Abstract 6030: Reconstructed Pancreas: A tumor-specific 3D culture platform for accurate evaluation of therapeutic agents in pancreatic cancer

Abstract

Abstract As it is rarely diagnosed early, the prognosis for patients with pancreatic cancer is grim. The average 5-year survival rate is 10% and only 3% for patients with metastatic disease. Partially because of the late diagnosis and partially because of its biology, treatment options for patients with pancreatic cancer are limited and new interventions are desperately needed to gain the upper hand on this disease. One of the challenges faced by the drug developers looking for agents against pancreatic cancer is capturing the elements of the tumor microenvironment, which provides both a physical barrier and stroma-driven resistance to therapeutic agents. We developed a tumor-specific Reconstructed Pancreas (r-Pancreas) model, which recapitulates the cellular and extracellular elements of the pancreatic tumor microenvironment. In the r-Pancreas model, tumor and stromal cells are embedded in a dense extracellular matrix (ECM) characteristic of pancreatic tumors. Pancreatic tumor cell lines, MiaPaca-2, Panc-1, and Bx-PC3 robustly proliferate and survive for 14 days providing an extended therapeutic window to test anti-tumor compounds in the context of pancreas-specific ECM. Mimicking clinical response pancreatic tumor cells grown in r-Pancreas are sensitive to gemcitabine (IC50=0.4-0.6µM) but are resistant to 5-fluorouracil (IC50=not reached). These cell lines were also 5-10 times less sensitive to gemcitabine when cultured in Matrigel (IC50=3-6µM), soft ECM rich in collagen IV/laminin neither of which is abundant in the pancreas. Incorporating a collagen-rich capsule into the r-Pancreas model further expands its physiological relevance as human pancreatic tumors have been shown to have an outer layer of stiff ECM, which provides a physical barrier that impedes drug access to the tumor. Finally, establishing a co-culture of pancreatic tumor cell lines with primary pancreatic stromal cells creates a complete model enabling testing of novel therapeutic agents within the pancreatic tumor microenvironment. Taken together these data suggest that to be clinically useful in vitro tumor models not only need to allow for 3-dimensional cell growth but also have to incorporate tumor-specific elements of the microenvironment. Citation Format: Eleanore J. Kirshner, Aayushi Ahlawat, Matthew Ryou. Reconstructed Pancreas: A tumor-specific 3D culture platform for accurate evaluation of therapeutic agents in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6030.