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contact
00 33 (0)5 62 74 45 22
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RESEARCH GROUP 'Environment & Intestinal Epithelium Interactions'
-EINSTEIN- |
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PLATEFORME ORGANOÏDES, Responsable scientifique
CORE FACILITY ORGANOÏDS, Scientific Head |
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Recherche/projet research/project
Interactions entre les cellules épithéliales et leur environnement dans les pathologies colorectales
Les cellules épithéliales colorectales interagissent constamment avec leur microenvironnement, et notamment avec les fibroblastes qui représentent la population cellulaire majoritaire au sein du stroma. Que ce soit en condition physiologique ou lors de pathologies comme les maladies inflammatoires chroniques de l’intestin ou le cancer, ces interactions entre l’épithélium et le stroma régulent les phénotypes et les comportements des cellules de ces tissus. Par exemple, les fibroblastes entourant la crypte colorectale, participent activement à la niche des cellules souches colorectales en régulant leur prolifération et les processus de différenciation et migration cellulaire permettant le renouvellement de l’épithélium colorectal. En condition inflammatoire ou tumorale, ces interactions sont altérées ce qui contribue au développement pathologique, y compris le processus métastatique lors d’un cancer.
En combinant des approches morphologiques, fonctionnelles, pharmacologiques et microfluidiques sur des primocultures cellulaires en 3D d’organoïdes colorectaux et de fibroblastes, couplées à des modèles de greffes orthotopiques sur modèles murins, nous étudions les interactions entre les cellules souches colorectales normales ou tumorales, et les fibroblastes, dans les différentes étapes du processus tumoral colorectal.
Interrelationship between epithelial cells and their environment in colorectal diseases
Colorectal epithelial cells constantly interact with their microenvironment, particularly with the fibroblasts which represent the major cell population within the stroma. Under physiological condition or during inflammatory bowel diseases or cancer, these interactions between the epithelium and the stroma regulate the phenotypes and behaviour of the cells in these tissues. For example, fibroblasts surrounding colorectal crypt actively participate to the colorectal stem cell niche by regulating their proliferation, differentiation but also the migration process involved in the renewal of the colorectal epithelium. Under tumoral or inflammatory conditions, these interactions are altered which contributes to the disease development, including the metastasis process in cancer.
By combining morphological, functional, pharmacological and microfluidic approaches to 3D cell primocultures of colorectal organoids and fibroblasts, coupled to orthotopic grafting on murine models, we study the interactions between normal or cancer stem cells and fibroblasts in the various stages of colorectal tumorigenesis.
Les cellules épithéliales colorectales interagissent constamment avec leur microenvironnement, et notamment avec les fibroblastes qui représentent la population cellulaire majoritaire au sein du stroma. Que ce soit en condition physiologique ou lors de pathologies comme les maladies inflammatoires chroniques de l’intestin ou le cancer, ces interactions entre l’épithélium et le stroma régulent les phénotypes et les comportements des cellules de ces tissus. Par exemple, les fibroblastes entourant la crypte colorectale, participent activement à la niche des cellules souches colorectales en régulant leur prolifération et les processus de différenciation et migration cellulaire permettant le renouvellement de l’épithélium colorectal. En condition inflammatoire ou tumorale, ces interactions sont altérées ce qui contribue au développement pathologique, y compris le processus métastatique lors d’un cancer.
En combinant des approches morphologiques, fonctionnelles, pharmacologiques et microfluidiques sur des primocultures cellulaires en 3D d’organoïdes colorectaux et de fibroblastes, couplées à des modèles de greffes orthotopiques sur modèles murins, nous étudions les interactions entre les cellules souches colorectales normales ou tumorales, et les fibroblastes, dans les différentes étapes du processus tumoral colorectal.
