Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRASG12D-driven Pancreatic TumorigenesisSummary
Background & Aims: Transforming growth factor beta (TGFβ) acts either as a tumor suppressor or as an oncogene, depending on the cellular context and time of activation. TGFβ activates the canonical SMAD pathway through its interaction with the serine/threonine kinase type I and II heterotetra...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2017-09-01
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| Series: | Cellular and Molecular Gastroenterology and Hepatology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352345X17300875 |
| _version_ | 1818821972886290432 |
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| author | Nicolas Chuvin David F. Vincent Roxane M. Pommier Lindsay B. Alcaraz Johann Gout Cassandre Caligaris Karam Yacoub Victoire Cardot Elodie Roger Bastien Kaniewski Sylvie Martel Celia Cintas Sophie Goddard-Léon Amélie Colombe Julie Valantin Nicolas Gadot Emilie Servoz Jennifer Morton Isabelle Goddard Anne Couvelard Vinciane Rebours Julie Guillermet Owen J. Sansom Isabelle Treilleux Ulrich Valcourt Stéphanie Sentis Pierre Dubus Laurent Bartholin |
| author_facet | Nicolas Chuvin David F. Vincent Roxane M. Pommier Lindsay B. Alcaraz Johann Gout Cassandre Caligaris Karam Yacoub Victoire Cardot Elodie Roger Bastien Kaniewski Sylvie Martel Celia Cintas Sophie Goddard-Léon Amélie Colombe Julie Valantin Nicolas Gadot Emilie Servoz Jennifer Morton Isabelle Goddard Anne Couvelard Vinciane Rebours Julie Guillermet Owen J. Sansom Isabelle Treilleux Ulrich Valcourt Stéphanie Sentis Pierre Dubus Laurent Bartholin |
| author_sort | Nicolas Chuvin |
| collection | DOAJ |
| description | Background & Aims: Transforming growth factor beta (TGFβ) acts either as a tumor suppressor or as an oncogene, depending on the cellular context and time of activation. TGFβ activates the canonical SMAD pathway through its interaction with the serine/threonine kinase type I and II heterotetrameric receptors. Previous studies investigating TGFβ-mediated signaling in the pancreas relied either on loss-of-function approaches or on ligand overexpression, and its effects on acinar cells have so far remained elusive. Methods: We developed a transgenic mouse model allowing tamoxifen-inducible and Cre-mediated conditional activation of a constitutively active type I TGFβ receptor (TβRICA) in the pancreatic acinar compartment. Results: We observed that TβRICA expression induced acinar-to-ductal metaplasia (ADM) reprogramming, eventually facilitating the onset of KRASG12D-induced pre-cancerous pancreatic intraepithelial neoplasia. This phenotype was characterized by the cellular activation of apoptosis and dedifferentiation, two hallmarks of ADM, whereas at the molecular level, we evidenced a modulation in the expression of transcription factors such as Hnf1β, Sox9, and Hes1. Conclusions: We demonstrate that TGFβ pathway activation plays a crucial role in pancreatic tumor initiation through its capacity to induce ADM, providing a favorable environment for KRASG12D-dependent carcinogenesis. Such findings are highly relevant for the development of early detection markers and of potentially novel treatments for pancreatic cancer patients. Keywords: Pancreas, Cancer, TGFβ, Acinar-to-Ductal Metaplasia, KRASG12D |
| first_indexed | 2024-12-18T23:16:41Z |
| format | Article |
| id | doaj.art-e49cd12ee88d4e9a90e40577438a5e07 |
| institution | Directory Open Access Journal |
| issn | 2352-345X |
| language | English |
| last_indexed | 2024-12-18T23:16:41Z |
| publishDate | 2017-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cellular and Molecular Gastroenterology and Hepatology |
