Acinar-to-Ductal Metaplasia Induced by Transforming Growth Factor Beta Facilitates KRAS G12D -driven Pancreatic Tumorigenesis
Nicolas Chuvin
(1)
,
David Vincent
(1)
,
Roxane Pommier
(1)
,
Lindsay B Alcaraz
(1)
,
Johann Gout
(1)
,
Cassandre Caligaris
(1)
,
Karam Yacoub
(1)
,
Victoire Cardot
(2, 1)
,
Elodie Roger
(3, 1)
,
Bastien Kaniewski
(1)
,
Sylvie Martel
(4, 1)
,
Celia Cintas
(5)
,
Sophie Goddard-Léon
(1)
,
Amélie Colombe
(1)
,
Julie Valantin
(1)
,
Nicolas Gadot
(1)
,
Emilie Servoz
(1)
,
Jennifer Morton
(6)
,
Isabelle Goddard
(1)
,
Anne Couvelard
(7)
,
Vinciane Rebours
(8)
,
Julie Guillermet
(5)
,
Owen Sansom
(6)
,
Isabelle Treilleux
(1)
,
Ulrich Valcourt
(1)
,
Stéphanie Sentis
(4, 1)
,
Pierre Dubus
(9, 10)
,
Laurent Bartholin
(1)
1
UNICANCER/CRCL -
Centre de Recherche en Cancérologie de Lyon
2 RDP - Reproduction et développement des plantes
3 UA - Université d'Artois
4 Oncogénèse et progression tumorale
5 CRCT - Centre de Recherches en Cancérologie de Toulouse
6 The Beatson Institute for Cancer Research
7 Département d'Anatomo-Pathologie [Hôpital Bichat]
8 CRI (UMR_S_1149 / ERL_8252 / U1149) - Centre de recherche sur l'Inflammation
9 Histologie et Pathologie Moléculaire des Tumeurs
10 Epidémiologie et Biostatistique [Bordeaux]
2 RDP - Reproduction et développement des plantes
3 UA - Université d'Artois
4 Oncogénèse et progression tumorale
5 CRCT - Centre de Recherches en Cancérologie de Toulouse
6 The Beatson Institute for Cancer Research
7 Département d'Anatomo-Pathologie [Hôpital Bichat]
8 CRI (UMR_S_1149 / ERL_8252 / U1149) - Centre de recherche sur l'Inflammation
9 Histologie et Pathologie Moléculaire des Tumeurs
10 Epidémiologie et Biostatistique [Bordeaux]
Nicolas Chuvin
- Fonction : Auteur
- PersonId : 781635
- ORCID : 0000-0002-2138-2330
David Vincent
- Fonction : Auteur
- PersonId : 771430
- ORCID : 0000-0001-6482-8040
- IdRef : 178037249
Roxane Pommier
- Fonction : Auteur
- PersonId : 773888
- ORCID : 0000-0002-5351-7367
Julie Guillermet
- Fonction : Auteur
- PersonId : 183007
- IdHAL : julie-guillermet-guibert
- ORCID : 0000-0003-3173-4907
- IdRef : 091965225
Laurent Bartholin
- Fonction : Auteur
- PersonId : 1210025
- ORCID : 0000-0002-5637-3223
- IdRef : 178038873
Résumé
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.
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.
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.