Dynamics of cell invasion in cancer

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In multicellular organisms, cells move, and they do it in a specific manner. This fundamental process obeys strict regulations that are essential for the proper occurrence of specific life features, for example embryonic development or activation of the immune defences. Dysregulated cell migration can cause major problems, such as metastasis formation, the process during which cancer cells from a primary tumour disseminate to other body sites, ultimately resulting in the patient’s death. Understanding how cancer cells become invasive and identifying the molecular processes that regulate their abnormal migration are crucial biological issues and constitute our area of research.

The p53 tumour suppressor is the most commonly mutated gene in human tumours and has attracted much attention since its discovery in 1979. Our studies are focused on the mechanisms used by tumour cells to inactivate p53 function. Despite the immense prevalence of p53 mutations in human tumours, p53 gene mutation status cannot precisely explain the acquisition of an invasive phenotype. Indeed, numerous clinical data show that p53 mutation status cannot be used as a prognostic marker of tumour progression. This suggests that mechanisms other than mutations are involved in the inhibition of p53 tumour suppressor function.

One of these mechanisms is the production of p53 variant proteins (isoforms) by alternative splicing of the gene, a process that controls the presence or absence of several p53 domains in the protein. Our team studies the p53 isoforms produced by cancer cells, the underlying molecular mechanisms of their formation and their consequences on metastatic invasion.

We analyse the role of p53 isoforms in cellular processes associated with tumour invasion: mode of migration, cellular senescence and tumour stem cell formation. A major objective is to determine whether specific isoforms are associated with tumour aggressiveness and may constitute novel therapeutic targets. In this context, we are currently identifying the cellular pathways that activate the expression of p53 isoforms during cancer invasion. We also try decoding the mechanisms by which these isoforms control cancer cell invasion through the identification of their partners and their targets.

Our in vivo studies are carried out in cells grown in 2D and also 3D culture systems that best recapitulate the tissue physiological conditions. We combine cell analysis techniques (live cell imaging, stem cell potential, mouse xenografts), human tumour sample analysis and high throughput proteomic and transcriptomic analyses.

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Pierre Roux

Members of the team

  • Nikola ARSIC
    (Research Assistant) +33 (0)4 34 35 95 12
  • Lara BOUMALHAB
    (Post-Doc) +33 (0)4 34 35 95 13
  • Philippe FORT
    (Staff Scientist) +33 (0)4 34 35 95 00
  • Veronique GIRE
    (Staff Scientist) +33 (0)4 34 35 95 13
  • Anaïs LUGAGNE
    (Trainee) +33 (0)4 34 35 95 12
  • Celima MOUROUVIN
    (Trainee) +33 (0)4 34 35 95 13
  • Peggy RAYNAUD
    (Staff Scientist) +33 (0)4 34 35 95 49
  • Pierre ROUX Group Leader
    (Staff Scientist) +33 (0)4 34 35 95 12
  • Fanny TOMAS
    (PhD Student) +33 (0)4 34 35 95 13
  • Emmanuel VIGNAL
    (Staff Scientist) +33 (0)4 34 35 95 01
    • 2018

      SOX9 has distinct regulatory roles in alternative splicing and transcription.

      Girardot M, Bayet E, Maurin J, Fort P, Roux P, Raynaud P.

      Nucleic Acids Res. doi: 10.1093/nar/gky553. Pubmed

    • 2018

      The RPAP3-Cterminal domain identifies R2TP-like quaternary chaperones.

      Maurizy C, Quinternet M, Abel Y, Verheggen C, Santo PE, Bourguet M, C F Paiva A, Bragantini B, Chagot ME,[...]

      Nat Commun. 9(1):2093. Pubmed

    • 2018

      ∆133p53 isoform promotes tumour invasion and metastasis via interleukin-6 activation of JAK-STAT and RhoA-ROCK signalling.

