Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer

Jad I. Belle; Devashish Sen; John M. Baer; Xiuting Liu; Varintra E. Lander; Jiayu Ye; Blake E. Sells; Brett L. Knolhoff; Ahmad Faiz; Liang I. Kang; Guhan Qian; Ryan C. Fields; Li Ding; Hyun Kim; Paolo P. Provenzano; Sheila A. Stewart; David G. Denardo

doi:10.1158/2159-8290.CD-23-0428

Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer

Jad I. Belle, Devashish Sen, John M. Baer, Xiuting Liu, Varintra E. Lander, Jiayu Ye, Blake E. Sells, Brett L. Knolhoff, Ahmad Faiz, Liang I. Kang, Guhan Qian, Ryan C. Fields, Li Ding, Hyun Kim, Paolo P. Provenzano, Sheila A. Stewart, David G. Denardo

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Pancreatic ductal adenocarcinoma (PDAC) therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with an abundance of cancerassociated fibroblasts (CAF). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAF) in mouse and human PDAC. These SenCAFs are a phenotypically distinct subset of myofibroblastic CAFs that localize near tumor ducts and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we used an LSL-KRAS^G12D;p53^flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Depletion of senescent stromal cells in genetic and pharmacologic PDAC models relieved immune suppression by macrophages, delayed tumor progression, and increased responsiveness to chemotherapy. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction. Significance: CAF heterogeneity in PDAC remains poorly understood. In this study, we identify a novel subpopulation of senescent CAFs that promotes PDAC progression and immunosuppression. Targeting CAF senescence in combination therapies could increase tumor vulnerability to chemo or immunotherapy.

Original language	English
Pages (from-to)	1324-1355
Number of pages	32
Journal	Cancer discovery
Volume	14
Issue number	7
DOIs	https://doi.org/10.1158/2159-8290.CD-23-0428
State	Published - Jul 1 2024

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Belle, J. I., Sen, D., Baer, J. M., Liu, X., Lander, V. E., Ye, J., Sells, B. E., Knolhoff, B. L., Faiz, A., Kang, L. I., Qian, G., Fields, R. C., Ding, L., Kim, H., Provenzano, P. P., Stewart, S. A., & Denardo, D. G. (2024). Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer. Cancer discovery, 14(7), 1324-1355. https://doi.org/10.1158/2159-8290.CD-23-0428

@article{62d051c62e75434ea28d968e90f18bcf,

title = "Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer",

abstract = "Pancreatic ductal adenocarcinoma (PDAC) therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with an abundance of cancerassociated fibroblasts (CAF). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAF) in mouse and human PDAC. These SenCAFs are a phenotypically distinct subset of myofibroblastic CAFs that localize near tumor ducts and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we used an LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Depletion of senescent stromal cells in genetic and pharmacologic PDAC models relieved immune suppression by macrophages, delayed tumor progression, and increased responsiveness to chemotherapy. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction. Significance: CAF heterogeneity in PDAC remains poorly understood. In this study, we identify a novel subpopulation of senescent CAFs that promotes PDAC progression and immunosuppression. Targeting CAF senescence in combination therapies could increase tumor vulnerability to chemo or immunotherapy.",

author = "Belle, {Jad I.} and Devashish Sen and Baer, {John M.} and Xiuting Liu and Lander, {Varintra E.} and Jiayu Ye and Sells, {Blake E.} and Knolhoff, {Brett L.} and Ahmad Faiz and Kang, {Liang I.} and Guhan Qian and Fields, {Ryan C.} and Li Ding and Hyun Kim and Provenzano, {Paolo P.} and Stewart, {Sheila A.} and Denardo, {David G.}",

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

year = "2024",

month = jul,

day = "1",

doi = "10.1158/2159-8290.CD-23-0428",

language = "English",

volume = "14",

pages = "1324--1355",

journal = "Cancer discovery",

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Belle, JI, Sen, D, Baer, JM, Liu, X, Lander, VE, Ye, J, Sells, BE, Knolhoff, BL, Faiz, A, Kang, LI, Qian, G, Fields, RC, Ding, L, Kim, H, Provenzano, PP, Stewart, SA & Denardo, DG 2024, 'Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer', Cancer discovery, vol. 14, no. 7, pp. 1324-1355. https://doi.org/10.1158/2159-8290.CD-23-0428

TY - JOUR

T1 - Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer

AU - Belle, Jad I.

AU - Sen, Devashish

AU - Baer, John M.

AU - Liu, Xiuting

AU - Lander, Varintra E.

AU - Ye, Jiayu

AU - Sells, Blake E.

AU - Knolhoff, Brett L.

AU - Faiz, Ahmad

AU - Kang, Liang I.

AU - Qian, Guhan

AU - Fields, Ryan C.

AU - Ding, Li

AU - Kim, Hyun

AU - Provenzano, Paolo P.

AU - Stewart, Sheila A.

AU - Denardo, David G.

PY - 2024/7/1

Y1 - 2024/7/1

N2 - Pancreatic ductal adenocarcinoma (PDAC) therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with an abundance of cancerassociated fibroblasts (CAF). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAF) in mouse and human PDAC. These SenCAFs are a phenotypically distinct subset of myofibroblastic CAFs that localize near tumor ducts and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we used an LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Depletion of senescent stromal cells in genetic and pharmacologic PDAC models relieved immune suppression by macrophages, delayed tumor progression, and increased responsiveness to chemotherapy. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction. Significance: CAF heterogeneity in PDAC remains poorly understood. In this study, we identify a novel subpopulation of senescent CAFs that promotes PDAC progression and immunosuppression. Targeting CAF senescence in combination therapies could increase tumor vulnerability to chemo or immunotherapy.

AB - Pancreatic ductal adenocarcinoma (PDAC) therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with an abundance of cancerassociated fibroblasts (CAF). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAF) in mouse and human PDAC. These SenCAFs are a phenotypically distinct subset of myofibroblastic CAFs that localize near tumor ducts and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we used an LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Depletion of senescent stromal cells in genetic and pharmacologic PDAC models relieved immune suppression by macrophages, delayed tumor progression, and increased responsiveness to chemotherapy. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction. Significance: CAF heterogeneity in PDAC remains poorly understood. In this study, we identify a novel subpopulation of senescent CAFs that promotes PDAC progression and immunosuppression. Targeting CAF senescence in combination therapies could increase tumor vulnerability to chemo or immunotherapy.

UR - http://www.scopus.com/inward/record.url?scp=85193835719&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-23-0428

DO - 10.1158/2159-8290.CD-23-0428

M3 - Article

C2 - 38683144

AN - SCOPUS:85193835719

SN - 2159-8274

VL - 14

SP - 1324

EP - 1355

JO - Cancer discovery

JF - Cancer discovery

IS - 7

ER -

Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer

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