CONTACT

David BERNARD
Group Leader

david.bernard
@lyon.unicancer.fr


+33 4 69 16 67 92
Cheney D - 2nd floor

Centre Léon Bérard
28 rue Laennec
69373 Lyon Cedex 08
France

BERNARD David
Team Leader, DR2 CNRS
david.bernard@lyon.unicancer.fr
VINDRIEUX David
MA XingJie

Ph.D. student

mxjsdau@163.com
MARTIN Nadine
FLAMAN Jean-Michel
HUNA Anda
LEERS Christopher
RAYNARD Clotilde
GOEHRIG Delphine
ZIEGLER Dorian
JABER Sara
PALAZZO Alberta
Voir les objectifs et projets Voir les publications

Collaborations 
N. Navaratnam, Imperial College, London / M. Bergo, Suède / PA. Defossez, Paris / N. Prévarskaya, Lille / JM. Vanacker, Lyon / M. Perrais et S. Aubert, INSERM, Lille / R. Rossignol, Bordeaux / R. Iggo, Institut Bergonié, Bordeaux  / G. Lambeau, IPMC, Nice  / P. Dubus, CHU Bordeaux

Founding
RTRS fondation Synergie Lyon Cancer  / Institut National du Cancer (INCA) / Fondation ARC / Fondation de France  / Agence Nationale pour la Recherche (ANR) / Ligue contre le Cancer

OBJECTIVES

Failsafe programs resulting in growth arrest and cell death are activated during tumor initiation to inhibit tumor progression. Our team is particularly interested in one anti-tumoral response that results in a stable proliferation arrest named senescence. Our aim is to describe new genetic events involved in escape from senescence, to understand the way in which they work to regulate senescence and their relevance in human cancers. In general, our work contributes to better understanding cancer biology and in some cases may allow us to investigate new strategies to detect or treat cancers, based on the novel mechanisms we have described.

PROJECT

We are currently developing two research axes in the team revolving around senescence escape mechanisms and their functions in cancer.

Axis 1: PLA2R1 function in senescence and cancer 
PLA2R1 is a membrane glysosylated protein of 180 KDa. This protein belongs to the C-type lectin super family and was uncovered in the nineties for its ability to bind secreted phospholipases A2 (sPLA2). Nevertheless, its biological functions, its endogenous ligands in human as well as the signaling pathways it regulates are largely unknown. We have recently isolated PLA2R1 during a loss of function genetic screen to identify new genes, which when lacking, favor senescence escape in human normal cells.

We have demonstrated that:
- its expression decreases in various human cancers (kidney, breast, melanoma);
- its decrease in expression in normal human epithelial cells allows cells to escape failsafe programs and favors tumorogenecity;
- its constitutive expression in various cancer cell lines results in apoptosis in a ROS-dependent manner;
- these ROS are byproducts of the respiratory chain.

We are currently setting up some in vivo models to examine the in vivo function of PLA2R1 during tumorogenesis. We are also interested in understanding the ways PLA2R1 is regulated by cellular ROS production.

Axis 2 : Characterization of new tumor suppressor genes impacting escape from oncogene induced senescence (OIS)
Escape from OIS is involved in the malignant conversion of benign lesions. We have performed a functional loss of function genetic screen to isolate new senescence regulators (eventually p53 and p16-independent). We have already isolated 2 new genetic events involved in OIS escape and others are currently under validation.
We are also interested in mechanisms involved in OIS reversibility. Indeed, senescence has been defined as irreversible but we now know that senescent cells may have the ability to grow back. We have setup a cellular model allowing us to study OIS reversibility. We are particularly interested in lysyl oxidases and their function in regulating extracellular-matrix stiffening. In this context, the lox family has been described to favor migration, invasion and the formation of metastasis. We have demonstrated that lox activity inhibition stabilizes OIS in vitro. Importantly, lox activity inhibition in vivo stabilizes senescence, delays tumor development and increases mice survival by 20% in a murine model of pancreatic adenocarcinoma.

Altogether our work contributes to a better understanding of the mechanisms involved in early tumoral escape. Besides this understanding, we aim at transfering this knowledge to new therapeutic and/or diagnostic strategies.

PUBLICATIONS

2018

Griveau A, Wiel C, Le Calvé B, Ziegler DV, Djebali S, Warnier M, Martin N, Marvel J, Vindrieux D, Bergo MO, Bernard D. Targeting the phospholipase A2 receptor ameliorates premature aging phenotypes. Aging Cell, In press

Ma X, Warnier M, Raynard C, Ferrand M, Kirsh O, Defossez PA, Martin N, Bernard D. The nuclear receptor RXRA controls cellular senescence by regulating calcium signalling. 
Aging Cell, In press

Bernard D. Instructive power of senescence. Nature Reviews Molecular Cell Biology, PMID: 30018342

