SMAD2/3 mediate oncogenic effects of TGF-β in the absence of SMAD4
Adrien Bertrand‐Chapel, Cassandre Caligaris, Tanguy Fenouil, Clara Savary, Sophie Aires, Sylvie Martel, Paul Huchedé, Christelle Chassot, Véronique Chauvet, Victoire Cardot‐Ruffino, Anne‐Pierre Morel, Fabien Subtil, Kayvan Mohkam, Jean‐Yves Mabrut, Laurie Tonon, Alain Viari, Philippe A. Cassier, Valérie Hervieu, Marie Castets, Alain Mauviel, Stéphanie Sentis, Laurent Bartholin
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.