期刊
CLINICAL CANCER RESEARCH
卷 27, 期 7, 页码 2023-2037出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-20-3715
关键词
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类别
资金
- NIH/NCI [R01CA151588, R01CA198074, U01CA224145, R01 CA118875, P01 DK062041, 5P30 CA046592]
- American Cancer Society
- University of Michigan Cancer Center support grant [P30CA046592, P30 CA046592]
- NIH [R01 DC014428, R01 CA198074, R01 118751, K99 CA241357, P30 DK034933, NIH P30 CA45508, U01 CA210240, R01 CA229699, U01 CA224013, R01 CA188134, R01 CA190092]
- Association of Academic Surgery Joel Roslyn Award
- NCI [P30CA046592, R37 CA214955]
- American Cancer Society [PF-19-096-01, RSG-16-005-01]
- Michigan Institute for Clinical and Healthy Research Postdoctoral Translational Scholar Program fellowship award
- American College of Gastroenterology Clinical Research award
- University of Michigan
- NIH Cancer Center Support grant [P30 CA045508]
- Lustgarten Foundation
- Thompson Foundation
- Cold Spring Harbor Laboratory
- Northwell Health Affiliation
- Northwell Health Tissue Donation Program
- Cold Spring Harbor Laboratory Association
- Simons Foundation [552716]
- Human Frontiers Science Program [LT000195/2015-L, LT000403/2014-L]
- EMBO [ALTF 1203-2014]
- Cancer Research UK [A27463]
- Cancer Research UK Cambridge Centre
- [K08CA201581]
- [T32 GM113900]
- [T32 CA009676]
- [T32 DK094775]
- [R50 CA211506]
The study reveals that Hedgehog signaling is uniquely activated in fibroblasts in PDAC, with varying levels of elevation in myofibroblastic CAFs compared to inflammatory CAFs. Inhibition of the Hedgehog pathway slows tumor growth, alters the composition of CAF subtypes, and impacts immune cell infiltration, leading to increased immunosuppression.
Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by an extensive fibroinflammatory stroma, which includes abundant cancer-associated fibroblast (CAF) populations. PDAC CAFs are heterogeneous, but the nature of this heterogeneity is incompletely understood. The Hedgehog pathway functions in PDAC in a paracrine manner, with ligands secreted by cancer cells signaling to stromal cells in the microenvironment. Previous reports investigating the role of Hedgehog signaling in PDAC have been contradictory, with Hedgehog signaling alternately proposed to promote or restrict tumor growth. In light of the newly discovered CAF heterogeneity, we investigated how Hedgehog pathway inhibition reprograms the PDAC microenvironment. Experimental Design: We used a combination of pharmacologic inhibition, gain- and loss-of-function genetic experiments, cytomar), by time-of-flight, and single-cell RNA sequencing to study the roles of Hedgehog signaling in PDAC. Results: We found that Hedgehog signaling is uniquely activated in fibroblasts and differentially elevated in myofibroblastic CAR (myCAF) compared with inflammatory CAFs (iCAF). Sonic Hedgehog overexpression promotes tumor growth, while Hedgehog pathway inhibition with the smoothened antagonist, LDE225, impairs tumor growth. Furthermore, Hedgehog pathway inhibition reduces myCAF numbers and increases iCAF numbers, which correlates with a decrease in cytotoxic T cells and an expansion in regulatory T cells, consistent with increased immunosuppression. Conclusions: Hedgehog pathway inhibition alters fibroblast composition and immune infiltration in the pancreatic cancer microenvironment.
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