Warnier M, Flaman JM, Chouabe C, Wiel C, Gras B, Blanc E, Foy JP, Mathot P, Saintigny P, Van Coppenolle F, Vindrieux D, Martin N, Bernard D. The SCN9A channel and plasma membrane depolarization promote cellular senescence through Rb pathway. Aging Cell, PMID: 29446526

Houssaini A, Breau M, Kebe K, Abid S, Marcos E, Lipskaia L, Rideau D, Parpaleix A, Huang J, Amsellem V, Vienney N, Validire P, Maitre B, Attwe A, Lukas C, Vindrieux D, Boczkowski J, Derumeaux G, Pende M, Bernard D, Meiners S, Adnot S. mTOR Pathway Activation Drives Lung-Cell Senescence and Emphysema. JCI insight, PMID: 29415880

Collin G, Huna A, Warnier M, Flaman JM, Bernard D. Transcriptional repression of DNA repair genes is a hallmark and a cause of cellular senescence. Cell Death & Disease, 
PMID: 29449545

Martin N, Bernard D. Calcium signaling and cellular senescence. Cell Calcium, PMID: 28410770

2017

Contrepois K, Coudereau C, Benayoun BA, Schuler N, Roux PF, Bischof O, Courbeyrette R, Carvalho C, Thuret JY, Ma Z, Derbois C, Nevers MC, Volland H, Redon CE, Bonner WM, Deleuze JF, Wiel C, Bernard D, Snyder MP, Rübe CE, Olaso R, Fenaille F, Mann C. Histone variant H2A.J accumulates in senescent cells and promotes inflammatory gene expression. Nature Communications, PMID: 28489069

2016

Griveau A, Devailly G,  Eberst L, Navaratnam N, Le Calvé B, Ferrand M, Faull P, Augert A, Dante R, Vanacker JM, Vindrieux D, Bernard D. The PLA2R1-JAK2 pathway upregulates ERRa and its mitochondrial program to exert tumor-suppressive action. Oncogene, PMID: 27041564

Le Calvé B, Griveau A, Vindrieux D, Maréchal R, Wiel C, Svrcek M, Gout J, Azzi L, Payen L, Cros J, de la Fouchardière C, Dubus P, Guitton J, Bartholin L, Bachet JB, Bernard D. Lysyl Oxidase family activity promotes resistance of pancreatic ductal adenocarcinoma to chemotherapy by limiting the intratumoral anticancer drug distribution. Oncotarget, PMID: 27050073

Wiel C, Gras B, Vindrieux D, Warnier M, Gitenay D, Le Calvé B, Ferrand M, Augert A,  Bernard D. Multidrug Resistance Protein 3 loss promotes tumor formation by inducing senescence escape. Oncogene,  PMID: 26073088

 

2015

Ferrand M, Kirsh O, Griveau A, Vindrieux D, Martin N, Defossez PA and Bernard D. Screening of a kinase library reveals novel pro-senescence kinases and their common NF-κB-dependent transcriptional program. Aging (Albany NY), PMID: 26583757

Bernard D & Wiel C. Transport and senescence. Oncosciences, 2015;2:741-742. PMID: 26501075

 

2014

Verbeke S, Richard E, Monceau E, Schmidt X, Rousseau B, Velasco V, Bernard D, Bonnefoi H, MacGrogan G, Iggo RD. Breast Cancer Res, PMID:25527189

Gitenay D, Lallet-Daher H, Bernard D. Caspase-2 regulates oncogene-induced senescence. Oncotarget, PMID:25114039

Bernard D & Wiel C. Lysyl oxidases: emerging promoters of senescence escape, tumor initiation and progression. Cancer Cell & Microenvironment, 2014;1:51-56.

Wiel C, Lallet-Daher H, Gitenay D, Gras B, Le Calvé B, Augert A, Ferrand M, Prevarskaya N, Simonnet H, Vindrieux D, Bernard D. Endoplasmic reticulum calcium release through ITPR2 channel leads to mitochondrial calcium accumulation and senescence. Nature communications, PMID:24797322

Bernard D, Vindrieux D. PLA2R1: expression and function in Cancer. BBA reviews on Cancer, PMID:24667060

Gitenay D, Wiel C, Lallet-Daher H, Vindrieux D, Aubert S, Payen L, Simonnet H, Bernard D. Glucose metabolism and hexosamine pathway regulate oncogene-induced senescence. Cell Death & Disease, PMID:24577087

Girard CA, Seitz-Polski B, Dolla G, Augert A, Vindrieux D, Bernard D, Lambeau G. New physiopathological roles for the PLA2R1 receptor in cancer and membranous nephropathy. Med Sci (Paris), in press.

