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, Samantha Guinn, Sneha Pramod, Elizabeth D. Thompson, Steven J. Hughes, Jennifer O'Connell, Josephine M. Egan, Elizabeth M. Jaffee, Ashani T. Weeraratna

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish
Pages (from-to)1221-1236
Number of pages16
JournalCancer Research
Volume84
Issue number8
DOIs
StatePublished - Apr 15 2024

Keywords

  • Animals
  • Cancer-Associated Fibroblasts/pathology
  • Cell Line, Tumor
  • Fibroblasts/pathology
  • Growth Differentiation Factor 15/genetics
  • Mice
  • Pancreas/pathology
  • Pancreatic Neoplasms/pathology
  • Proto-Oncogene Proteins c-akt
  • Tumor Microenvironment

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