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Updated: Aug 26, 2025

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

Adrien Bertrand-Chapel1, Cassandre Caligaris1, Tanguy Fenouil2,3

  • 1TGF-β & Pancreatic Cancer Lab, Centre de Recherche en Cancérologie de Lyon (CRCL), Centre Léon Bérard, INSERM 1052, CNRS 5286, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France.

Communications Biology
|October 7, 2022
PubMed

Insights

In pancreatic cancer (PDAC), loss of SMAD4 allows SMAD2/3 to promote tumor growth and spread. Targeting SMAD2/3 may offer new therapeutic strategies for aggressive PDAC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling Pathways

Background:

  • Transforming Growth Factor-beta (TGF-β) signaling is crucial in pancreatic ductal adenocarcinoma (PDAC) development.
  • SMAD4 is frequently lost in PDAC, but the role of SMAD2/3 in SMAD4-deficient PDAC remains unclear.

Purpose of the Study:

  • To investigate the oncogenic role of SMAD2/3 in SMAD4-null PDAC cells.
  • To elucidate the mechanisms by which SMAD2/3 signaling contributes to PDAC aggressiveness.

Main Methods:

  • Utilized SMAD4-negative human PDAC cell lines.
  • Performed TGF-β1 stimulation and inactivation of SMAD2/3.
  • Conducted RNA-sequencing and analyzed phospho-SMAD2 levels in PDAC patient tumors.

Main Results:

  • SMAD2/3 activation drives TGF-β1-induced collective cell migration via FAK and Rho/Rac signaling in SMAD4-null PDAC cells.
  • A TGF-β gene signature associated with SMAD2/3-driven aggressiveness was identified.
  • SMAD4-negative PDAC tumors with high phospho-SMAD2 expression correlate with poorer prognosis.

Conclusions:

  • Loss of SMAD4 tumor suppressor function in PDAC results in an oncogenic gain-of-function for SMAD2/3.
  • SMAD2/3 signaling contributes to PDAC aggressiveness and poor patient outcomes.

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