Accueil > TERI Department > Apoptosis, cancer and development
Apoptosis, cancer and development

Objectives
The team originally proposed the dependence receptor theory. These receptors have a dual signaling ability : when bound to their ligand they induce survival pathways, whereas they induce an active signal of cell death in the absence of their ligand. The team currently works on three approaches: (1) deciphering the molecular mechanisms of dependence receptor-induced cell death; (2) characterizing new dependence receptors; (3) analizing the physiological role of these receptors in tumor progression. Finally, the team aims at transforming basic knowlegde into therapeutic approaches to restore cell death induced by these receptors in tumors.
Projects
Our team investigates all aspects related to dependence receptors (DR). These receptors have a dual signaling ability: in the presence of their cognate ligand they induce a survival signal, whereas they transduce an active apoptotic signal in the absence of such ligands. More than twenty such receptors have been described to date and we speculated that their activity is instrumental for embryonic development as well as for the regulation of tumorigenesis (Mehlen et al., 2011, Nat Rev Cancer).
This concept of dependence receptors arose by highlighting the importance of such receptors in developmental processes and in tumor development. We initially proposed that the dependence receptor function was important to regulate migration and localization of cells during development (for example neurons and endothelial cells) (Thibert et al., 2003, Science; Mille et al., 2009, Nature Cell Biology; Castets et al., 2009, Dev Cell). We also showed that they had a tumor suppressive function by limiting tumor cell development in the absence of their ligands (Mazelin et al., 2004, Nature; Castets et al., 2012, Nature). Beyond the fact that the loss of receptors can lead to tumor progression, we have also shown that tumoral escape can be achieved through autocrine secretion of the ligand by cancer cells (Fitamant et al., 2008, PNAS). This observation led us to propose a therapeutic strategy based on inhibiting the binding of ligands, thus restoring the pro-apoptotic function of dependence receptors (Delloye-Bourgeois et al., 2009a, JEM; Delloye-Bourgeois et al., 2009b, JNCI; Bouzas-Rodriguez et al., 2010, JCI).
An antibody blocking the interaction between Netrin-1 and its dependence receptors was preclinically developed (Grandin et al., Cancer Cell 2016) and has been tested in patients with advanced cancer since 2017 as part of a phase 1 trial with very encouraging clinical results
Today, the overall project of the team members has two facets:
1) the deepening of knowledge on molecular mechanisms downstream of these receptors, and thus, better understand of their implications on tumor progression.
2) aims to support the translation of the research observation to clinical trials.
-
Patrick MEHLEN
patrick.mehlen@lyon.unicancer.fr
04 78 78 28 70Cheney B – 5th floor
Centre Léon Bérard
Team members
Main fundings
CNRS / INSERM / Université Claude Bernard Lyon1 / Equipe Labellisée Ligue Contre Le Cancer / ANR / INCA / Fondation ARC / Investissement d’avenir Laboratoire d’Exellence : projet DEVweCAN / Institut Convergence/ Centre Léon Bérard
Main collaborations
Alain Chedotal, Jorg Stetfeld, Manuel Koch, Pan-Chyr Yang, Dale Bredesen, Jean-Luc Ferrer, Fréderic Padilla, Dan Liebl, Keqiang Ye, Mart saarma, Andreas Trump, Cedric Blanpain, Cyrus Ghajar, Enrico Giraudo, Darren Carpizo, Igor Astsaturov, Yoshinori Murakami, Fanny Mann, Olivier Ayrault, Marie Castets, Fabrice Lavial, Gabriel Ichim.
Publication
-
Netrin-1 blockade inhibits tumour growth and EMT features in endometrial cancer
Philippe A. Cassier, Raul Navaridas, Melanie Bellina, Nicolas Rama, Benjamin Ducarouge, Hector Hernandez-Vargas, Jean-Pierre Delord, Justine Lengrand, Andrea Paradisi, Laurent Fattet, Gwenaële Garin, Hanane Gheit, Cecile Dalban, Ievgenia Pastushenko, David Neves, Remy Jelin, Nicolas Gadot, Nicolas Braissand, Sophie Léon, Cyril Degletagne, Xavier Matias-Guiu, Mojgan Devouassoux-Shisheboran, Eliane Mery-Lamarche, Justine Allard, Egor Zindy, Christine Decaestecker, Isabelle Salmon, David Perol, Xavi Dolcet, Isabelle Ray-Coquard, Cédric Blanpain, Agnès Bernet & Patrick Mehlen Nature
-
Targeting netrin-3 in small cell lung cancer and neuroblastoma.
