title: TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma.
abstract: Advances made in pancreatic cancer therapy have been far from sufficient and have allowed only a slight improvement in global survival of patients with pancreatic ductal adenocarcinoma (PDA). Recent progresses in chemotherapy have offered some hope for an otherwise gloomy outlook, however, only a limited number of patients are eligible because of important cytotoxicity. In this context, enhancing our knowledge on PDA initiation and evolution is crucial to highlight certain weaknesses on which to specifically target therapy. We found that loss of transcriptionally active p73 (TAp73), a p53 family member, impacted PDA development. In two relevant and specific engineered pancreatic cancer mouse models, we observed that TAp73 deficiency reduced survival and enhanced epithelial-to-mesenchymal transition (EMT). Through proteomic analysis of conditioned media from TAp73 wild-type (WT) and deficient pancreatic tumor cells, we identified a secreted protein, biglycan (BGN), which is necessary and sufficient to mediate this pro-EMT effect. Interestingly, BGN is modulated by and modulates the transforming growth factor-β (TGF-β) pathway, a key regulator of the EMT process. We further examined this link and revealed that TAp73 impacts the TGF-β pathway by direct regulation of BGN expression and Sma and Mad-related proteins (SMADs) expression/activity. Absence of TAp73 leads to activation of TGF-β signaling through a SMAD-independent pathway, favoring oncogenic TGF-β effects and EMT. Altogether, our data highlight the implication of TAp73 in the aggressiveness of pancreatic carcinogenesis through modulation of the TGF-β signaling. By suggesting TAp73 as a predictive marker for response to TGF-β inhibitors, our study could improve the classification of PDA patients with a view to offering combined therapy involving TGF-β inhibitors.
authors.affiliation: CRCM, INSERM, U1068, Paoli-Calmettes Institute, Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France.
authors.forename: A K
authors.initials: AK
authors.lastname: Thakur
authors.affiliation: CRCM, INSERM, U1068, Paoli-Calmettes Institute, Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France.
authors.forename: J
authors.identifier: 0000-0003-1358-1863
authors.initials: J
authors.lastname: Nigri
authors.affiliation: CRCM, INSERM, U1068, Paoli-Calmettes Institute, Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France.
authors.forename: S
authors.initials: S
authors.lastname: Lac
authors.affiliation: CRCM, INSERM, U1068, Paoli-Calmettes Institute, Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France.
authors.forename: J
authors.initials: J
authors.lastname: Leca
authors.affiliation: CRCM, INSERM, U1068, Paoli-Calmettes Institute, Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France.
authors.forename: C
authors.initials: C
authors.lastname: Bressy
authors.affiliation: CRCM, INSERM, U1068, Paoli-Calmettes Institute, Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France.
authors.forename: P
authors.initials: P
authors.lastname: Berthezene
authors.affiliation: CRCL, INSERM, U1052; CNRS 5286, Centre Léon Bérard, Lyon, France.
authors.forename: L
authors.initials: L
authors.lastname: Bartholin
authors.affiliation: PISSARO Proteomic facility, (IRIB), U-Rouen, Mont Saint- Aignan, France.
authors.forename: P
authors.initials: P
authors.lastname: Chan
authors.affiliation: Molecular Endocrinology and Oncology Research Center, CHUL Research Center, Quebec, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Calvo
authors.affiliation: CRCM, INSERM, U1068, Paoli-Calmettes Institute, Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France.
authors.forename: J L
authors.initials: JL
authors.lastname: Iovanna
authors.affiliation: CRCM, INSERM, U1068, Paoli-Calmettes Institute, Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France.
authors.forename: S
authors.initials: S
authors.lastname: Vasseur
authors.affiliation: CRCM, INSERM, U1068, Paoli-Calmettes Institute, Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France.
authors.forename: F
authors.initials: F
authors.lastname: Guillaumond
authors.affiliation: CRCM, INSERM, U1068, Paoli-Calmettes Institute, Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France.
authors.forename: R
authors.initials: R
authors.lastname: Tomasini
mesh_terms: D000818:Animals; D058578:Biglycan / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D034622:RNA Interference; D015398:Signal Transduction / Q000502:physiology; D051785:Smad Proteins / Q000378:metabolism*; D015996:Survival Rate; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D058578:Biglycan; D009687:Nuclear Proteins; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C454920:delta Np73, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3