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The Desmoid Tumor Research Foundation

December 2023

TGF-β signaling promotes desmoid tumor formation via CSRP2 upregulation

Author Information

Yu Li 1 2, Teruaki Fujishita 1, Emi Mishiro-Sato 1 3, Yasushi Kojima 1, Yanqing Niu 1, Makoto Mark Taketo 4, Yuya Urano 5, Tomohisa Sakai 6, Atsushi Enomoto 5, Yoshihiro Nishida 7, Masahiro Aoki 1 8

1Division of Pathophysiology, Aichi Cancer Center Research Institute, Nagoya, Japan. 2Department of Plastic Reconstructive Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan. 3Molecular Structure Center, Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Nagoya, Japan. 4Colon Cancer Project, Kyoto University Hospital-iACT, Graduate School of Medicine, Kyoto University, Kyoto, Japan. 5Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan. 6Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan. 7Department of Rehabilitation, Nagoya University Hospital, Nagoya, Japan. 8Department of Cancer Physiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Publication

Cancer Sci

Summary

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.

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