Jiang S, Richaud M, Vieugué P, Rama N, Delcros JG, Siouda M, Sanada M, Redavid AR, Ducarouge B, Hervieu M, Breusa S, Manceau A, Gattolliat CH, Gadot N, Combaret V, Neves D, Ortiz-Cuaran S, Saintigny P, Meurette O, Walter T, Janoueix-Lerosey I, Hofman P, Mulligan P, Goldshneider D, Mehlen P, Gibert B. EMBO Molecular Medicine
Niche derived netrin-1 regulates hematopoietic stem cell dormancy via its receptor neogenin-1.
Renders S, Svendsen AF, Panten J, Rama N, Maryanovich M, Sommerkamp P, Ladel L, Redavid AR, Gibert B, Lazare S, Ducarouge B, Schönberger K, Narr A, Tourbez M, Dethmers-Ausema B, Zwart E, Hotz-Wagenblatt A, Zhang D, Korn C, Zeisberger P, Przybylla A, Sohn M, Mendez-Ferrer S, Heikenwälder M, Brune M, Klimmeck D, Bystrykh L, Frenette PS, Mehlen P, de Haan G, Cabezas-Wallscheid N, Trumpp A. Nature Communications
Immune checkpoint inhibitor treatment of a first cancer is associated with a decreased incidence of second primary cancer.
Heudel P, Chabaud S, Perol D, Flechon A, Fayette J, Combemale P, Tredan O, Desseigne F, de la Fouchardiere C, Boyle H, Perol M, Bachelot T, Cassier P, Avrillon V, Terret C, Michallet AS, Neidhardt-Berard EM, Nicolas-Virelizier E, Dufresne A, Belhabri A, Brahmi M, Lebras L, Nicolini F, Sarabi M, Rey P, Bonneville-Levard A, Rochefort P, Provensal AM, Eberst L, Assaad S, Swalduz A, Saintigny P, Toussaint P, Guillermin Y, Castets M, Coutzac C, Meeus P, Dupré A, Durand T, Crochet H, Fervers B, Gomez F, Rivoire M, Gregoire V, Claude L, Chassagne-Clement C, Pilleul F, Mognetti T, Russias B, Soubirou JL, Lasset C, Chvetzoff G, Mehlen P, Beaupère S, Zrounba P, Ray-Coquard I, Blay JY. ESMO Open
-
Netrin-1 and its receptor DCC modulate survival and death of dopamine neurons and Parkinson’s disease features.
Jasmin M, Ahn EH, Voutilainen MH, Fombonne J, Guix C, Viljakainen T, Kang SS, Yu LY, Saarma M, Mehlen P, Ye K. The EMBO Journal
BDNF and Netrin-1 repression by C/EBPβ in the gut triggers Parkinson’s disease pathologies, associated with constipation and motor dysfunctions.
Ahn EH, Kang SS, Liu X, Cao X, Choi SY, Musazzi L, Mehlen P, Ye K. Progress in Neurobiology
Blocking SHH/Patched Interaction Triggers Tumor Growth Inhibition through Patched-Induced Apoptosis.
Bissey PA, Mathot P, Guix C, Jasmin M, Goddard I, Costechareyre C, Gadot N, Delcros JG, Mali SM, Fasan R, Arrigo AP, Dante R, Ichim G, Mehlen P, Fombonne J. Cancer Research
Netrin-1 promotes naive pluripotency through Neo1 and Unc5b co-regulation of Wnt and MAPK signalling.
