Fibroblasts in the Aged Pancreas Drive Pancreatic Cancer Progression-Reference-Cited by-同舟云学术

Fibroblasts in the Aged Pancreas Drive Pancreatic Cancer Progression

Published:2024-02-08 Issue:8 Volume:84 Page:1221-1236
ISSN:0008-5472
Container-title:Cancer Research
language:en
Short-container-title:

Author:

Zabransky Daniel J.¹²³^ORCID,Chhabra Yash¹²^ORCID,Fane Mitchell E.¹²⁴^ORCID,Kartalia Emma¹³^ORCID,Leatherman James M.¹³^ORCID,Hüser Laura¹²⁵⁶^ORCID,Zimmerman Jacquelyn W.¹³^ORCID,Delitto Daniel⁷⁸^ORCID,Han Song⁹^ORCID,Armstrong Todd D.¹³^ORCID,Charmsaz Soren¹,Guinn Samantha¹³^ORCID,Pramod Sneha¹²^ORCID,Thompson Elizabeth D.¹⁰^ORCID,Hughes Steven J.⁹^ORCID,O'Connell Jennifer¹¹^ORCID,Egan Josephine M.¹¹^ORCID,Jaffee Elizabeth M.¹³¹²^ORCID,Weeraratna Ashani T.¹²^ORCID

Affiliation:

1. 1Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

2. 2Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

3. 3Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland.

4. 4Fox Chase Cancer Center, Cancer Signaling and Microenvironment Program, Philadelphia, Pennsylvania.

5. 5Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.

6. 6Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.

7. 7Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, California.

8. 8Department of Surgery, Stanford University School of Medicine, Stanford, California.

9. 9Department of Surgery, University of Florida College of Medicine, Gainesville, Florida.

10. 10Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.

11. 11Diabetes Section/Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.

12. 12The Johns Hopkins Cancer Convergence Institute, Baltimore, Maryland.

Abstract

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

Funder

National Cancer Institute

Conquer Cancer Foundation

Johns Hopkins University

University of Texas MD Anderson Cancer Center

Maryland Cancer Moonshot Research Grant

National Institute of Diabetes and Digestive and Kidney Diseases

National Institute on Aging

Lustgarten Foundation

Melanoma Research Alliance

Publisher

American Association for Cancer Research (AACR)