Interrelationship between epithelial cells and their environment in colorectal diseases
Colorectal epithelial cells constantly interact with their microenvironment, particularly with the fibroblasts which represent the major cell population within the stroma. Under physiological condition or during inflammatory bowel diseases or cancer, these interactions between the epithelium and the stroma regulate the phenotypes and behaviour of the cells in these tissues. For example, fibroblasts surrounding colorectal crypt actively participate to the colorectal stem cell niche by regulating their proliferation, differentiation but also the migration process involved in the renewal of the colorectal epithelium. Under tumoral or inflammatory conditions, these interactions are altered which contributes to the disease development, including the metastasis process in cancer.
By combining morphological, functional, pharmacological and microfluidic approaches to 3D cell primocultures of colorectal organoids and fibroblasts, coupled to orthotopic grafting on murine models, we study the interactions between normal or cancer stem cells and fibroblasts in the various stages of colorectal tumorigenesis.
Projets principaux/Main Projects
Impact des altérations du stroma sur le phénotype et les fonctions des cellules souches de la crypte intestinale /
Impact of stroma alteration on teh phenotype and functions of the Intestinal Stem cells
Travaillant sur le projet/ working on the project:
- Dimitri Hamel (PhD student in co-supervision with Laurent Malaquin, LAAS-CNRS, Toulouse)
- Fanny Boche (M2R student-Cancerology)
Financement/Funding :
- Plan Cancer 'Biologie des systèmes' 2018-2021 (PI, coordination: Audrey Ferrand)
- Cancéropôle GSO, label ‘Emergence’ (PI, coordination : Audrey Ferrand)
- Université Toulouse III - Paul Sabatier
- Région Occitanie
Collaborations :
- Laurent Malaquin, LAAS-CNRS, Toulouse
- Marie-Isabelle Garcia, ULB, Bruxelles, Belgium
- Scott Magness, University of Noth Carolina, Chapel Hill, USA
- Florian Bugarin, Institut Clément Ader, Toulouse
- Guillaume Gay, Morphogenie Logiciels
Impact de l’absorption intestinale de nanoparticules alimentaires sur le risque de cancer colorectal / Impact of the intestinal absorption of alimentary nanoparticles on colorectal cancer risk
Travaillant sur le projet/Working on the project
- Raphaël Durant, AI CDD
Financement/Funding : Plan Cancer 2014-2019, (PI, coordination: Audrey Ferrand)
Collaborations :
Frédérick Barreau, IRSD, Toulouse Marie Carrière, CEA, Grenoble Robert Mauricot, CEMES, Toulouse
Développement d’un criblage sur organoïdes colorectaux humains en 3D pour l’identification de drogues candidates contre le cancer colorectal / Development of a screening model based on 3D human colon organoïd to identify drug candidates against colorectal cancer
Travaillant sur le projet/Working on the project : Muriel Quaranta-Nicaise, IE UPS, Morgane Sébert, Doctorante (co-tutelle de thèse avec N. Vergnolle, 2015-2018, CDD FUI) et Aude Rubio (CDD FUI)
Financement/Funding : FUI , (PI : Philippe Lluel)
Collaborations :
- Philippe Lluel et Sophie Chabot, Urosphère, Toulouse
- Fédération digestive des hôpitaux de Toulouse
- Institut de Recherche Pierre Fabre, Toulouse
Lien : Plateforme ‘Organoïdes’ IRSD / IRSD Organoid platform
Impact of stroma alteration on teh phenotype and functions of the Intestinal Stem cells
Travaillant sur le projet/ working on the project:
- Dimitri Hamel (PhD student in co-supervision with Laurent Malaquin, LAAS-CNRS, Toulouse)
- Fanny Boche (M2R student-Cancerology)
Financement/Funding :
- Plan Cancer 'Biologie des systèmes' 2018-2021 (PI, coordination: Audrey Ferrand)
- Cancéropôle GSO, label ‘Emergence’ (PI, coordination : Audrey Ferrand)
