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

ABSTRACT: The tumor suppressive effects of TGF-β are classically associated with the activation of the “canonical” SMAD-mediated pathway, whereas its oncogenic effects are largely attributed to its “non-canonical signaling”. We herein provide evidence of an oncogenic effect for SMAD2 and 3 in response to TGF-β in SMAD4-null cancer cells. Using the CRISPR/Cas9 technology, we report that simultaneous knockout of Smad2 and 3 in Smad4-negative pancreatic ductal adenocarcinoma (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 and 3 in the absence of SMAD4. Using PDAC patients cohorts, 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 is associated with oncogenic gain-of-function of SMAD2 and 3 and the onset of associated deleterious effects.

ORGANISM(S): Homo sapiens

PROVIDER: GSE178714 | GEO | 2022/10/09

REPOSITORIES: GEO

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