Inhibition of Hedgehog Signaling Alters Fibroblast Composition in Pancreatic Cancer.

Steele, Nina G, Biffi, Giulia, Kemp, Samantha B, Zhang, Yaqing, Drouillard, Donovan, Syu, LiJyun, Hao, Yuan, Oni, Tobiloba E, Brosnan, Erin, Elyada, Ela, Doshi, Abhishek, Hansma, Christa, Espinoza, Carlos, Abbas, Ahmed, The, Stephanie, Irizarry-Negron, Valerie, Halbrook, Christopher J, Franks, Nicole E, Hoffman, Megan T, Brown, Kristee, Carpenter, Eileen S, Nwosu, Zeribe C, Johnson, Craig, Lima, Fatima, Anderson, Michelle A, Park, Youngkyu, Crawford, Howard C, Lyssiotis, Costas A, Frankel, Timothy L, Rao, Arvind, Bednar, Filip, Dlugosz, Andrzej A, Preall, Jonathan B, Tuveson, David A, Allen, Benjamin L, Pasca di Magliano, Marina (April 2021) Inhibition of Hedgehog Signaling Alters Fibroblast Composition in Pancreatic Cancer. Clinical Cancer Research, 27 (7). pp. 2023-2037. ISSN 1078-0432

URL: https://www.ncbi.nlm.nih.gov/pubmed/33495315
DOI: 10.1158/1078-0432.CCR-20-3715

Abstract

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, cytometry 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 CAFs (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.

Item Type: Paper
Subjects: organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > cell signaling
diseases & disorders > cancer > cancer types > pancreatic cancer
Investigative techniques and equipment > assays > RNA-seq
CSHL Authors:
Communities: CSHL labs > Hammell M. lab
CSHL labs > Preall lab
CSHL labs > Tuveson lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 1 April 2021
Date Deposited: 27 Apr 2021 17:58
Last Modified: 27 Apr 2021 17:58
PMCID: PMC8026631
Related URLs:
URI: https://repository.cshl.edu/id/eprint/39933

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