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

doi:10.1158/0008-5472.CAN-24-0086

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 journal › Article › peer-review

3 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 language	English
Pages (from-to)	1221-1236
Number of pages	16
Journal	Cancer Research
Volume	84
Issue number	8
DOIs	https://doi.org/10.1158/0008-5472.CAN-24-0086
State	Published - 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1158/0008-5472.CAN-24-0086

Cite this

Zabransky, D. J., Chhabra, Y., Fane, M. E., Kartalia, E., Leatherman, J. M., Hüser, L., Zimmerman, J. W., Delitto, D., Han, S., Armstrong, T. D., Guinn, S., Pramod, S., Thompson, E. D., Hughes, S. J., O'Connell, J., Egan, J. M., Jaffee, E. M., & Weeraratna, A. T. (2024). Fibroblasts in the aged pancreas drive pancreatic cancer progression. Cancer Research, 84(8), 1221-1236. https://doi.org/10.1158/0008-5472.CAN-24-0086

@article{2ff86c3895c44c9b877d18ae99281d3c,

title = "Fibroblasts in the aged pancreas drive pancreatic cancer progression",

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.",

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",

author = "Zabransky, {Daniel J.} and Yash Chhabra and Fane, {Mitchell E.} and Emma Kartalia and Leatherman, {James M.} and Laura H{\"u}ser and Zimmerman, {Jacquelyn W.} and Daniel Delitto and Song Han and Armstrong, {Todd D.} and Samantha Guinn and Sneha Pramod and Thompson, {Elizabeth D.} and Hughes, {Steven J.} and Jennifer O'Connell and Egan, {Josephine M.} and Jaffee, {Elizabeth M.} and Weeraratna, {Ashani T.}",

note = "{\textcopyright}2024 American Association for Cancer Research.",

year = "2024",

month = apr,

day = "15",

doi = "10.1158/0008-5472.CAN-24-0086",

language = "English",

volume = "84",

pages = "1221--1236",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

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Zabransky, DJ, Chhabra, Y , Fane, ME, Kartalia, E, Leatherman, JM, Hüser, L, Zimmerman, JW, Delitto, D, Han, S, Armstrong, TD, Guinn, S, Pramod, S, Thompson, ED, Hughes, SJ, O'Connell, J, Egan, JM, Jaffee, EM & Weeraratna, AT 2024, 'Fibroblasts in the aged pancreas drive pancreatic cancer progression', Cancer Research, vol. 84, no. 8, pp. 1221-1236. https://doi.org/10.1158/0008-5472.CAN-24-0086

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 - Hüser, Laura

AU - Zimmerman, Jacquelyn W.

AU - Delitto, Daniel

AU - Han, Song

AU - Armstrong, Todd D.

AU - Guinn, Samantha

AU - Pramod, Sneha

AU - Thompson, Elizabeth D.

AU - Hughes, Steven J.

AU - O'Connell, Jennifer

AU - Egan, Josephine M.

AU - Jaffee, Elizabeth M.

AU - Weeraratna, Ashani T.

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. 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.

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. 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.

KW - Animals

KW - Cancer-Associated Fibroblasts/pathology

KW - Cell Line, Tumor

KW - Fibroblasts/pathology

KW - Growth Differentiation Factor 15/genetics

KW - Mice

KW - Pancreas/pathology

KW - Pancreatic Neoplasms/pathology

KW - Proto-Oncogene Proteins c-akt

KW - Tumor Microenvironment

UR - https://doi.org/10.1158/0008-5472.CAN-24-0086

UR - https://pubmed.ncbi.nlm.nih.gov/38330147/

UR - http://www.scopus.com/inward/record.url?scp=85190754269&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-24-0086

DO - 10.1158/0008-5472.CAN-24-0086

M3 - Article

C2 - 38330147

SN - 0008-5472

VL - 84

SP - 1221

EP - 1236

JO - Cancer Research

JF - Cancer Research

IS - 8

ER -

Fibroblasts in the aged pancreas drive pancreatic cancer progression

Abstract

Keywords

UN SDGs

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Findings in Pancreatic Cancer Reported from Johns Hopkins University School of Medicine (Fibroblasts in the aged pancreas drive pancreatic cancer progression)

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Fibroblasts in the aged pancreas drive pancreatic cancer progression

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Press/Media

Findings in Pancreatic Cancer Reported from Johns Hopkins University School of Medicine (Fibroblasts in the aged pancreas drive pancreatic cancer progression)

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