{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T19:06:27Z","timestamp":1770750387036,"version":"3.50.0"},"reference-count":51,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T00:00:00Z","timestamp":1701043200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"NIH\/NCI","doi-asserted-by":"publisher","award":["R03CA235001"],"award-info":[{"award-number":["R03CA235001"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The transforming growth factor \u03b2 (TGF\u03b2) superfamily, consisting of protein ligands, receptors, and intracellular SMAD transducers, regulates fundamental biological processes and cancer development. Our previous study has shown that sustained activation of TGF\u03b2 receptor 1 (TGFBR1) driven by anti-Mullerian hormone receptor type 2 (Amhr2)-Cre in the mouse testis induces the formation of testicular granulosa cell tumors (TGCTs). As Amhr2-Cre is expressed in both Sertoli cells and Leydig cells, it remains unclear whether the activation of TGFBR1 in Sertoli cells alone is sufficient to induce TGCT formation. Therefore, the objective of this study was to determine whether Sertoli cell-activation of TGFBR1 drives oncogenesis in the testis. Our hypothesis was that overactivation of TGFBR1 in Sertoli cells would promote their transdifferentiation into granulosa-like cells and the formation of TGCTs. To test this hypothesis, we generated mice harboring constitutive activation of TGFBR1 in Sertoli cells using anti-Mullerian hormone (Amh)-Cre. Disorganized seminiferous tubules and tumor nodules were found in TGFBR1CA; Amh-Cre mice. A histological analysis showed that Sertoli cell-specific activation of TGFBR1 led to the development of neoplasms resembling granulosa cell tumors, which derailed spermatogenesis. Moreover, TGCTs expressed granulosa cell markers including FOXL2, FOXO1, and INHA. Using a dual fluorescence reporter line, the membrane-targeted tdTomato (mT)\/membrane-targeted EGFP (mG) mouse, we provided evidence that Sertoli cells transdifferentiated toward a granulosa cell fate during tumorigenesis. Thus, our findings indicate that Sertoli cell-specific activation of TGFBR1 leads to the formation of TGCTs, supporting a key contribution of Sertoli cell reprogramming to the development of this testicular malignancy in our model.<\/jats:p>","DOI":"10.3390\/cells12232717","type":"journal-article","created":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T07:56:10Z","timestamp":1701071770000},"page":"2717","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Sertoli Cell-Specific Activation of Transforming Growth Factor Beta Receptor 1 Leads to Testicular Granulosa Cell Tumor Formation"],"prefix":"10.3390","volume":"12","author":[{"given":"Xin","family":"Fang","sequence":"first","affiliation":[{"name":"Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linfeng","family":"Nie","sequence":"additional","affiliation":[{"name":"Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satwikreddy","family":"Putluri","sequence":"additional","affiliation":[{"name":"Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nan","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurent","family":"Bartholin","sequence":"additional","affiliation":[{"name":"INSERM U1052, CNRS UMR5286, Centre de Recherche en Canc\u00e9rologie de Lyon, Universit\u00e9 Lyon 1, F-69000 Lyon, France"},{"name":"Centre L\u00e9on B\u00e9rard, F-69008 Lyon, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qinglei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1210\/er.2011-0014","article-title":"Molecular pathogenesis of granulosa cell tumors of the ovary","volume":"33","author":"Jamieson","year":"2012","journal-title":"Endocr. 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