Evolution Darwinienne du Cancer Michael Hochberg CNRS - Université Montpellier II

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Evolution Darwinienne du Cancer Michael Hochberg CNRS - Université Montpellier II Santa Fe Institute. Frédéric Thomas MIVEGEC, Montpellier. Darwinian Evolution of Cancer Consortium GDR3530. Jean Clairambault INRIA, Paris. Michael Hochberg ISEM, Montpellier. - PowerPoint PPT Presentation

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Evolution Darwinienne du Cancer

Michael HochbergCNRS - Universit Montpellier IISanta Fe Institute

Urszula HibnerIGMM, Montpellier

Frdric ThomasMIVEGEC, Montpellier

Benot PerthameINRIA, Paris

Eric Solary INSERM, Villejuif

Jean-Pierre Marie INSERM, Paris

Vitaly Volpert INRIA, Lyon

Daniel FisherIGMM, Montpellier

Christoph Grunau Universit PerpignanPhilippe FortCRBM, Montpellier

Darwinian Evolution of Cancer ConsortiumGDR3530Michael Hochberg ISEM, Montpellier

Jean ClairambaultINRIA, Paris

Hanahan & Weinberg. 2000. CellQuest ce que le cancer? Des maladies caractrises par lautonomie dmographique : y compris la prolifration cellulaire incontrle, l'vasion de lapoptose et la migration (crant les mtastases)autonomie =rupture dans le pacte de multicellularit

Un phnomne cologique et volutif

La slection somatique cellulaire est moteur de la malignit, l'induction de l'angiogense, l'vasion du systme immunitaire, les mtastases et la rsistance aux thrapies

Podlaha et al. 2012. Trends in GeneticsSlection et l'volution intra-individuelle

Reid B. J Cancer Prev Res 2008L'expansion clonale et la driveTP53 variants have pleiotropic effects including loss of cell cycle checkpoint control, evasion of apoptosis and genomic instability that increase genetic diversity within the neoplasm, and they are permissive for subsequent evolution of tetraploid and aneuploid clones.Clonal evolution. X axis, time; Y axis, the extent of a neoplasm, in this case Barretts segment length. Barretts esophagus arises in a subset of patients inresponse to the harsh environment of gastroesophageal reflux. Loss of one or both alleles of CDKN2A provides a selective advantage leading to clonal expansion.Neutral mutations also arise during clonal evolution. If they arise in a clone that has a selected mutation such as those affecting CDKN2A. the neutral mutationcan expand as a hitchhiker on the selected mutation. Otherwise, neutral mutations expand or contract through a random process of genetic drift. TP53 mutations andLOH are selected as later events in neoplastic evolution, but TP53 variants seem to be selected almost exclusively in the genetic background of CDKN2A variants.TP53 variants have pleiotropic effects including loss of cell cycle checkpoint control, evasion of apoptosis and genomic instability that increase genetic diversitywithin the neoplasm, and they are permissive for subsequent evolution of tetraploid and aneuploid clones. The sizes of genetically unstable clones with TP53abnormalities and aneuploidy are predictive of future progression to esophageal adenocarcinoma. A panel of chromosomal instability biomarkers (9p, 17p LOH,tetraploidy, aneuploidy) provides independent cancer risk prediction in Barretts esophagus, but mutations in CDKN2A and TP53 and methylation of the CDKN2Apromoter do not.7

Plusieurs Systmes ComplexesSystme complexe ncessitant une approche interdisciplinaire

Expliquer

Emergence: cd la slection naturelle sur les oncognes et gnes suppresseurs de tumeurs

Progression: l'interaction entre micro-environnement et le processus volutif ; dterminisme versus stochasticit

Thrapies: stratgies novatrices dans "l'ingnierie volutionnaire" pour prvenir et traiter les cancers

Runion du GDR 3580 Darwinian Cancer Evolution le 10 avril 2012

Colloque International le 11 avril 2012 - http://www.darevcan.univ-montp2.fr/PUBLICATIONS

1- Lorz A, Lorenzi T, Hochberg ME, Clairambault J & B Perthame. 2012. Populational adaptive evolution, chemotherapeutic resistance and multiple anti-cancer therapies. Accepted Mathematical Modelling and Numerical Analysis http://hal.archivesouvertes. 2- Roche B, Hochberg ME, Caulin AF, Maley C, Gatenby RA, Miss D & F Thomas. Natural resistance to cancers: a Darwinian hypothesis to explain Peto's paradox. In press. BMC cancer3- Thomas F et DarEvCan consortium. Applying ecological and evolutionary approaches to cancer research: A long and winding road. Accepted Evolutionary Applications4- Roche B, Hbid H, Miss D & F Thomas. Petos paradox revisited: Theoretical profiles of evolutionary cancer dynamics in wildlife. Submitted to Evolutionary Applications5- Hochberg ME, Thomas F, Assenat E & U Hibner. Preventative Evolutionary Medicine of Cancers. Submitted to Evolutionary Applications2- Roche B, Hochberg ME, Caulin AF, Maley C, Gatenby RA, Miss D & F Thomas. Natural resistance to cancers: a Darwinian hypothesis to explain Peto's paradox. In press. BMC cancer

Le Paradoxe de Peto

Davantage de cancers?NOLes animaux qui ont volu pour tre plus grand en tant qu'espce ont dvelopp des mcanismes pour compenser le risque accru de cancer13

CancerPrincipales causes de dcs?

Other causes

CancerPrincipales causes de dcs?Other causesCancerOther causes

?

Summary of the current knowledge on Petos paradox . Body mass seems to be a relevant surrogate for cancer prevalence at an intra-species level, but not an inter-species levelRoche et al. 2012. BMC Cancer

Roche et al. 2012. BMC CancerLe rseau d'interactions entre le cancer et diverses variables qui agissent sur les individus et les espces dans les cosystmes

Urszula HibnerIGMM, Montpellier

Frdric ThomasMIVEGEC, Montpellier

Benot PerthameINRIA, Paris

Eric Solary INSERM, Villejuif

Jean-Pierre Marie INSERM, Paris

Vitaly Volpert INRIA, Lyon

Daniel FisherIGMM, Montpellier

Christoph Grunau Universit PerpignanPhilippe FortCRBM, Montpellier

Sans mursDarwinian Evolution of Cancer ConsortiumGDR3530Michael Hochberg ISEM, Montpellier

Jean ClairambaultINRIA, Paris

CREECCENTRE DE RECHERCHES ECOLOGIQUES ET EVOLUTIVES SUR LE CANCERMichael.Hochberg@um2.fr (CNRS - UM2) Frdric Thomas (CNRS IRD)Ula Hibner (INSERM - IGMM)