CONTACT

Laurent Bartholin
Team leader

laurent.bartholin@
lyon.unicancer.fr

+33 4 78 78 28 63

BARTHOLIN Laurent
Team Leader, CR1 Inserm
laurent.bartholin@inserm.fr
FOUREL Geneviève
VALCOURT Ulrich

Lecturer Université Lyon 1

ulrich.valcourt@lyon.unicancer.fr
MARTEL Sylvie
CHUVIN Nicolas
GOUT Johann
Postdoctoral fellow
johan.gout@lyon.unicancer.fr
ALCARAZ Lindsay
POMMIER Roxane
SENTIS Stéphanie
Voir les objectifs et projets Voir les publications
Founding 
INSERM Programme Avenir
Ligue nationale contre le cancer
Fondation ARC 
INCa (Institut National du Cancer)

OBJECTIVES

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive neoplasm; it is always fatal and is the fifth most common cause of cancer-associated mortality in the Western world. No efficient treatment is currently available, so it is essential to develop new therapeutic strategies. In our team, we are interested in the cellular and molecular mechanisms controlling pancreatic cancer initiation, progression and metastatic dissemination. We are particularly interested in deciphering the precise role of the Transforming Growth Factor Signaling Beta (TGFβ), the signaling of which is impaired in virtually all cases of pancreatic cancers. To that end, we have developed murine models of pancreatic cancer with genetic alterations targeting different branches of TGFβ signaling. Eventually, we will rely on these models to test new therapeutic approaches.

PROJECT

Our team works on PDAC, a highly aggressive tumor which is resistant to most of the treatments available currently. Pancreatic cancer is the 5th cause of cancer-associated mortality, with a 3-year survival rate estimated at 5%. It thus constitutes a major public health issue, all the more so since population aging increases its incidence rate. It is therefore essential to develop and offer more efficient treatments for patients.

Our team is particularly interested in TGFβ (Transforming Growth Factor Beta), an instrumental cytokin in pancreas tumorigensesis, the signaling of which is affected in virtually all pancreatic cancers. TGFβ signaling hence constitutes a potentially attractive therapeutic target.

Our research projects are characterized by their continuity, from fundamental aspects involving the different steps resulting in malignant transformation (tumor initiation, progression and dissemination) to the implementation of clinical trials to test novel therapeutic approaches. In addition, our aim is to identify predictive markers expressed at an early stage of the disease (since it is generally detected at an advanced stage), as well as prognostic markers (which may provide an indication of the development of restistance to a treatment).


PUBLICATIONS

Publications originales

Wiel C., Augert A., Vincent D.F., Gitenay D., Vindrieux D., Le Calvé B., Arfi V., Lallet-Daher H., Reynaud C., Treilleux I., Bartholin L., Lelievre E., Bernard D. Lysyl oxidase activity regulates oncogenic stress response and tumorigenesis. Cell Death Dis., Oct 10;4:e855, 2013

Cano C.E., Hamidi T., Garcia M.N., Grasso D., Loncle C, Garcia S., Calvo E., Lomberk G., Dusetti N., Bartholin L., Urrutia R., Iovanna J.L. Genetic Inactivation of Nupr1 acts as a dominant suppressor event in a two Hit Model of pancreatic carcinogenesis. Gut, Sep 14. doi: 10.1136/gutjnl-2013-30522, 2013

Gout J., Pommier R.M., Vincent D.F., Kaniewski B., Martel S., Valcourt U., Bartholin L. Isolation and culture of mouse primary pancreatic acinar cells. J. Vis. Exp., (78): e50514, 2013

Gout J., Pommier R.M., Vincent D.F., Ripoche D., Goddard-Leon S., Colombe A., Treilleux I., Valcourt U., Tomasini R., Dufresne M., Bertolino P., Bartholin L. The conditional expression of KRASG12D in mouse pancreas induces disorganization of endocrine islets prior the onset of ductal pre-cancerous lesions. Pancreatology 13(3): 191-195, 2013

Ripoche D., Gout J., Pommier R.M., Jaafar R., Zhang C.X., Bartholin L., Bertolino P. Generation of a conditional mouse model to inactivate Acvr1b in adult tissues. Genesis 51(2): 120-127, 2013

Cano C.E., Sandí M.J., Hamidi T., Calvo E.L., Turrini O., Bartholin L., Loncle C., Secq V., Garcia S., Lomberk G., Kroemer G., Urrutia R. Iovanna J.L. Homotypic cell cannibalism, a cell-death process regulated by the nuclear protein 1, opposes to metastasis in pancreatic cancer. EMBO Mol. Med. Sep;4(9):964-79, 2012

Pommier R.M., Gout J., Vincent D.F., Cano C.E., Kaniewski B., Martel S., Rodriguez J., Fourel G., Valcourt U., Marie J.C., Iovanna J.L., Bartholin L. The human NUPR1/P8 gene is transcriptionally activated by transforming growth factor β via the SMAD signalling pathway. Biochem. J. Jul 15;445(2):285-93, 2012

