Caspase-1-dependent pyroptosis converts αSMA+ CAFs into collagen-IIIhigh iCAFs to fuel chemoresistant cancer stem cells
- bgtaylor1
- Nov 4, 2025
- 2 min read
Date: | June 13, 2025 |
PMID: | |
Category: | N/A |
Authors: | Hongbo Gao, Stephen Q R Wong, Ethan Subel, Yung Hsing Huang, Yu-Cheng Lee, Kazukuni Hayashi, Mark Ellie Alonzo, Mustafa Karabicici, Xen Ping Hoi, Armine Kasabyan 1, Qianxing Mo, Zachary Melchiode, Ziad El-Zaatari, Steven Shen, Raj Satkunasivam, Fotis Nikolos, Keith Syson Chan |
Abstract: | 40498841 |
The impact of chemotherapy-induced tumor cell pyroptosis on fibroblasts, a key stromal cell type within the tumor microenvironment (TME), remains unexplored. Here, we report morphologically and molecularly distinct subtypes of cancer-associated fibroblasts (CAFs) in bladder cancer, including αSMA+IL-6- myofibroblastic CAFs (myCAFs), αSMA-IL-6+ inflammatory CAFs (iCAFs), and hybrid i/myCAFs. Caspase-1-dependent tumor pyroptosis releases several inflammatory chemokines, converting αSMA+ CAF into iCAFs in a CCR6-dependent manner. This is clinically relevant, as a fibroblast gene signature driven by iCAF markers and collagen type III is enriched in patients with chemoresistant bladder cancer after neoadjuvant chemotherapy. Contrary to the current notion, iCAFs, rather than myCAFs, produce collagen III in response to chemotherapy, supporting the expansion of cancer stem cells (CSCs). Thus, tumor cell pyroptosis initiates an iCAF-CSC feedforward loop that drives chemoresistance, indicating that inflammatory cell death is not universally beneficial to anticancer therapy, depending on the target cell type.
Acknowledgements:
The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, or the National Institute of Health.
The Translational and Basic Science Research in Early Lesions (TBEL) Research Consortia is supported and funded by grants from the National Cancer Institute and the National Institutes of Health under the following award numbers:
Project Number: | Awardee Organization |
U54CA274374 | Fred Hutchinson Cancer Center |
U54CA274375 | Houston Methodist Research Institute |
U54CA274370 | Johns Hopkins University |
U54CA274371 | UT MD Anderson Cancer Center |
U54CA274367 | Vanderbilt University Medical Center |
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