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Journal Articles Communications Biology Year : 2022

SMAD2/3 mediate oncogenic effects of TGF-β in the absence of SMAD4

Kayvan Mohkam
Jean‐yves Mabrut

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.
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hal-03915470 , version 1 (29-12-2022)

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Adrien Bertrand-Chapel, Cassandre Caligaris, Tanguy Fenouil, Clara Savary, Sophie Aires, et al.. SMAD2/3 mediate oncogenic effects of TGF-β in the absence of SMAD4. Communications Biology, 2022, 5 (1), pp.1068. ⟨10.1038/s42003-022-03994-6⟩. ⟨hal-03915470⟩
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