Tyrosine kinase signalling in human cancer

  • Research
  • Team
  • Publications
  • More...

During tumour progression, cancer cells acquire specific properties, including the ability to invade the surrounding tissues and metastasize to distant organs. These properties reflect perturbations in the cell signalling pathways that control the proliferation, motility and survival of normal cells. Cell signalling mediated by protein tyrosine phosphorylation plays an essential role in the control of these cellular properties. We seek to define how deregulation of this kinase-dependent mechanism, which frequently occurs in human cancer, induces metastatic tumours.
We have characterized the central metastatic role of the non-receptor tyrosine kinase Src and of the collagen receptor tyrosine kinase DDR1 in colorectal cancer (CRC). From extensive phosphoproteomic analyses in CRC, we have identified critical metastatic substrates and discovered an essential post-translational mechanism that promotes Src oncogenic activity. This complex mechanism involves the tumour suppressive function of the adaptor SLAP that promotes Src substrate degradation upon aberrant protein phosphorylation.
We currently study the pro-tumoral role of novel Src substrates and SLAP targets identified in our proteomic studies. We also address the contribution of the tumour microenvironment in the promotion of Src-dependent metastatic tumour formation. Besides, we explore a novel mechanism to control Src substrate selection and signalling through its intrinsically disordered domain. Finally, we use this information to define novel therapeutic points of intervention in metastatic cancer.

Main publications

Jeitany et al. Inhibition of DDR1-BCR signalling by nilotinib as a new therapeutic strategy for metastatic colorectal cancer (2018) EMBO Mol Med DOI: 10.15252/emmm.201707918

Imjeti et al. Syntenin mediates SRC function in exosomal cell to cell communication (2017) Proc Natl Acad Sci U S A. 2017 114:12495-12500

Arbesú et al. The unique domain forms a fuzzy intramolecular complexes in Src family of kinases. (2017) Structure 25, 630–640.

Chevalier et al. TOM1L1 drives membrane delivery of MT1-MMP to promote ERBB2-induced breast cancer cell invasion. (2016) Nature Commun 7:10765

Maffei et al. The SH3 Domain Acts as a Scaffold for the N-Terminal Intrinsically Disordered Regions of c-Src. (2015) Structure 23, 893-902

Naudin et al. SLAP displays tumor suppression function in colorectal cancer via destabilization of the SRC substrate EPHA2. (2014) Nature Commun 5 :3159

Fialin et al. The short form of RON is expressed in Acute Myeloid Leukemia and sensitizes leukemic cells to cMET inhibitors. (2013) Leukemia 27(2):325-35

Sirvent et al. Analysis of Src oncogenic signalling in colorectal cancer by Stable Isotope Labeling in mouse Xenografts. (2012) Mol Cell & Proteomics 11:1937-1950

Sirvent et al. Src family tyrosine kinases-driven colon cancer cell invasion is induced by Csk membrane delocalization. (2010) Oncogene 29; 1303-1315

Leroy et al. Quantitative phosphoproteomics reveals a cluster of tyrosine kinases that mediates Src invasive activity in advanced colon carcinoma cells. Cancer Res (2009) 69;2279-2296

Veracini et al. The Csk binding protein PAG regulates PDGF-induced Src mitogenic signalling via GM1. J Cell Biol (2008) 182; 603-614

Contact our team

Replace the name and address below with that of the member to contact

Serge Roche

Members of the team

  • Emilie APONTE
    (PhD Student) +33 (0)4 34 35 95 04
  • Eloine BESTION
    (Trainee) +33 (0)4 34 35 95 03
  • Audrey COQUARD-SIRVENT
    (Staff Scientist) +33 (0)4 34 35 95 03
  • Diya DUTTA
    (Trainee) +33 (0)4 34 35 95 03
  • Clement KERNEUR
    (Research Assistant) +33 (0)4 34 35 95 03
  • Marie LAFITTE
    (Post-Doc) +33 (0)4 34 35 95 70
  • Celine LECOINTRE
    (Post-Doc) +33 (0)4 34 35 95 05
  • Rudy MEVIZOU
    (PhD Student) +33 (0)4 34 35 95 05
  • Serge ROCHE Group Leader
    (Staff Scientist) +33 (0)4 34 35 95 03
  • Valerie SIMON
    (Research Assistant) +33 (0)4 34 35 95 03
    • 2018

      Dimerization of the Pragmin Pseudo-Kinase Regulates Protein Tyrosine Phosphorylation.

