Electronic Resource
Inhibition of Hedgehog Signaling Alters Fibroblast Composition in Pancreatic Cancer.
| العنوان: | Inhibition of Hedgehog Signaling Alters Fibroblast Composition in Pancreatic Cancer. |
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| المؤلفون: | Steele, Nina G, 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 |
| المصدر: | Clinical cancer research : an official journal of the American Association for Cancer Research; vol 27, iss 7, 2023-2037; 1078-0432 |
| بيانات النشر: | eScholarship, University of California 2021-04-01 |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | PurposePancreatic 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 designWe 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.ResultsWe 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.ConclusionsHedgehog pathway inhibition alters fibroblast composition and immune infiltration in the pancreatic cancer microenvironment. |
| مصطلحات الفهرس: | Animals, Mice, Inbred C57BL, Humans, Carcinoma, Pancreatic Ductal, Pancreatic Neoplasms, Signal Transduction, Hedgehog Proteins, Tumor Microenvironment, Cancer-Associated Fibroblasts, Digestive Diseases, Cancer, Rare Diseases, Pancreatic Cancer, Aetiology, 2.1 Biological and endogenous factors, Oncology and Carcinogenesis, Oncology & Carcinogenesis, article |
| URL: | |
| الاتاحة: | Open access content. Open access content public |
| ملاحظة: | application/pdf Clinical cancer research : an official journal of the American Association for Cancer Research vol 27, iss 7, 2023-2037 1078-0432 |
| Other Numbers: | CDLER oai:escholarship.org:ark:/13030/qt2mz309fm qt2mz309fm https://escholarship.org/uc/item/2mz309fm https://escholarship.org/ 1391596765 |
| المصدر المساهم: | UC MASS DIGITIZATION From OAIster®, provided by the OCLC Cooperative. |
| رقم الانضمام: | edsoai.on1391596765 |
| قاعدة البيانات: | OAIster |
| الوصف غير متاح. |