Academic Journal
SMAD2/3 mediate oncogenic effects of TGF-β in the absence of SMAD4.
| Title: | SMAD2/3 mediate oncogenic effects of TGF-β in the absence of SMAD4. |
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| Authors: | Bertrand-Chapel, Adrien, Caligaris, Cassandre, Fenouil, Tanguy, Savary, Clara, Aires, Sophie, Martel, Sylvie, Huchedé, Paul, Chassot, Christelle, Chauvet, Véronique, Cardot-Ruffino, Victoire, Morel, Anne-Pierre, Subtil, Fabien, Mohkam, Kayvan, Mabrut, Jean-Yves, Tonon, Laurie, Viari, Alain, Cassier, Philippe, Hervieu, Valérie, Castets, Marie, Mauviel, Alain |
| Source: | Communications Biology; 10/7/2022, Vol. 5 Issue 1, p1-13, 13p |
| Abstract: | TGF-β signaling is involved in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis, representing one of the four major pathways genetically altered in 100% of PDAC cases. TGF-β exerts complex and pleiotropic effects in cancers, notably via the activation of SMAD pathways, predominantly SMAD2/3/4. Though SMAD2 and 3 are rarely mutated in cancers, SMAD4 is lost in about 50% of PDAC, and the role of SMAD2/3 in a SMAD4-null context remains understudied. We herein provide evidence of a SMAD2/3 oncogenic effect in response to TGF-β1 in SMAD4-null human PDAC cancer cells. We report that inactivation of SMAD2/3 in SMAD4-negative PDAC cells compromises TGF-β-driven collective migration mediated by FAK and Rho/Rac signaling. Moreover, RNA-sequencing analyses highlight a TGF-β gene signature related to aggressiveness mediated by SMAD2/3 in the absence of SMAD4. Using a PDAC patient cohort, we reveal that SMAD4-negative tumors with high levels of phospho-SMAD2 are more aggressive and have a poorer prognosis. Thus, loss of SMAD4 tumor suppressive activity in PDAC leads to an oncogenic gain-of-function of SMAD2/3, and to the onset of associated deleterious effects. In pancreatic ductal adenocarcinoma cells and patient tissue, SMAD2/3 is shown to mediate oncogenic effects of TGF-β in the absence of SMAD4. [ABSTRACT FROM AUTHOR] |
| Subject Terms: | SMAD proteins, PANCREATIC duct, CANCER cells, RNA sequencing |
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| ISSN: | 23993642 |
| DOI: | 10.1038/s42003-022-03994-6 |
| Database: | Complementary Index |