Year: 2024
Type: article
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.
Source: Cancer Research
Authors: 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
Institutions: Johns Hopkins University, Johns Hopkins Medicine, Sidney Kimmel Comprehensive Cancer Center, Fox Chase Cancer Center, German Cancer Research Center, Heidelberg University, University Medical Centre Mannheim, Stanford Medicine, Stanford University, University of Florida Health, University of Florida, National Institutes of Health, National Institute on Aging
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Conquer Cancer Foundation, Melanoma Research Alliance, Lustgarten Foundation, American Society of Clinical Oncology, Johns Hopkins University, National Institutes of Health, University of Texas MD Anderson Cancer Center, National Institute on Aging, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Moonshot Research and Development Program, Cancer Moonshot
Awards: G1013684226, G1165598027, G13490240, A plasticity and reprogramming paradigm for therapy resistance at the single cell level, G1454999011, G1733189847, Effect of the aged microenvironment on tumor dormancy, G351856440, G3616507840, The role of MER/PROS1 in promoting stromal induced emergence from metastatic melanoma dormancy, G4657618903, G6578412251, G7002324183, G9000060776, G9000063761, G9000315831, Molecular Targets for Cancer Detection and Treatment
OpenAlex ID: W4391658069