      Campbell H, Fleming N, Roth I, Mehta S, Wiles A, Williams G, Vennin C, Arsic N, Parkin A, Pajic M,[...]

      Nat Commun. 9(1):254. Pubmed

    • 2017

      The Evolutionary Landscape of Dbl-Like RhoGEF Families: Adapting Eukaryotic Cells to Environmental Signals

      Fort P, Blangy A.

      Genome Biol Evol. 9:1471-1486. Pubmed

    • 2017

      Heterogeneity in sarcoma cell lines reveals enhanced motility of tetraploid versus diploid cells.

      Jemaà M, Abdallah S, Lledo G, Perot G, Lesluyes T, Teyssier C, Roux P, van Dijk J, Chibon F, Abrieu[...]

      Oncotarget. 14291 Pubmed

    • 2017

      Binding site density enables paralog-specific activity of SLM2 and Sam68 proteins in Neurexin2 AS4 splicing control.

      Danilenko M, Dalgliesh C, Pagliarini V, Naro C, Ehrmann I, Feracci M, Kheirollahi-Chadegani M, Tyson-Capper A, Clowry GJ, Fort P,[...]

      Nucleic Acids Res. pii: gkw1277. Pubmed

    • 2017

      The p53 isoform delta133p53ß regulates cancer cell apoptosis in a RhoB-dependent manner.

      Arsic N, Ho-Pun-Cheung A, Evelyne C, Assenat E, Jarlier M, Anguille C, Colard M, Pezet M, Roux P, Gadea G.

      PLoS One. 12:e0172125. Pubmed

    • 2016

      TP53 drives invasion through expression of its Δ133p53β variant.

      Gadea G, Arsic N, Fernandes K, Diot A, Joruiz SM, Abdallah S, Meuray V, Vinot S, Anguille C, Remenyi J,[...]

      Elife. 5: e14734. Pubmed

    • 2016

      A SLM2 Feedback Pathway Controls Cortical Network Activity and Mouse Behavior.

      Ehrmann I, Gazzara MR, Pagliarini V, Dalgliesh C, Kheirollahi-Chadegani M, Xu Y, Cesari E, Danilenko M, Maclennan M, Lowdon K,[...]

      Cell Rep. 17:3269-3280. Pubmed

    • 2016

      STARs in the CNS.

      Ehrmann I, Fort P, Elliott DJ.

      Biochem Soc Trans. 44:1066-72. Pubmed

    • 2016

      High chlorpyrifos resistance in Culex pipiens mosquitoes: strong synergy between resistance genes.

      Alout H, Labbé P, Berthomieu A, Makoundou P, Fort P, Pasteur N, Weill M.

      Heredity (Edinb). 116:224-31. Pubmed

    • 2015

      Greatwall promotes cell transformation by hyperactivating AKT in human malignancies.

      Vera J, Lartigue L, Vigneron S, Gadea G, Gire V, Del Rio M, Soubeyran I, Chibon F, Lorca T, Castro[...]

      Elife. 4:e10115. Pubmed

    • 2015

      Senescence from G2 arrest, revisited.

      Gire V, Dulic V.

      Cell Cycle. 14:297-304. Pubmed

    • 2015

      Evolution of proteasome regulators in eukaryotes.

      Fort P, Kajava AV, Delsuc F, Coux O.

      Genome Biol Evol. 7:1363-79. Pubmed

    • 2015

      Atypical RhoV and RhoU GTPases control development of the neural crest.

      Faure S, Fort P.

      Small GTPases. 6:174-7. Pubmed

    • 2015

      Stable coexistence of incompatible Wolbachia along a narrow contact zone in mosquito field populations.

      Atyame CM, Labbé P, Rousset F, Beji M, Makoundou P, Duron O, Dumas E, Pasteur N, Bouattour A, Fort P,[...]

      Mol Ecol. 24:508-21. Pubmed

    • 2015

      The p53 isoform Δ133p53β promotes cancer stem cell potential.