Vindrieux D, Devailly G, Augert A, Le Calvé B, Ferrand M, Pigny P, Payen L, Lambeau G, Perrais M, Aubert S, Simonnet H, Dante R, Bernard D. Repression of PLA2R1 by c-MYC and HIF-2alpha promotes cancer growth. Oncotarget, PMID:24657971

Gnemmi V, Bouillez A, Gaudelot K, Hémon B, Ringot B, Pottier N, Glowacki F, Villers A, Vindrieux D, Cauffiez C, Van Seuningen I, Bernard D, Leroy X, Aubert S, Perrais M. MUC1 drives epithelial–mesenchymal transition in renal carcinoma through Wnt/b-catenin pathway and interaction with SNAIL promoter. Cancer Lett, PMID:24384091

Machon C, Le Calve B, Coste S, Riviere M, Payen L, Bernard D, Guitton J. Quantification of beta-aminopropionitrile (BAPN), an inhibitor of lysyl oxidase activity, in plasma and tumor of mice by liquid chromatography tandem mass spectrometry. Biomedical Chromatography, PMID:24424787

2013

Wiel C, Augert A, Vincent DF, Gitenay D, Vindrieux D, Le Calvé B, Arfi A, Lallet-Daher H, Reynaud C, Treilleux I, Bartholin L, Lelievre E, Bernard D. Lysyl oxidase activity regulates oncogenic stress response and tumorigenesis. Cell Death & Disease, PMID:24113189

Vindrieux D, Augert A, Girard CA, Gitenay D, Lallet-Daher H, Wiel C, Le Calvé B, Gras B, Ferrand M, Verbeke S, de Launoit Y, Leroy X, Puisieux A, Aubert S, Perrais M, Gelb M, Simonnet H, Lambeau G, Bernard D. PLA2R1 mediates tumor suppression by activating JAK2. Cancer Res, PMID:24008317

Augert A, Vindrieux D, Girard CA, Le Calvé B, Gras B, Ferrand M, Bouchet BP, Puisieux A, de Launoit Y, Simonnet H, Lambeau G, Bernard D. PLA2R1 kills cancer cells by inducing a mitochondrial stress. Free Radical Biology & Medicine, PMID:23994771

Lallet-Daher H, Wiel C, Gitenay D, Navaratnam N, Augert A, Le Calvé B, Verbeke S, Carling D, Aubert S, Vindrieux D, Bernard D. Potassium channel KCNA1 modulates oncogene-induced senescence and transformation. Cancer Res, PMID:23774215

Vindrieux D, Gras B, Garcia-Belinchon M, Mourah S, Lebbe C, Augert A, Bernard D. Platelet-derived growth factor B induces senescence and transformation in normal human fibroblasts. Aging (Albany NY), PMID:23934686

Avant 2013

Humbert N, Navaratnam N, Augert A, Da Costa M, Martien S, Wang J, Martinez D, Abbadie C, Carling D, de Launoit Y, Gil J, Bernard D. Regulation of ploidy and senescence by the AMPK-related kinase NUAK1. EMBO J, PMID: 19927127

Bernard D, Augert A. NUAK1 links genomic instability and senescence. Aging (Albany NY). PMID: 20603521

Humbert N, Martien S, Augert A, Da Costa M,  Mauen S, Abbadie C, de Launoit Y, Jesus Gil, Bernard D. A genetic screen identifies Topoisomerase 1 as a regulator of senescence. Cancer Res, PMID: 19435923

Augert A, Payré C, de Launoit Y, Gil J, Lambeau G, Bernard, D. The M-type receptor PLA2R regulates senescence through the p53 pathway. EMBO R, PMID: 19197340

Acosta JC, O’Loghlen A, Banito A, Guijarro MV, Augert A, Raguz S, Fumagalli M, Da costa M, Brown C, Popov N, Takatsu Y, Melamed J, d’adda di fagagna F, Bernard D, Henando E, Gil J. Chemokine signaling via CXCR2 receptor reinforces senescence. Cell, PMID: 18555777

Bernard D, Gil J, Dumont P, Monté D, Quatannens B, Hudson D, Visakorpi T, Fuks F, de Launoit Y . Methyl CpG binding protein MeCP2 is required for prostate cancer cell growth. Oncogene, PMID: 16331274

Viré E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, de Launoit Y and Fuks F. The Polycomb group protein EZH2 directly controls DNA methylation. Nature, PMID: 16357870

Bernard D, Martinez-Leal JF, Rizzo S, Hudson D, Visakorpi T, Peters G, Carnero A, Beach D and Gil J. CBX7 Controls the Growth of Normal and Cancer Prostate Cells by Repressing the Ink4a/Arf Locus. Oncogene, PMID: 15897876

Bernard D, Gosselin K, Monte D, Vercamer C, Bouali F, Pourtier A, Vandenbunder B and Abbadie C. Involvement of Rel/NF-kB transcription factors in keratinocyte senescence. Cancer Res, PMID: 14744759

Gil J, Bernard D, Martinez D, Beach D. Polycomb CBX7: a unifying role in cellular lifespan. Nat. Cell Biol, PMID: 14647293

Bernard D, Pourtier-Manzanedo A, Gil J, Beach DH. c-myc confers androgen-independent prostate cancer cell growth. J Clin Invest, PMID: 14660748

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