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

被引：40

作者：

Bertrand-Chapel, Adrien ^{[1
]}

Caligaris, Cassandre ^{[1
]}

Fenouil, Tanguy ^{[2
,3
]}

Savary, Clara ^{[4
]}

Aires, Sophie ^{[1
]}

Martel, Sylvie ^{[1
]}

Huchede, Paul ^{[4
]}

Chassot, Christelle ^{[5
]}

Chauvet, Veronique ^{[1
]}

Cardot-Ruffino, Victoire ^{[1
]}

Morel, Anne-Pierre ^{[5
]}

Subtil, Fabien ^{[6
,7
]}

Mohkam, Kayvan ^{[8
]}

Mabrut, Jean-Yves ^{[8
]}

Tonon, Laurie ^{[9
]}

Viari, Alain ^{[9
]}

Cassier, Philippe ^{[1
,10
]}

Hervieu, Valerie

Castets, Marie ^{[4
]}

Mauviel, Alain ^{[11
]}

Sentis, Stephanie ^{[1
]}

Bartholin, Laurent ^{[1
]}

机构：

[1] Univ Claude Bernard Lyon 1, Univ Lyon, INSERM 1052,CNRS 5286,Ctr Leon Berard, TGF SS & Pancreat Canc Lab,Ctr Rech Cancerol Lyon, Lyon, France

[2] Hosp Civils Lyon, Inst Pathol, Grp Hosp Est, Bron, France

[3] Univ Lyon, Univ Claude Bernard Lyon 1, Ribosome Translat & Canc Lab,CNRS 5286, Ctr Rech Cancerol Lyon CRCL,INSERM 1052,Ctr Leon, Lyon, France

[4] Univ Claude Bernard Lyon 1, Cell Death & Childhood Cancers Lab,Inst Convergen, Ctr Rech Cancerol Lyon CRCL,Labex DevWeCan, Ctr Leon Berard,CNRS 5286,INSERM 1052,Univ Lyon, Lyon, France

[5] Univ Claude Bernard Lyon 1, Univ Lyon, Ctr Rech Cancerol Lyon CRCL,CNRS 5286, EMT & Canc Cell Plast Lab,Ctr Leon Berard,INSERM, Lyon, France

[6] Hosp Civils Lyon, Serv Biostat, Lyon, France

[7] Univ Lyon 1, Univ Lyon, CNRS, Lab Biometrie & Biol Evolut,UMR 5558, Villeurbanne, France

[8] Claude Bernard Lyon 1 Univ, Croix Rousse Univ Hosp, Hosp Civils Lyon, Dept Gen Surg & Liver Transplantat, Lyon, France

[9] Ctr Leon Berard, Fondat Lyon Synergie Canc, Plateforme Bioinformat Gilles Thomas, Lyon, France

[10] Ctr Leon Berard, Dept Oncol Med, Unite Phase 1, Lyon, France

[11] PSL Res Univ, Team TGF SS & Oncogenesis, Inst Curie, INSERM 1021,CNRS 3347, Equipe Labellisee Ligue 2016, F-91400 Orsay, France

来源：

COMMUNICATIONS BIOLOGY | 2022年 / 5卷 / 01期

关键词：

GROWTH-FACTOR-BETA; MESENCHYMAL TRANSITION; SIGNALING PATHWAY; EPITHELIAL-CELLS; CANCER; EXPRESSION; GENES; PHOSPHORYLATION; ADENOCARCINOMA; PROLIFERATION;

D O I：

10.1038/s42003-022-03994-6

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

In pancreatic ductal adenocarcinoma cells and patient tissue, SMAD2/3 is shown to mediate oncogenic effects of TGF-beta in the absence of SMAD4. TGF-beta signaling is involved in pancreatic ductal adenocarcinoma (PDAC) tumorigenesis, representing one of the four major pathways genetically altered in 100% of PDAC cases. TGF-beta 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-beta 1 in SMAD4-null human PDAC cancer cells. We report that inactivation of SMAD2/3 in SMAD4-negative PDAC cells compromises TGF-beta-driven collective migration mediated by FAK and Rho/Rac signaling. Moreover, RNA-sequencing analyses highlight a TGF-beta 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.

引用

页数：13

共 76 条

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