Huyghe A, Furlan G, Ozmadenci D, Galonska C, Charlton J, Gaume X, Combémorel N, Riemenschneider C, Allègre N, Zhang J, Wajda P, Rama N, Vieugué P, Durand I, Brevet M, Gadot N, Imhof T, Merrill BJ, Koch M, Mehlen P, Chazaud C, Meissner A, Lavial F. Nature Cell Biology
Neogenin neutralization prevents photoreceptor loss in inherited retinal degeneration
Charish J, Shabanzadeh AP, Chen D, Mehlen P, Sethuramanujam S, Harada H, Bonilha VL, Awatramani G, Bremner R, Monnier PP. The Journal of Clinical Investigation
-
Netrin-1 and Its Receptor DCC Are Causally Implicated in Melanoma Progression
Boussouar A, Tortereau A, Manceau A, Paradisi A, Gadot N, Vial J, Neves D, Larue L, Battistella M, Leboeuf C, Lebbé C, Janin A, Mehlen P. Cancer Research
Cancer-Associated Fibroblasts Produce Netrin-1 to Control Cancer Cell Plasticity
Sung PJ, Rama N, Imbach J, Fiore S, Ducarouge B, Neves D, Chen HW, Bernard D, Yang PC, Bernet A, Depil S, Mehlen P Cancer Research
Synergistic Activity of Floor-Plate- and Ventricular-Zone-Derived Netrin-1 in Spinal Cord Commissural Axon Guidance
Moreno-Bravo JA, Roig Puiggros S, Mehlen P, Chédotal A Neuron
-
The Proto-oncogene c-Kit Inhibits Tumor Growth by Behaving as a Dependance Receptor
Wang H, Boussouar A, Mazelin L, Tauszig-Delamasure S, Sun Y, Goldschneider D, Paradisi A, Mehlen P Molecular Cell
The dependence receptor TrkC regulates the number of sensory neurons during DRG development
Ménard M, Costechareyre C, Coelho-Aguiar JM, Jarrosson-Wuilleme L, Rama N, Blachier J, Kindbeiter K, Bozon M, Cabrera JR, Dupin E, Le Douarin N, Mehlen P, Tauszig-Delamasure S Developmental Biology
Ultrasound molecular imaging as a non-invasive companion diagnostic for netrin-1 interference therapy in breast cancer
Wischhusen J, Wilson KE, Delcros JG, Molina-Peña R, Gibert B, Jiang S, Ngo J, Goldschneider D, Mehlen P, Willmann JK, Padilla F. Theranostics Theranostics
Notch Signaling in the Tumor Microenvironment
Meurette O, Mehlen P Cancer Cell
The Ectodysplasin receptor EDAR acts as a tumor suppressor in melanoma by conditionally inducing cell death
Vial J, Royet A, Cassier P, Tortereau A, Dinvaut S, Maillet D, Gratadou-Hupon L, Creveaux M, Sadier A, Tondeur G, Léon S, Depaepe L, Pantalacci S, de la Fouchardière A, Micheau O, Dalle S, Laudet V, Mehlen P, Castets M Cell Death and Differentiation
Hey1- and p53-dependent TrkC proapoptotic activity controls neuroblastoma growth
Ménard M, Costechareyre C, Ichim G, Blachier J, Neves D, Jarrosson-Wuilleme L, Depping R, Koster J, Saintigny P, Mehlen P, Tauszig-Delamasure S PLoS Biology
Dependence receptors – the dark side awakens
Negulescu AM, Mehlen P FEBS Journal
Hepatocellular carcinoma-associated depletion of the netrin-1 receptor Uncoordinated Phenotype-5A (UNC5A) skews the hepatic unfolded protein response towards prosurvival outcomes
Barnault R, Lahlali T, Plissonnier ML, Romero-López C, Laverdure N, Ducarouge B, Rivoire M, Mehlen P, Zoulim F, Parent R Biochemical and Biophysical Research Communications
Commissural neurons transgress the CNS/PNS boundary in absence of ventricular zone-derived netrin 1
Moreno-Bravo JA, Roig Puiggros S, Blockus H, Dominici C, Zelina P, Mehlen P, Chédotal A Development
-
Reciprocal antagonism between the netrin-1 receptor uncoordinated-phenotype-5A (UNC5A) and the hepatitis C virus
Plissonnier ML, Lahlali T, Raab M, Michelet M, Romero-López C, Rivoire M, Strebhardt K, Durantel D, Levrero M, Mehlen P, Zoulim F, Parent R Oncogene
DNA methylation signal has a major role in the response of human breast cancer cells to the microenvironment
Mathot P, Grandin M, Devailly G, Souaze F, Cahais V, Moran S, Campone M, Herceg Z, Esteller M, Juin P, Mehlen P, Dante R Oncogenesis
Alu RNA accumulation induces epithelial-to-mesenchymal transition by modulating miR-566 and is associated with cancer progression
Di Ruocco F, Basso V, Rivoire M, Mehlen P, Ambati J, De Falco S, Tarallo V. Oncogene
p53-dependent programmed necrosis controls germ cell homeostasis during spermatogenesis
Napoletano F, Gibert B, Yacobi-Sharon K, Vincent S, Favrot C, Mehlen P, Girard V, Teil M, Chatelain G, Walter L, Arama E, Mollereau B PLoS Genetics
Non-canonical NOTCH3 signalling limits tumour angiogenesis
Lin S, Negulescu A, Bulusu S, Gibert B, Delcros JG, Ducarouge B, Rama N, Gadot N, Treilleux I, Saintigny P, Meurette O, Mehlen P Nature Comunications
Floor-plate-derived netrin-1 is dispensable for commissural axon guidance
Dominici C, Moreno-Bravo JA, Puiggros SR, Rappeneau Q, Rama N, Vieugue P, Bernet A, Mehlen P, Chédotal A Nature
Ephrin-B3 supports glioblastoma growth by inhibiting apoptosis induced by the dependence receptor EphA4.
