期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 214, 期 3, 页码 579-596出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20162024
关键词
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资金
- Cold Spring Harbor Cancer Center Support Grant (CCSG)
- National Cancer Institute
- Lustgarten Foundation
- Cold Spring Harbor Laboratory Association
- National Institutes of Health (NIH) [5P30CA45508-26, 5P50CA101955-07, 1U10CA180944-02, 5U01CA168409-5, 1R01CA188134, 1R01CA190092-03]
- Stand Up to Cancer/KWF
- STARR Foundation [I7-A718]
- DOD [W81XWH-13-PRCRP-IA]
- Precision Medicine Research Associates (PMRA)
- Swedish Research Council [537-2013-7277]
- Kempe Foundations [JCK-1301]
- Swedish Society of Medicine [SLS-326921, SLS-250831, SLS175991, SLS-591551]
- county council of Vasterbotten [ALFVLL269081, VLL242121, VLL322391, VLL400421, VLL493371, VLL582681]
- Cancer Research Foundation in Northern Sweden [AMP15-793, LP11-1927]
- Human Frontiers Science Program [LT000403/2014, LT000195/2015-L, LT000190/2013]
- Weizmann Institute of Science Women in Science award
- EMBO [ALTF 1203-2014]
- Italian Ministry of Health [FIRB - RBAP10AHJ]
- Associazione Italiana Ricerca Cancro (AIRC) [18718]
- NIH [R50CA311506-01]
- NIH awards [CA101955 UAB/UMN SPORE, 5T32CA148056, F32CA192904]
- Damon Runyon Cancer Research Foundation [DRG-2165-13]
- National Cancer Institute (NCI) [1K99CA204725-01A1]
- Nancy Gay fellowship
Pancreatic stellate cells (PSCs) differentiate into cancer-associated fibroblasts (CAFs) that produce desmoplastic stroma, thereby modulating disease progression and therapeutic response in pancreatic ductal adenocarcinoma (PDA). However, it is unknown whether CAFs uniformly carry out these tasks or if subtypes of CAFs with distinct phenotypes in PDA exist. We identified a CAF subpopulation with elevated expression of a-smooth muscle actin (alpha SMA) located immediately adjacent to neoplastic cells in mouse and human PDA tissue. We recapitulated this finding in co-cultures of murine PSCs and PDA organoids, and demonstrated that organoid-activated CAFs produced desmoplastic stroma. The co-cultures showed cooperative interactions and revealed another distinct subpopulation of CAFs, located more distantly from neoplastic cells, which lacked elevated aSMA expression and instead secreted IL6 and additional inflammatory mediators. These findings were corroborated in mouse and human PDA tissue, providing direct evidence for CAF heterogeneity in PDA tumor biology with implications for disease etiology and therapeutic development.
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