and communication with heterocellular stromal partners, which remain understudied as determinants of tumor heterogeneity and variability in treatment response. Strategies that leverage photodynamic therapy (PDT) a photochemistry-based biophysical treatment modality to regionally target and prime stubborn tumor populations may be essential to overcoming key barriers to durable cancer management while minimizing toxicity from traditional agents. A multi-faceted approach is needed to evaluate and optimize PDT-based combination therapies, including the development of bioengineered 3D models that integrate cues such as physical forces and heterotypic cellular communication. Here the impact of hydrodynamic stress and stromal biology is evaluated in the context of ovarian cancer (OvCa). Metastatic OvCa spreads predominantly via flushing of ascites along preferential fluidic pathways and communicates with local microenvironment, including the extracellular matrix (ECM) and TECs, to form peritoneal implants. A microfluidic model that supports 3D tumor growth was developed to investigate the role of fluidic stress on the heterogeneity of metastatic OvCa. The motivation for this study was based on clinical observations that the most stubborn tumors are often found in regions such as the peritoneal gutter, a common site of resistance and recurrence, and a region that is subjected to fluidic stress from ascites. Tumor nodules cultured under flow showed increased epithelial-mesenchymal transition (EMT) compared to non-flow 3D cultures. Molecular and morphological changes consistent with EMT included a transcriptionally-regulated significant decrease in E-cadherin, a significant increase in vimentin, and significant decrease in fractal dimension, a metric adapted to quantify spindle-like morphology. A concomitant significant post-translational upregulation of epidermal growth factor receptor (EGFR) expression and activation was seen under flow. The impact of heterotypic communication between TECs and OvCa cells was investigated in a 3D model. Tumors grown in the presence of TECs were differentially susceptible to chemotherapy and benzoporphyrin derivative (BPD)-based PDT and showed increased heterogeneity in treatment response in the presence of endothelial cells. The potential value of using bioengineered models to guide customized, rationally-designed PDT-based combination regimens will be presented.