Abstract 2114: Targeting invasive and drug-resistant PDAC with photodynamic therapy

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is associated with an extensive desmoplastic reaction and a characteristic extracellular matrix (ECM)-rich stromal microenvironment which is a major determinant of disease progression and therapeutic response. Using 3D cell culture models of PDAC, we recently showed that an invasion-promoting ECM composition leads to differential response to chemotherapy agents and photodynamic therapy (PDT), in which cytotoxic response is triggered by light activation of a photosensitizing agent. In particular, ECM-infiltrating populations with characteristic mesenchymal phenotype display a marked increase in sensitivity to PDT (using the photosensitizer verteporfin), while the same cells exhibit increased chemoresistance. Here, motivated by these findings we systematically disentangle influences associated with the physical and biochemical properties of ECM as regulators of PDAC growth behavior and treatment response. In 3D tumor spheroids transplanted into invasion-promoting type 1 collagen gels, we use riboflavin-mediated photocrosslinking as a tool to regulate ECM stiffness (independent of its concentration), combined with high-content imaging to co-register invasive progression and differential response to chemotherapy and PDT. Increased extent of photocrosslinking correlates with increased collagen stiffness as confirmed by bulk oscillatory rheology, and is associated with a decrease in the invasive velocity (migration speed directed away from the primary transplanted spheroid) of ECM-infiltrating PDAC cells. Preliminary comparisons of PDT and oxaliplatin chemotherapy in low and high collagen crosslinking conditions show that PDT is significantly more effective than oxaliplatin in ECM-invading populations regardless of collagen stiffness. We also compare oxaliplatin chemotherapy and PDT before and after PDAC invasion into Matrigel ECM, and find that PDT efficacy is only enhanced after extensive invasion into the surrounding matrix. These results support the efficacy of PDT in targeting locally invasive PDAC while stressing the importance of elucidating how both biochemical and biophysical ECM interactions regulate therapeutic susceptibilities. Citation Format: Gwendolyn Cramer, Seyedehrojin Jafari, Hamid El-Hamidi, Dustin Jones, Jonathan Celli. Targeting invasive and drug-resistant PDAC with photodynamic therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2114. doi:10.1158/1538-7445.AM2017-2114