Abstract 3638: Age-related changes in pancreatic fibroblasts promote growth and progression of pancreatic cancer
Authors: Zabransky Daniel J. , Chhabra Yash , Fane Mitchell E. , Delitto Daniel , Zimmermann Jacquelyn W. , Jaffee Elizabeth M. , Weeraratna Ashani T. 
Published: June 2022

Aging is an important independent risk factor for the development of pancreatic ductal adenocarcinoma (PDAC). However, the ways in which aging alters cell populations that comprise the PDAC tumor microenvironment (TME) and impacts tumor growth are incompletely understood. PDAC tumors are highly desmoplastic, and fibroblasts are a key component of the TME that are known to alter the behavior of cancer cells and impact treatment responses. Here, we report that normal pancreatic fibroblasts acquire tumor-promoting properties during aging and alter the properties of PDAC cells both in vitro and in vivo.

To determine if PDAC tumors may be influenced by an aged microenvironment, we performed orthotopic KPC cell injections into the pancreata of aged (&gt;64-week-old) and young (6-8-week-old) syngeneic C57Bl/6J mice. Aged mice have significantly larger tumors, increased incidence of metastases, and decreased survival compared to young mice. Tumors from aged mice also have increased neovascularization as evidenced by increased CD31 and CD105 expression. We next queried whether aged pancreatic fibroblasts may contribute to this increase in tumor growth. We have generated a panel of aged (donors &gt;55 years old) and young (donors &lt;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. We confirmed this finding using the KPC mouse cell line and conditioned media from aged (&gt;68-week-old) or young (6-8-week-old) normal mouse pancreatic fibroblasts, providing evidence that aged fibroblasts may contribute to the increased tumor growth observed in our in vivo experiments. In addition, aged fibroblast conditioned media increases the migratory potential of PDAC cells in vitro.

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.

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 is tumor-promoting. We will present these and ongoing studies examining age-related changes in pancreatic fibroblasts in the context of PDAC tumorigenesis.

Citation Format: Daniel J. Zabransky, Yash Chhabra, Mitchell E. Fane, Daniel Delitto, Jacquelyn W. Zimmermann, Elizabeth M. Jaffee, Ashani T. Weeraratna. Age-related changes in pancreatic fibroblasts promote growth and progression of 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 3638.