- Université Toulouse III - Paul Sabatier
- Région Occitanie
Collaborations :
- Laurent Malaquin, LAAS-CNRS, Toulouse
- Marie-Isabelle Garcia, ULB, Bruxelles, Belgium
- Scott Magness, University of Noth Carolina, Chapel Hill, USA
- Florian Bugarin, Institut Clément Ader, Toulouse
- Guillaume Gay, Morphogenie Logiciels
Impact de l’absorption intestinale de nanoparticules alimentaires sur le risque de cancer colorectal / Impact of the intestinal absorption of alimentary nanoparticles on colorectal cancer risk
Travaillant sur le projet/Working on the project
- Raphaël Durant, AI CDD
Financement/Funding : Plan Cancer 2014-2019, (PI, coordination: Audrey Ferrand)
Collaborations :
Frédérick Barreau, IRSD, Toulouse Marie Carrière, CEA, Grenoble Robert Mauricot, CEMES, Toulouse
Développement d’un criblage sur organoïdes colorectaux humains en 3D pour l’identification de drogues candidates contre le cancer colorectal / Development of a screening model based on 3D human colon organoïd to identify drug candidates against colorectal cancer
Travaillant sur le projet/Working on the project : Muriel Quaranta-Nicaise, IE UPS, Morgane Sébert, Doctorante (co-tutelle de thèse avec N. Vergnolle, 2015-2018, CDD FUI) et Aude Rubio (CDD FUI)
Financement/Funding : FUI , (PI : Philippe Lluel)
Collaborations :
- Philippe Lluel et Sophie Chabot, Urosphère, Toulouse
- Fédération digestive des hôpitaux de Toulouse
- Institut de Recherche Pierre Fabre, Toulouse
Lien : Plateforme ‘Organoïdes’ IRSD / IRSD Organoid platform
Mini CV
- 2000-04 : Doctorante, INSERM U531, Toulouse, France
- 2000-04 : Monitrice en biologie cellulaire et pharmacologie, Université Paul Sabatier, Toulouse, France
- 2002 : Scientifique invitée, Université de Massachusetts Medical School, département de médecine, Worcester, USA
- 2003 : Scientifique invitée, Université de Massachusetts Medical School, département de médecine, Worcester, USA
- 2005-06: Post-Doctoral Fellow, Massachusetts General Hospital, Harvard Medical School, Boston, USA
- 2006-09 : Scientifique en biomédecine, Université de Melbourne, Département de chirurgie, Melbourne, Australie
- Depuis 2009, Chercheuse INSERM (CR1), INSERM, Toulouse, France
- 2000-04: PhD Student, INSERM U531, Toulouse, France
- 2000-04: Lecturer in Cell Biology and Pharmacology, Université Paul Sabatier, Toulouse, France
- 2002: Visiting Scientist, University of Massachusetts Medical School, Medicine department, Worcester, USA
- 2003: Visiting Scientist, University of Massachusetts Medical School, Medicine department, Worcester, USA
- 2005-06: Post-Doctoral Fellow, Massachusetts General Hospital, Harvard Medical School, Boston, USA
- 2006-09: Medical Scientist, University of Melbourne, Department of Surgery, Melbourne, Australia
- Since 2009 : INSERM permanent researcher-Principal Investigator (CR1), INSERM, Toulouse, France
expertise
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Cellular models :
- Human colorectal fibroblast primocultures - Human and murine 3D colon organoid primocultures Animal models : - Sub-cutaneous or caecum orthotopic grafting in murine models Methods: - 2D and 3D cell culture - Animal experimentation - Protein expression (Western-blot, invalidation ...) - RT-qPCR - Capillary Electrophoresis - Confocal and bi-photon imaging |
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Production scientifique scientific production
PUBLICATIONS
-Ingrid langer, Irina G. Tikhonova, Corinne Boulègue, Jean-Pierre Estève, Sébastien Vatinel, Audrey Ferrand, Luis Moroder, Patrick Robberecht, Daniel Fourmy.
Evidence for a direct and functional interaction between the regulators of G protein signaling-2 and phosphorylated C terminus of cholecystokinin-2 receptor.
