TY - JOUR
T1 - Fibroblasts in the Aged Pancreas Drive Pancreatic Cancer Progression
AU - Zabransky, Daniel J.
AU - Chhabra, Yash
AU - Fane, Mitchell E.
AU - Kartalia, Emma
AU - Leatherman, James M.
AU - Huser, Laura
AU - Zimmerman, Jacquelyn W.
AU - Delitto, Daniel
AU - Han, Song
AU - Armstrong, Todd D.
AU - Charmsaz, Soren
AU - Guinn, Samantha
AU - Pramod, Sneha
AU - Thompson, Elizabeth D.
AU - Hughes, Steven J.
AU - Connell, Jennifer O.
AU - Egan, Josephine M.
AU - Jaffee, Elizabeth M.
AU - Weeraratna, Ashani T.
N1 - Publisher Copyright:
©2024 American Association for Cancer Research.
PY - 2024/4/15
Y1 - 2024/4/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-24-0086
DO - 10.1158/0008-5472.CAN-24-0086
M3 - Article
C2 - 38330147
AN - SCOPUS:85190754269
SN - 0008-5472
VL - 84
SP - 1221
EP - 1236
JO - Cancer Research
JF - Cancer Research
IS - 8
ER -