TGF‐β signaling promotes desmoid tumor formation via CSRP2 upregulation

• Published in: Cancer science 2024-02, Vol.115 (2), p.401-411
• Main Authors: Li, Yu, Fujishita, Teruaki, Mishiro‐Sato, Emi, Kojima, Yasushi, Niu, Yanqing, Taketo, Makoto Mark, Urano, Yuya, Sakai, Tomohisa, Enomoto, Atsushi, Nishida, Yoshihiro, Aoki, Masahiro
• Format: Article
• Language: English
• Subjects: Albinism; Animals; beta Catenin - genetics; beta Catenin - metabolism; Cell proliferation; CTNNB1 gene; Data analysis; desmoid tumors; Experiments; Fibromatosis, Aggressive - genetics; Fibromatosis, Aggressive - pathology; fibrosis; Humans; Laboratories; LIM Domain Proteins - genetics; Mice; Mice, Knockout; mouse models; Muscle Proteins - metabolism; Mutation; Nuclear Proteins - genetics; Original; Phosphorylation; Proteomics; Smad2 protein; Smad4 protein; Statistical analysis; Stromal cells; TGF‐β; Therapeutic targets; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Tumors; Up-Regulation; Wnt signaling; β-Catenin
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.16037

Desmoid tumors (DTs), also called desmoid‐type fibromatoses, are locally aggressive tumors of mesenchymal origin. In the present study, we developed a novel mouse model of DTs by inducing a local mutation in the Ctnnb1 gene, encoding β‐catenin in PDGFRA‐positive stromal cells, by subcutaneous injection of 4‐hydroxy‐tamoxifen. Tumors in this model resembled histologically clinical samples from DT patients and showed strong phosphorylation of nuclear SMAD2. Knockout of SMAD4 in the model significantly suppressed tumor growth. Proteomic analysis revealed that SMAD4 knockout reduced the level of Cysteine‐and‐Glycine‐Rich Protein 2 (CSRP2) in DTs, and treatment of DT‐derived cells with a TGF‐β receptor inhibitor reduced CSRP2 RNA levels. Knockdown of CSRP2 in DT cells significantly suppressed their proliferation. These results indicate that the TGF‐β/CSRP2 axis is a potential therapeutic target for DTs downstream of TGF‐β signaling. A novel mouse model of sporadic extra‐abdominal desmoid tumors was generated by inducing a local mutation in the Ctnnb1 gene encoding β‐catenin in PDGFRA‐positive stromal cells. Analysis of the model revealed that TGF‐β/SMAD4 signaling enhances the proliferation of desmoid tumor cells, at least partially through positive regulation of CSRP2. These results indicate that the TGF‐β/CSRP2 axis is a potential biomarker and/or therapeutic target for desmoid tumors.