Abstract IA013: Age-related changes in pancreatic fibroblasts drive pancreatic cancer growth and progression

Abstract

Abstract Aging is an independent risk factor for the development of pancreatic ductal adenocarcinoma (PDAC). However, the ways in which aging alters cell populations that will ultimately comprise the PDAC tumor microenvironment (TME) are incompletely understood. PDAC tumors are highly desmoplastic, and fibroblasts alter the behavior of pancreatic cancer cells and impact treatment responses. Here, we show that normal pancreatic fibroblasts acquire tumor-promoting properties during aging using both in vitro and in vivo models. To determine if PDAC tumors may be influenced by an aged microenvironment, we performed orthotopic KPC cell injections into the pancreata of aged (>52-week-old) and young (6-8-week-old) syngeneic C57Bl/6J mice. Aged mice have significantly larger tumors, increased incidence of liver metastases, and decreased survival compared to young mice. We next queried whether aged pancreatic fibroblasts contribute to this increase in tumor growth. We generated a panel of aged (donors >55 years old) and young (donors <35 years old) normal human pancreatic fibroblasts to determine the effects of healthy aging fibroblasts on PDAC cell behavior. Conditioned media from aged human pancreatic fibroblasts significantly increases the proliferation of PDAC cells, suggesting that secreted factors produced by aged fibroblasts enhance cancer cell growth. Next, we evaluated changes in the invasiveness of PDAC cells in a 3D co-culture system with either aged or young pancreatic fibroblasts. PDAC spheroids containing cancer cells and aged fibroblasts exhibit a significant increase in invasiveness compared to those containing young fibroblasts. Aged (>52-week-old) compared to young (6-8-week-old) mouse pancreatic fibroblasts also increase the proliferation and invasiveness of KPC cells in vitro, providing evidence that aged fibroblasts may contribute to the phenotypes observed in vivo experiments using aged mouse models. In conclusion, we show that aged, non-cancer-associated pancreatic fibroblasts have the potential to promote growth, migration, and invasiveness in multiple models of pancreatic ductal adenocarcinoma. We hypothesize that factors secreted by pancreatic fibroblast change during aging and that this aged secretome may serve to establish a tumor-promoting niche for pancreatic cancer cells. Citation Format: Daniel Zabransky, Elizabeth Jaffee, Ashani Weeraratna. Age-related changes in pancreatic fibroblasts drive pancreatic cancer growth and progression [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA013.