Mol Pharmacol, 2009, Mar 75(3):502-13
- Audrey Ferrand, Mauro S. Sandrin, Arthur Shulkes, Graham Baldwin
Expression of gastrin precursors by CD133-positive colorectal cancer cells is crucial for tumour growth. BBA Mol Cell Res, 2009, Mar, 1793(3):477-488
- Suzana Kovac, Audrey Ferrand, Jean-Pierre Estève, Anne B. Mason, Graham S. Baldwin.
Definition of the residues required for the interaction between glycine-extended gastrin and transferrin in vitro. FEBS J. 2009 Sep;276(17):4866-74.
- Claudine Bertrand, Aline Kowalski-Chauvel, Catherine Do, Cécile Résa, Souad Najib, Laurence Daulhac, Timothy C. Wang, Audrey Ferrand, Catherine Seva.
A gastrin precursor, gastrin-gly, upregulates VEGF expression in colonic epithelial cells through an HIF-1-independent mechanism. Int J Cancer. 2010 Jun 15;126(12):2847-57.
- Audrey Ferrand, Shamila Lachal , Gianni Bramante, Suzana Kovac, Arthur Shulkes, Graham S. Baldwin.
Stimulation of proliferation in the colorectal mucosa by gastrin precursors is blocked by desferrioxamine. Am J Physiol Gastrointest Liver Physiol. 2010 Apr 15.
- Kowalski-Chauvel A, Najib S, Tikhonova IG, Huc L, Lopez F, Martinez LO, Cohen-Jonathan-Moyal E, Ferrand A, Seva C Identification of the F1-ATPase at the cell surface of colonic epithelial cells: role in mediating cell proliferation. J Biol Chem. 2012 Nov 30; 287(49):41458-68.
- Do C, Bertrand C, Palasse J, Delisle MB, Shulkes A, Cohen-Jonathan-Moyal E, Ferrand A, Seva C. A new biomarker that predicts colonic neoplasia outcome in patients with hyperplastic colonic polyps. Cancer Prev Res (Phila). 2012 Apr; 5(4):675-84.
- Baldwin GS, Lio DS, Ferrand A, Catimel B, Shehan BP, Norton RS, Cheng HC. Activation of Src family tyrosine kinases by ferric ions. Biochim Biophys Acta. 2014 Mar;1844(3):487-96.
- Nasri I, Bonnet D, Zwarycz B, d'Aldebert E, Khou S, Mezghani-Jarraya R, Quaranta M, Rolland C, Bonnart C, Mas E, Ferrand A, Cenac N, Magness S, Van Landeghem L, Vergnolle N, Racaud-Sultan C."PAR2-dependent activation of GSK3β regulates the survival of colon stem/progenitor cells". Am J Physiol Gastrointest Liver Physiol. 2016 Aug 1;311(2):G221-36.
- Nasri I, Chawech R, Girardi C, Mas E, Ferrand A, Vergnolle N, Fabre N, Mezghani-Jarraya R, Racaud-Sultan C. Anti-inflammatory and anticancer effects of flavonol glycosides from Diplotaxis harra through GSK3β regulation in intestinal cells. Pharm Biol. 2017 Dec;55(1):124-131.
- Sébert M, Denadai-Souza A, Quaranta M, Racaud-Sultan C, Chabot S, Lluel P, Monjotin N, Alric L, Portier G, Kirzin S, Bonnet D, Ferrand A*, Vergnolle N*. (*: co-last author). Thrombin modifies growth, proliferation and apoptosis of human colon organoids: a PAR1- and PAR4-dependent mechanism. Br J Pharmacol. 2018 Jun 30, doi: 10.1111/bph.14430
PATENTS
PCT/EP2014/057343 and PCT/EP2012/060289, Method for predicting the risk of developing a colonic neoplasia.
-Ingrid langer, Irina G. Tikhonova, Corinne Boulègue, Jean-Pierre Estève, Sébastien Vatinel, Audrey Ferrand, Luis Moroder, Patrick Robberecht, Daniel Fourmy.