Zerlanko B.J., Bartholin L., Wotton D. Premature senescence and increased TGFβ signaling in the absence of Tgif1. PLoS ONE 7(4):e35460. Epub 2012 Apr 13., 2012

Vincent D.F., Gout J., Chuvin N., Arfi V., Pommier R.M., Bertolino P., Jonckheere N., Ripoche D., Kaniewski B., Martel S., Langlois J.B., Goddard-Léon S., Colombe A., Janier M., Van Seuningen I., Valcourt U., Treilleux I., Dubus P., Bardeesy N., Bartholin L. TIF1γ and SMAD4 act in Separate Pathways to Suppress Kras-driven Pancreatic Tumorigenesis.  Am. J. Pathol. Jun;180(6):2214-21. Epub 2012 Mar 3, 2012

Vincent D., Kaniewski B., Powers S., Havenar-Daughton C., Marie J.C., Wotton D. Bartholin L. Allele in LSL-TβRICA Transgenic mice. Genesis Sep;48(9):559-62, 2010

Vincent D.F., Yan K.P., Treilleux I., Gay F., Arfi V., Kaniewski B., Marie J.C., Lepinasse F., Martel S.,  Goddard-Léon S., Iovanna J.L., Dubus P., Garcia S.,  Puisieux A., Rimokh R., Bardeesy N., Scoazec J.Y., Losson R., Bartholin L. Inactivation of TIF1γ Cooperates with KrasG12D to Induce Cystic Tumors of the Pancreas. PLoS Genet. Jul;5(7):e1000575. Epub 2009 Jul 24, 2009

Doisne J.M.#, Bartholin L. #, Yan K., Garcia C.N., Duarte N., Le Luduec J.B., Martel S., Horvat B.,  Vincent D.F., Cyprian F., Rimokh R., Losson R., Benlagha K., Marie J.C. iNKT Cell-development is Orchestrated by Different Branches of TGFβ Signaling. J. Exp. Med. Jun 8;206(6):1365-78. Epub 2009 May 18, 2009 #equal contribution

Bartholin L. *, Cyprian F.S., Vincent D.F., Garcia C.N., Martel S., Horvat B., Berthet C., Goddard-Léon S., Treilleux I., Rimokh R., Marie J.C. Generation of mice with conditionally activated transforming growth factor beta signaling through the TbetaRI/ALK5 receptor. Genesis Dec;46(12):724-31, 2008 *corresponding author

Bartholin L., Melhuish T.A.,. Powers S.E., Goddard-Léon S., Treilleux I., Sutherland A.E., Wotton D. Maternal Tgif is required for vascularization of the embryonic placenta. Dev. Biol. Jul 15;319(2):285-97, 2008

Razanajaona D., Joguet S., Ay A.S., Treilleux I., Goddard-Leon S., Bartholin L., Rimokh R. Silencing of FLRG, an Antagonist of Activin, Inhibits Human Breast Tumor Cell Growth. Cancer Res. Aug 1;67(15):7223-9, 2007

Forissier S., Razanajaona D., Ay A.S., Martel S., Bartholin L., Rimokh R. AF10 dependent transcription is enhanced by its interaction with FLRG. Biol. Cell  Oct;99(10):563-71, 2007

Bartholin L., Guindon S., Martel S., Corbo L., Rimokh R. Identification of NF-kappaB responsive elements in follistatin related gene (FLRG) promoter. Gene May 15;393(1-2):153-62, 2007

El-Jaick K.B., Powers S.E., Bartholin L., Myers K.R., Hahn J., Orioli I.M., Ouspenskaia M., Lacbawan F., Roessler E., Wotton D., Muenke M. Functional analysis of mutations in TGIF associated with holoprosencephaly. Mol. Genet. Metab. Jan;90(1):97-111, 2007

Bartholin L., Wessner L., Chirgwin J.M., Guise T.A. Transcriptional activation of hCCN1/Cyr61 gene by TGFβ. Cancer Lett.  Feb 8;246(1-2):230-236, 2007

Bartholin L., Powers S.E., Melhuish T.A., Lasse S., Weinstein M. and Wotton D. TGIF inhibits retinoid signaling.  Mol. Cell. Biol. Feb;26(3):990-1001.26, 2006

Maguer-Satta V., Forissier S., Bartholin L., Martel S., Jeanpierre S., Bachelard E., Rimokh. A novel role for fibronectin type I domain in the regulation of human hematopoietic cell adhesiveness through binding to follistatin domains of FLRG and follistatin. Exp. Cell Res. Feb 15;312(4):434-42, 2006

Bartholin L., Destaing O., Forissier S., Martel S., Maguer-Satta V., Jurdic P., Rimokh R. FLRG, a new ADAM12-associated protein, modulates osteoclast differentiation. Biol. Cell Jul;97(7):577-88, 2005

