Inhibition of hedgehog signaling alters fibroblast composition in pancreatic cancer

Nina G. Steele, Giulia Biffi, Samantha B. Kemp, Yaqing Zhang, Donovan Drouillard, Li Jyun Syu, Yuan Hao, Tobiloba E. Oni, Erin Brosnan, Ela Elyada, Abhishek Doshi, Christa Hansma, Carlos Espinoza, Ahmed Abbas, Stephanie The, Valerie Irizarry-Negron, Christopher J. Halbrook, Nicole E. Franks, Megan T. Hoffman, Kristee BrownEileen S. Carpenter, Zeribe C. Nwosu, Craig Johnson, Fatima Lima, Michelle A. Anderson, Youngkyu Park, Howard C. Crawford, Costas A. Lyssiotis, Timothy L. Frankel, Arvind Rao, Filip Bednar, Andrzej A. Dlugosz, Jonathan B. Preall, David A. Tuveson*, Benjamin L. Allen*, Marina Pasca Di Magliano*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

135 Scopus citations

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 PDACin 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.

Original languageAmerican English
Pages (from-to)2023-2037
Number of pages15
JournalClinical Cancer Research
Volume27
Issue number7
DOIs
StatePublished - Apr 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021 American Association for Cancer Research.

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