Desmoplastic (desmo) stroma is a prognostic marker for pancreatic cancer, yet mechanisms behind its tumorigenic effects remain poorly understood. Tumor stroma, known to act permissive to naïve cells, may exacerbate tumor progression in mutated cells, whereas normal stroma acts restrictive to even aggressively mutated cells. The mechanistic details of these responses remain unclear. Previous studies suggested that a 3D microenvironment (i.e. Matrigel) is necessary for the manifestation of the metastatic phenotype in vitro in aggressively K-Ras mutated pancreatic cancer cells. Here we describe a new 3D in vitro model to study how human pancreatic stromal extracellular matrices (ECMs) interact with pancreatic epithelial cells, how these interactions activate specific integrins and downstream signaling pathways such as PI3K and ERK1/2, and how these signaling pathways may synergize with intrinsic mutational cues to enhance progression of pancreatic cancer. Our model is comprised of physiologically relevant desmo and normal 3D cell-derived matrices as well as polyacrylamide gel-based bioengineered ECMs. The influences of cell-derived and bioengineered ECMs were tested using a series of isogenic pancreatic ductal epithelial cells (PDEC) displaying different aggressive behavior.

In preliminary studies, we established that physiological desmo ECMs are tumor permissive (i.e. induce growth and/or invasion) for all PDEC cells (especially kRas mutated cells) when compared with matched restrictive/normal ECMs. In addition, K-Ras cells cultured on stromal activated (i.e. desmo) myofibroblast-derived 3D ECMs resulted in enhanced ERK1/2 activity, similar to what had been previously observed with Matrigel based system. In order to discern distinct cellular and signal responses mediated by cell-derived ECM in the various PDEC cells, we independently modulated microenvironmental cues such as stiffness, topography, and biochemical composition in the bioengineered ECMs. Our initial data suggests that the various PDEC cells differentially respond to alterations in microenvironmental cues. We anticipate that our studies will lead to better understanding of ECM-PDEC interactions in more detail, and help in identification of novel biomarker for early detection or prevention of pancreatic cancer.

Citation Format: Ruchi Malik, Tiffany Luong, Seda Karamil, Peter Lelkes, Edna Cukierman. Desmoplastic stroma affects growth and invasion of progressively mutated human pancreatic cancer cells in vitro. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5089. doi:10.1158/1538-7445.AM2015-5089