Baseggio L., Bartholin L., Chantome A,. Charlot C., Rimokh R., Salles G. Allele-specific binding to the -308 single nucleotide polymorphism site in the tumour necrosis factor-alpha promoter. Eur. J. Immunogenet. Feb;31(1):15-9, 2004

Hyman C.A., Bartholin L., Newfeld S.J., Wotton D. Drosophila TGIF proteins are transcriptional activators. Mol. Cell. Biol. Dec;23(24):9262-74, 2003

Maguer-Satta V.#, Bartholin L.#, Jeanpierre S., Ffrench M.,  Magaud J.P., Rimokh R. Regulation of human erythropoiesis by Activin A, BMP2 and BMP4, two members of the TGFbeta family. Exp. Cell Res. Jan 15;282(2):110-20, 2003 #equal contribution
 
Hayette S., Tigaud I., Maguer-Satta V., Bartholin L., Thomas X., Charrin C., Gadoux, M., Magaud J.P., Rimokh R. Recurrent involvement of the MLL gene in adult T-lineage acute lymphoblastic leukemia. Blood Jun 15;99(12):4647-9, 2002

Bartholin L., Maguer-Satta V., Hayette S., Martel S., Gadoux M., Corbo L., Magaud J.P., Rimokh R. Transcription activation of FLRG and follistatin by activin A, through Smad proteins, participates in a negative feedback loop to modulate activin A function.  Oncogene Mar 28;21(14):2227-35, 2002

Bartholin L., Maguer-Satta V., Hayette S., Martel S., Gadoux M., Bertrand S., Corbo L., Lamadon C., Morera A.M., Magaud J.P., Rimokh R. FLRG, an activin-binding protein, is a new target of TGFbeta transcription activation through Smad proteins. Oncogene Sep 6;20(39):5409-19, 2001

Maguer-Satta V., Bartholin L., Jeanpierre S., Gadoux M., Bertrand S., Martel S., Magaud J.P., Rimokh R. Expression of FLRG, a novel activin A ligand, is regulated by TGFbeta and during hematopoiesis. Exp. Hematol. Mar;29(3):301-8, 2001

Birot A.M.,  Duret L., Bartholin L., Santalucia B., Tigaud I.,  Magaud J.P., Rouault J.P. Identification and molecular analysis of BANP. Gene Aug 8;253(2):189-96, 2000

Revues générales/Chapitres d'ouvrages spécialisés

1-Principe D.R., Doll J.A., Bauer J., Jung B., Munshi H.G., Bartholin L., Pasche B., Lee C., Grippo P.J., “TGFb: Duality of function between tumor prevention and carcinogenesis”, JNCI, Sous presse

2-Valcourt U., Carthy J., Okita Y., Alcaraz L., Kato M., Thuault S., Bartholin L., Moustakas A. Comprehensive chapter in special volume on “TGF-beta Signaling for Methods in Molecular Biology” for Methods in Molecular Biology (Chapter title: “Analysis of epithelial-mesenchymal transition induced by transforming growth factor β”). Edited by Feng X.H, Humana Press, Springer publishing group, Sous presse

3-Valcourt U., Pommier R., Vincent D.F., Bartholin L. Culture primaire de cellules pancréatiques exocrines de souris : un outil indispensable pour la compréhension de l’étiologie de la carcinogenèse pancréatique. Ouvrage: Culture de cellules animales (in French). Barlovatz-Meimon G., Guillouzo C., Ronot X. 3ème édition, Ed. Lavoisier, Sous presse

4- Bartholin L., Vincent D.F., Valcourt U. Comprehensive chapter in special volume on "TGF-beta in human disease" (Chapter title: “TGF-beta as tumor suppressor: in vitro mechanistic aspects of growth inhibition"). Edited by Moustakas A. and Miyazawa K. Springer Special Research Volumes, p113-138, 2013

5-Valcourt U., Vincent D., Bartholin L. Comprehensive chapter in special volume on "TGF-beta in human disease" (Chapter title: “TGF-beta as tumor suppressor: Lessons from mouse models”). Edited by Moustakas A. and Miyazawa K. Springer Special Research Volumes, p139-168, 2013

6-Bartholin L. Comprehensive chapter in “Mouse Models and Mesenchymal Targeting” book. (Chapter title “Pancreatic Cancer and the Tumor Microenvironment: Mesenchyme’s role in Pancreatic Carcinogenesis”). Edited by Paul J. Grippo (Northwestern University, Chicago, USA). Research Signpost Ed, 2012

7-Bartholin L. and Guise TyA. Comprehensive chapter in “TGF-beta in Cancer Therapy”, Beverly Teicher’s Methods in Molecular Biology series on “Cancer Drug Discovery and Development”. (Chapter title “Role of TGFb in osteolytic bone lesions”). Edited by Sonia B. Jakowlew (NIH, Bethesda, USA). Humana Press Book and Journal, Vol II “Cancer Treatment and Therapy”, 95-123, 2008

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