| spelling | doaj.art-e49cd12ee88d4e9a90e40577438a5e072022-12-21T20:48:08ZengElsevierCellular and Molecular Gastroenterology and Hepatology2352-345X2017-09-0142263282Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRASG12D-driven Pancreatic TumorigenesisSummaryNicolas Chuvin0David F. Vincent1Roxane M. Pommier2Lindsay B. Alcaraz3Johann Gout4Cassandre Caligaris5Karam Yacoub6Victoire Cardot7Elodie Roger8Bastien Kaniewski9Sylvie Martel10Celia Cintas11Sophie Goddard-Léon12Amélie Colombe13Julie Valantin14Nicolas Gadot15Emilie Servoz16Jennifer Morton17Isabelle Goddard18Anne Couvelard19Vinciane Rebours20Julie Guillermet21Owen J. Sansom22Isabelle Treilleux23Ulrich Valcourt24Stéphanie Sentis25Pierre Dubus26Laurent Bartholin27Université de Lyon, Université Claude Bernard Lyon 1, Inserm 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Lyon, FranceCancer Research UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Glasgow, United KingdomUniversité de Lyon, Université Claude Bernard Lyon 1, Inserm 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Lyon, FranceUniversité de Lyon, Université Claude Bernard Lyon 1, Inserm 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Lyon, FranceUniversité de Lyon, Université Claude Bernard Lyon 1, Inserm 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Lyon, FranceUniversité de Lyon, Université Claude Bernard Lyon 1, Inserm 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Lyon, FranceUniversité de Lyon, Université Claude Bernard Lyon 1, Inserm 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Lyon, FranceUniversité de Lyon, Université Claude Bernard Lyon 1, Inserm 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Lyon, FranceUniversité de Lyon, Université Claude Bernard Lyon 1, Inserm 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Lyon, FranceUniversité de Lyon, Université Claude Bernard Lyon 1, Inserm 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Lyon, FranceUniversité de Lyon, Université Claude Bernard Lyon 1, Inserm 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Lyon, FranceInserm U1037, Université Toulouse III, Centre de Recherches en Cancérologie de Toulouse (CRCT), Oncopole de Toulouse, Toulouse, FranceUniversité de Lyon, Université Claude Bernard Lyon 1, Inserm 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Lyon, FranceUniversité de Lyon, Université Claude Bernard Lyon 1, Inserm 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Lyon, FrancePlateforme Anatomopathologie Recherche, Département de Recherche Translationnelle et de lâInnovation, Centre Léon Bérard, Lyon, FrancePlateforme Anatomopathologie Recherche, Département de Recherche Translationnelle et de lâInnovation, Centre Léon Bérard, Lyon, FranceDépartement de Recherche Translationnelle et de lâInnovation, Centre de Recherche en Cancérologie de Lyon (CRCL), Inserm U1052-CNRS UMR5286, Université de Lyon Centre Léon Bérard, Laboratoire des Modèles Tumoraux (LMT) Fondation Synergie Lyon Cancer, Lyon, FranceCancer Research UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Glasgow, United KingdomDépartement de Recherche Translationnelle et de lâInnovation, Centre de Recherche en Cancérologie de Lyon (CRCL), Inserm U1052-CNRS UMR5286, Université de Lyon Centre Léon Bérard, Laboratoire des Modèles Tumoraux (LMT) Fondation Synergie Lyon Cancer, Lyon, FranceInserm U1149, Faculté de Médecine Xavier Bichat, Paris, France; Université Denis Diderot-Paris 7, Paris, France; AP-HP, DHU UNITY, Hôpital Bichat, Département de Pathologie Beaujon-Bichat, Paris, FrancePancreatology Unit, DHU UNITY, Beaujon Hospital, APHP; Inserm - UMR 1149, University Paris 7, Paris, FranceInserm U1037, Université Toulouse III, Centre de Recherches en Cancérologie de Toulouse (CRCT), Oncopole de Toulouse, Toulouse, FranceCancer Research UK Beatson Institute, Institute of Cancer Sciences, University of Glasgow, Glasgow, United KingdomPlateforme Anatomopathologie Recherche, Département de Recherche Translationnelle et de lâInnovation, Centre Léon