Transdifferentiation of tongue muscle cells into cancer-associated fibroblasts in response to tongue squamous cell carcinoma

Weifan Lin, Wuheng Huang, Shiqiang Mei, Xiangwan Lu, Junheng Zheng, Hua Wang, Lingling Zheng () and Yan Zhang ()
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Weifan Lin: Sun Yat-sen University
Wuheng Huang: Sun Yat-sen University
Shiqiang Mei: Sun Yat-sen University
Xiangwan Lu: Sun Yat-sen University
Junheng Zheng: Sun Yat-sen University
Hua Wang: Sun Yat-sen University
Lingling Zheng: Sun Yat-sen University
Yan Zhang: Sun Yat-sen University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Tongue Squamous Cell Carcinoma (TSCC) represents a significant subtype of malignant oral cancer, characterized by a heterogeneous tumor microenvironment (TME). The tongue, a complex muscular organ, naturally presents an initial microenvironment that is largely inhospitable to the initiation and progression of TSCC. However, advanced-stage TSCC exhibits a pronounced accumulation of cancer-associated fibroblasts (CAFs), indicative of a drastic microenvironmental transformation. In this study, through comprehensive analysis combining cell model assessments and single-cell RNA sequencing data from a 4-NQO-induced TSCC mouse model, along with a lineage tracing-in-transplant assay, we elucidate and confirm the process of transdifferentiation whereby tongue muscle cells (TMCs) convert into CAFs in the TSCC context. Furthermore, we demonstrate that targeting TSCC with an IL-17a inhibitor offers a viable strategy to inhibit the reprogramming of TMCs into CAFs. Additionally, our research also identifies four critical marker genes involved in the transdifferentiation of TMCs to CAFs, Thbs1, Crabp1, Ifi205, and Cxcl5. Collectively, these findings delineate a mechanism through which TSCC cells induce the transdifferentiation of TMCs into CAFs, thereby transforming the cancer-suppressive microenvironment of the tongue into one that is conducive to TSCC progression.

Date: 2025
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DOI: 10.1038/s41467-025-61951-3

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