Sertoli Cell-Specific Activation of Transforming Growth Factor Beta Receptor 1 Leads to Testicular Granulosa Cell Tumor Formation
The transforming growth factor β (TGFβ) 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 TGFβ receptor 1 (TGFBR1) driven by anti-Mull...
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MDPI AG
2023-11-01
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| Series: | Cells |
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| author | Xin Fang Linfeng Nie Satwikreddy Putluri Nan Ni Laurent Bartholin Qinglei Li |
| author_facet | Xin Fang Linfeng Nie Satwikreddy Putluri Nan Ni Laurent Bartholin Qinglei Li |
| author_sort | Xin Fang |
| collection | DOAJ |
| description | The transforming growth factor β (TGFβ) 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 TGFβ receptor 1 (TGFBR1) driven by anti-Mullerian hormone receptor type 2 (<i>Amhr2</i>)-Cre in the mouse testis induces the formation of testicular granulosa cell tumors (TGCTs). As <i>Amhr2</i>-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 (<i>Amh</i>)-Cre. Disorganized seminiferous tubules and tumor nodules were found in <i>TGFBR1</i><sup>CA</sup>; <i>Amh</i>-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. |
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| language | English |
| last_indexed | 2024-03-09T01:53:38Z |
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| series | Cells |
| spelling | doaj.art-39e377c9b73247ecbc07adc8b66753942023-12-08T15:13:08ZengMDPI AGCells2073-44092023-11-011223271710.3390/cells12232717Sertoli Cell-Specific Activation of Transforming Growth Factor Beta Receptor 1 Leads to Testicular Granulosa Cell Tumor FormationXin Fang0Linfeng Nie1Satwikreddy Putluri2Nan Ni3Laurent Bartholin4Qinglei Li5Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USADepartment of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USADepartment of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USADepartment of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USAINSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, Université Lyon 1, F-69000 Lyon, FranceDepartment of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USAThe transforming growth factor β (TGFβ) 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 TGFβ receptor 1 (TGFBR1) driven by anti-Mullerian hormone receptor type 2 (<i>Amhr2</i>)-Cre in the mouse testis induces the formation of testicular granulosa cell tumors (TGCTs). As <i>Amhr2</i>-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 (<i>Amh</i>)-Cre. Disorganized seminiferous tubules and tumor nodules were found in <i>TGFBR1</i><sup>CA</sup>; <i>Amh</i>-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.https://www.mdpi.com/2073-4409/12/23/2717transforming growth factor betaSertoli celltesticular granulosa cell tumorTGFBR1 |
| spellingShingle | Xin Fang Linfeng Nie Satwikreddy Putluri Nan Ni Laurent Bartholin Qinglei Li Sertoli Cell-Specific Activation of Transforming Growth Factor Beta Receptor 1 Leads to Testicular Granulosa Cell Tumor Formation Cells transforming growth factor beta Sertoli cell testicular granulosa cell tumor TGFBR1 |
| title | Sertoli Cell-Specific Activation of Transforming Growth Factor Beta Receptor 1 Leads to Testicular Granulosa Cell Tumor Formation |
| title_full | Sertoli Cell-Specific Activation of Transforming Growth Factor Beta Receptor 1 Leads to Testicular Granulosa Cell Tumor Formation |
| title_fullStr | Sertoli Cell-Specific Activation of Transforming Growth Factor Beta Receptor 1 Leads to Testicular Granulosa Cell Tumor Formation |
| title_full_unstemmed | Sertoli Cell-Specific Activation of Transforming Growth Factor Beta Receptor 1 Leads to Testicular Granulosa Cell Tumor Formation |
| title_short | Sertoli Cell-Specific Activation of Transforming Growth Factor Beta Receptor 1 Leads to Testicular Granulosa Cell Tumor Formation |
| title_sort | sertoli cell specific activation of transforming growth factor beta receptor 1 leads to testicular granulosa cell tumor formation |
| topic | transforming growth factor beta Sertoli cell testicular granulosa cell tumor TGFBR1 |
| url | https://www.mdpi.com/2073-4409/12/23/2717 |
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