Evidence for a direct and functional interaction between the regulators of G protein signaling-2 and phosphorylated C terminus of cholecystokinin-2 receptor.
Mol Pharmacol, 2009, Mar 75(3):502-13
- Audrey Ferrand, Mauro S. Sandrin, Arthur Shulkes, Graham Baldwin
Expression of gastrin precursors by CD133-positive colorectal cancer cells is crucial for tumour growth. BBA Mol Cell Res, 2009, Mar, 1793(3):477-488
- Suzana Kovac, Audrey Ferrand, Jean-Pierre Estève, Anne B. Mason, Graham S. Baldwin.
Definition of the residues required for the interaction between glycine-extended gastrin and transferrin in vitro. FEBS J. 2009 Sep;276(17):4866-74.
- Claudine Bertrand, Aline Kowalski-Chauvel, Catherine Do, Cécile Résa, Souad Najib, Laurence Daulhac, Timothy C. Wang, Audrey Ferrand, Catherine Seva.
A gastrin precursor, gastrin-gly, upregulates VEGF expression in colonic epithelial cells through an HIF-1-independent mechanism. Int J Cancer. 2010 Jun 15;126(12):2847-57.
- Audrey Ferrand, Shamila Lachal , Gianni Bramante, Suzana Kovac, Arthur Shulkes, Graham S. Baldwin.
Stimulation of proliferation in the colorectal mucosa by gastrin precursors is blocked by desferrioxamine. Am J Physiol Gastrointest Liver Physiol. 2010 Apr 15.
- Kowalski-Chauvel A, Najib S, Tikhonova IG, Huc L, Lopez F, Martinez LO, Cohen-Jonathan-Moyal E, Ferrand A, Seva C Identification of the F1-ATPase at the cell surface of colonic epithelial cells: role in mediating cell proliferation. J Biol Chem. 2012 Nov 30; 287(49):41458-68.
- Do C, Bertrand C, Palasse J, Delisle MB, Shulkes A, Cohen-Jonathan-Moyal E, Ferrand A, Seva C. A new biomarker that predicts colonic neoplasia outcome in patients with hyperplastic colonic polyps. Cancer Prev Res (Phila). 2012 Apr; 5(4):675-84.
- Baldwin GS, Lio DS, Ferrand A, Catimel B, Shehan BP, Norton RS, Cheng HC. Activation of Src family tyrosine kinases by ferric ions. Biochim Biophys Acta. 2014 Mar;1844(3):487-96.
- Nasri I, Bonnet D, Zwarycz B, d'Aldebert E, Khou S, Mezghani-Jarraya R, Quaranta M, Rolland C, Bonnart C, Mas E, Ferrand A, Cenac N, Magness S, Van Landeghem L, Vergnolle N, Racaud-Sultan C."PAR2-dependent activation of GSK3β regulates the survival of colon stem/progenitor cells". Am J Physiol Gastrointest Liver Physiol. 2016 Aug 1;311(2):G221-36.
- Nasri I, Chawech R, Girardi C, Mas E, Ferrand A, Vergnolle N, Fabre N, Mezghani-Jarraya R, Racaud-Sultan C. Anti-inflammatory and anticancer effects of flavonol glycosides from Diplotaxis harra through GSK3β regulation in intestinal cells. Pharm Biol. 2017 Dec;55(1):124-131.
- Sébert M, Denadai-Souza A, Quaranta M, Racaud-Sultan C, Chabot S, Lluel P, Monjotin N, Alric L, Portier G, Kirzin S, Bonnet D, Ferrand A*, Vergnolle N*. (*: co-last author). Thrombin modifies growth, proliferation and apoptosis of human colon organoids: a PAR1- and PAR4-dependent mechanism. Br J Pharmacol. 2018 Jun 30, doi: 10.1111/bph.14430
PATENTS
PCT/EP2014/057343 and PCT/EP2012/060289, Method for predicting the risk of developing a colonic neoplasia.
