Fibroblasts in the Aged Pancreas Drive Pancreatic Cancer Progression
Daniel J. Zabransky, Yash Chhabra, Mitchell E. Fane, Emma Kartalia, James M. Leatherman, Laura Hüser, Jacquelyn W. Zimmerman, Daniel Delitto, Song Han, Todd D. Armstrong, Soren Charmsaz, Samantha Guinn, Sneha Pramod, Elizabeth D. Thompson, Steven J. Hughes, Jennifer O’Connell, Josephine M. Egan, Elizabeth M. Jaffee, Ashani T. Weeraratna
Abstract
Pancreatic cancer is more prevalent in older individuals and often carries a poorer prognosis for them. The relationship between the microenvironment and pancreatic cancer is multifactorial, and age-related changes in nonmalignant cells in the tumor microenvironment may play a key role in promoting cancer aggressiveness. Because fibroblasts have profound impacts on pancreatic cancer progression, we investigated whether age-related changes in pancreatic fibroblasts influence cancer growth and metastasis. Proteomics analysis revealed that aged fibroblasts secrete different factors than young fibroblasts, including increased growth/differentiation factor 15 (GDF-15). Treating young mice with GDF-15 enhanced tumor growth, whereas aged GDF-15 knockout mice showed reduced tumor growth. GDF-15 activated AKT, rendering tumors sensitive to AKT inhibition in an aged but not young microenvironment. These data provide evidence for how aging alters pancreatic fibroblasts and promotes tumor progression, providing potential therapeutic targets and avenues for studying pancreatic cancer while accounting for the effects of aging. SIGNIFICANCE: Aged pancreatic fibroblasts secrete GDF-15 and activate AKT signaling to promote pancreatic cancer growth, highlighting the critical role of aging-mediated changes in the pancreatic cancer microenvironment in driving tumor progression. See related commentary by Isaacson et al., p. 1185.