      Arsic N, Gadea G, Lagerqvist EL, Busson M, Cahuzac N, Brock C, Hollande F, Gire V, Pannequin J, Roux P.

      Stem Cell Reports. 4:531-40. Pubmed

    • 2014

      Postprandial triglyceride-rich lipoproteins promote invasion of human coronary artery smooth muscle cells in a fatty-acid manner through PI3k-Rac1-JNK signaling.

      Varela LM, Bermúdez B, Ortega-Gómez A, López S, Sánchez R, Villar J, Anguille C, Muriana FJ, Roux P, Abia R.

      Mol Nutr Food Res. 58:1349-64. Pubmed

    • 2014

      PleiotRHOpic: Rho pathways are essential for all stages of Neural Crest development.

      Fort P, Théveneau E.

      Small GTPases. 5:e27975. Pubmed

    • 2013

      Eroded human telomeres are more prone to remain uncapped and to trigger a G2 checkpoint response.

      Jullien L, Mestre M, Roux P, Gire V.

      Nucleic Acids Res. 41(2):900-11. Pubmed

    • 2013

      MBNL1 and RBFOX2 cooperate to establish a splicing programme involved in pluripotent stem cell differentiation.

      Venables JP, Lapasset L, Gadea G, Fort P, Klinck R, Irimia M, Vignal E, Thibault P, Prinos P, Chabot B,[...]

      Nat Commun. 2013;4:2480. Pubmed

    • 2013

      Targeting the Dbl and dock-family RhoGEFs: a yeast-based assay to identify cell-active inhibitors of Rho-controlled pathways.

      Blangy A, Fort P.

      Enzymes. 2013;33 Pt A:169-91. Pubmed

    • 2012

      Matrix-bound PAI-1 supports cell blebbing via RhoA/ROCK1 signaling.

      Cartier-Michaud A, Malo M, Charrière-Bertrand C, Gadea G, Anguille C, Supiramaniam A, Lesne A, Delaplace F, Hutzler G, Roux P,[...]

      PLoS One. 7(2):e32204. Pubmed

    • 2012

      ZNF217 is a marker of poor prognosis in breast cancer that drives epithelial-mesenchymal transition and invasion.

      Vendrell JA, Thollet A, Nguyen NT, Ghayad SE, Vinot S, Bièche I, Grisard E, Josserand V, Coll JL, Roux P,[...]

      Cancer Res. 72(14):3593-606. Pubmed

    • 2012

      Cooperative anti-invasive effect of Cdc42/Rac1 activation and ROCK inhibition in SW620 colorectal cancer cells with elevated blebbing activity.

      de Toledo M, Anguille C, Roger L, Roux P, Gadea G.

      PLoS One. 7(11):e48344. Pubmed

    • 2012

      Using a modified yeast two-hybrid system to screen for chemical GEF inhibitors.

      Blangy A, Fort P.

      Methods Mol Biol. 2012;928:81-95. Pubmed

    • 2011

      Activity of the RhoU/Wrch1 GTPase is critical for cranial neural crest cell migration.

      Fort P, Guémar L, Vignal E, Morin N, Notarnicola C, de Santa Barbara P, Faure S.

      Dev Biol. 350(2):451-63. Pubmed

    • 2010

      What makes cells move: requirements and obstacles for spontaneous cell motility.

      Binamé F, Pawlak G, Roux P, Hibner U.

      Mol Biosyst. 6(4):648-61. Pubmed

    • 2010

      Gain of oncogenic function of p53 mutants regulates E-cadherin expression uncoupled from cell invasion in colon cancer cells.

      Roger L, Jullien L, Gire V, Roux P.

      J Cell Sci. 123(Pt 8):1295-305. Pubmed

    • 2008

      Analysis of cell migration and its regulation by Rho GTPases and p53 in a three-dimensional environment.

      Vinot S, Anguille C, de Toledo M, Gadea G, Roux P.

      Methods Enzymol. 439:413-24. Pubmed