Bérard, Lyon, FranceUniversité de Lyon, Université Claude Bernard Lyon 1, Inserm 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Lyon, FranceUniversité de Lyon, Université Claude Bernard Lyon 1, Inserm 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Lyon, FranceUniversité Bordeaux, Inserm U1053, Bordeaux, France; CHU Bordeaux, Bordeaux, FranceUniversité de Lyon, Université Claude Bernard Lyon 1, Inserm 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon (CRCL), Lyon, France; Correspondence Address correspondence to: Laurent Bartholin, PhD, Centre de Recherche en Cancérologie de Lyon (CRCL), Inserm U1052, CNRS 5286, Université Claude Bernard Lyon 1, 69008, Lyon, France. fax: +33 (0)4 69 96 68 26.Background & Aims: Transforming growth factor beta (TGFβ) acts either as a tumor suppressor or as an oncogene, depending on the cellular context and time of activation. TGFβ activates the canonical SMAD pathway through its interaction with the serine/threonine kinase type I and II heterotetrameric receptors. Previous studies investigating TGFβ-mediated signaling in the pancreas relied either on loss-of-function approaches or on ligand overexpression, and its effects on acinar cells have so far remained elusive. Methods: We developed a transgenic mouse model allowing tamoxifen-inducible and Cre-mediated conditional activation of a constitutively active type I TGFβ receptor (TβRICA) in the pancreatic acinar compartment. Results: We observed that TβRICA expression induced acinar-to-ductal metaplasia (ADM) reprogramming, eventually facilitating the onset of KRASG12D-induced pre-cancerous pancreatic intraepithelial neoplasia. This phenotype was characterized by the cellular activation of apoptosis and dedifferentiation, two hallmarks of ADM, whereas at the molecular level, we evidenced a modulation in the expression of transcription factors such as Hnf1β, Sox9, and Hes1. Conclusions: We demonstrate that TGFβ pathway activation plays a crucial role in pancreatic tumor initiation through its capacity to induce ADM, providing a favorable environment for KRASG12D-dependent carcinogenesis. Such findings are highly relevant for the development of early detection markers and of potentially novel treatments for pancreatic cancer patients. Keywords: Pancreas, Cancer, TGFβ, Acinar-to-Ductal Metaplasia, KRASG12Dhttp://www.sciencedirect.com/science/article/pii/S2352345X17300875 |
| spellingShingle | Nicolas Chuvin David F. Vincent Roxane M. Pommier Lindsay B. Alcaraz Johann Gout Cassandre Caligaris Karam Yacoub Victoire Cardot Elodie Roger Bastien Kaniewski Sylvie Martel Celia Cintas Sophie Goddard-Léon Amélie Colombe Julie Valantin Nicolas Gadot Emilie Servoz Jennifer Morton Isabelle Goddard Anne Couvelard Vinciane Rebours Julie Guillermet Owen J. Sansom Isabelle Treilleux Ulrich Valcourt Stéphanie Sentis Pierre Dubus Laurent Bartholin Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRASG12D-driven Pancreatic TumorigenesisSummary Cellular and Molecular Gastroenterology and Hepatology |
| title | Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRASG12D-driven Pancreatic TumorigenesisSummary |
| title_full | Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRASG12D-driven Pancreatic TumorigenesisSummary |
| title_fullStr | Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRASG12D-driven Pancreatic TumorigenesisSummary |
| title_full_unstemmed | Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRASG12D-driven Pancreatic TumorigenesisSummary |
| title_short | Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRASG12D-driven Pancreatic TumorigenesisSummary |
| title_sort | acinar to ductal metaplasia induced by transforming growth factor beta facilitates krasg12d driven pancreatic tumorigenesissummary |
| url | http://www.sciencedirect.com/science/article/pii/S2352345X17300875 |
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