Royet A, Broutier L, Coissieux MM, Malleval C, Gadot N, Maillet D, Gratadou-Hupon L, Bernet A, Nony P, Treilleux I, Honnorat J, Liebl D, Pelletier L, Berger F, Meyronet D, Castets M, Mehlen P. Oncotarget
-
Structural decoding of netrin-4 reveals a regulatory function towards mature basement membranes
Reuten R, Patel TR, McDougall M, Rama N, Nikodemus D, Gibert B, Delcros JG, Prein C, Meier M, Metzger S, Zhou Z, Kaltenberg J, McKee KK, Bald T, Tüting T, Zigrino P, Djonov V, Bloch W, Clausen-Schaumann H, Poschl E, Yurchenco PD, Ehrbar M, Mehlen P, Stetefeld J, Koch M Nature Communications
Inhibition of DNA methylation promotes breast tumor sensitivity to netrin-1 interference
Grandin M, Mathot P, Devailly G, Bidet Y, Ghantous A, Favrot C, Gibert B, Gadot N, Puisieux I, Herceg Z, Delcros JG, Bernet A, Mehlen P, Dante R EMBO Mol Med
Netrin-1 Interrupts Amyloid-β Amplification, Increases sAβPPα in vitro and in vivo, and Improves Cognition in a Mouse Model of Alzheimer’s Disease.
Spilman PR, Corset V, Gorostiza O, Poksay KS, Galvan V, Zhang J, Rao R, Peters-Libeu C, Vincelette J, McGeehan A, Dvorak-Ewell M, Beyer J, Campagna J, Bankiewicz K, Mehlen P, John V, Bredesen DE. Journal of Alzheimer's Disease
Epidermal Growth Factor Receptor-Dependent Mutual Amplification between Netrin-1 and the Hepatitis C Virus.
Plissonnier ML, Lahlali T, Michelet M, Lebossé F, Cottarel J, Beer M, Neveu G, Durantel D, Bartosch B, Accardi R, Clément S, Paradisi A, Devouassoux-Shisheboran M, Einav S, Mehlen P, Zoulim F, Parent R. PLOS Biology
Structural Decoding of the Netrin-1/UNC5 Interaction and its Therapeutical Implications in Cancers.
Grandin M, Meier M, Delcros JG, Nikodemus D, Reuten R, Patel TR, Goldschneider D, Orriss G, Krahn N, Boussouar A, Abes R, Dean Y, Neves D, Bernet A, Depil S, Schneiders F, Poole K, Dante R, Koch M, Mehlen P, Stetefeld J. Cancer Cell
Targeting netrin-1/DCC interaction in diffuse large B-cell and mantle cell lymphomas
Broutier L, Creveaux M, Vial J, Tortereau A, Delcros JG, Chazot G, McCarron MJ, Léon S, Pangault C, Gadot N, Colombe A, Boulland ML, Blachier J, Marie JC, Traverse-Glehen A, Donzé O, Chassagne-Clément C, Salles G, Tarte K, Mehlen P, Castets M EMBO Mol Med .
Netrin-1 Protects Hepatocytes Against Cell Death Through Sustained Translation During the Unfolded Protein Response
Lahlali T, Plissonnier ML, Romero-López C, Michelet M, Ducarouge B, Berzal-Herranz A, Zoulim F, Mehlen P, Parent R Cell Mol Gastroenterol Hepatol
-
Dependence Receptors and Cancer: Addiction to Trophic Ligands.
Gibert B, Mehlen P. Cancer Research