      Lecointre C, Simon V, Kerneur C, Allemand F, Fournet A, Montarras I, Pons JL, Gelin M, Brignatz C, Urbach S,[...]

      Structure. pii: S0969-2126(18)30040-6. Pubmed

    • 2018

      Inhibition of DDR1-BCR signalling by nilotinib as a new therapeutic strategy for metastatic colorectal cancer.

      Jeitany M, Leroy C, Tosti P, Lafitte M, Le Guet J, Simon V, Bonenfant D, Robert B, Grillet F, Mollevi[...]

      EMBO Mol Med. pii: e7918. Pubmed

    • 2017

      Syntenin mediates SRC function in exosomal cell-to-cell communication.

      Imjeti NS, Menck K, Egea-Jimenez AL, Lecointre C, Lembo F, Bouguenina H, Badache A, Ghossoub R, David G, Roche S,[...]

      Proc Natl Acad Sci U S A. pii: 201713433. Pubmed

    • 2017

      The Unique Domain Forms a Fuzzy Intramolecular Complex in Src Family Kinases.

      Arbesú M, Maffei M, Cordeiro TN, Teixeira JM, Pérez Y, Bernadó P, Roche S, Pons M.

      Structure. 2126:30042-4. Pubmed

    • 2016

      The role of small adaptor proteins in the control of oncogenic signalingr driven by tyrosine kinases in human cancer.

      Naudin C, Chevalier C, Roche S.

      Oncotarget. 7:11033-55. Pubmed

    • 2016

      TOM1L1 drives membrane delivery of MT1-MMP to promote ERBB2-induced breast cancer cell invasion.

      Chevalier C, Collin G, Descamps S, Touaitahuata H, Simon V, Reymond N, Fernandez L, Milhiet PE, Georget V, Urbach S,[...]

      Nat Commun. 7:10765. Pubmed

    • 2016

      Vesicular trafficking regulators are new players in breast cancer progression: Role of TOM1L1 in ERBB2-dependent invasion.

      Chevalier C, Roche S, Bénistant C.

      Mol Cell Oncol. 3:e1182241. Pubmed

    • 2015

      Contribution of phosphoproteomics in understanding SRC signaling in normal and tumor cells.

      Sirvent A, Urbach S, Roche S.

      Proteomics. 15:232-44. Pubmed

    • 2015

      Progastrin a new pro-angiogenic factor in colorectal cancer.

      Najib S, Kowalski-Chauvel A, Do C, Roche S, Cohen-Jonathan-Moyal E, Seva C.

      Oncogene. 34:3120-30. Pubmed

    • 2015

      Neural differentiation modulates the vertebrate brain specific splicing program.

      Madgwick A, Fort P, Hanson PS, Thibault P, Gaudreau MC, Lutfalla G, Möröy T, Abou Elela S, Chaudhry B, Elliott[...]

      PLoS One. 10:e0125998. Pubmed

    • 2015

      The SH3 Domain Acts as a Scaffold for the N-Terminal Intrinsically Disordered Regions of c-Src.

      Maffei M, Arbesú M, Le Roux AL, Amata I, Roche S, Pons M.

      Structure. 23:893-902. Pubmed

    • 2015

      CBL controls a tyrosine kinase network involving AXL, SYK and LYN in nilotinib-resistant chronic myeloid leukaemia.

      Gioia R, Trégoat C, Dumas PY, Lagarde V, Prouzet-Mauléon V, Desplat V, Sirvent A, Praloran V, Lippert E, Villacreces A,[...]

      J Pathol. 237:14-24. Pubmed

    • 2015

      YES oncogenic activity is specified by its SH4 domain and regulates RAS/MAPK signaling in colon carcinoma cells.

      Dubois F, Leroy C, Simon V, Benistant C, Roche S.

      Am J Cancer Res. 5:1972-87. Pubmed

    • 2015

      ABL tyrosine kinase inhibition variable effects on the invasive properties of different triple negative breast cancer cell lines.

      Chevalier C, Cannet A, Descamps S, Sirvent A, Simon V, Roche S, Benistant C.

      PLoS One. 10:e0118854 Pubmed

    • 2014

      Analysis of oncogenic signaling induced by tyrosine kinases in tumors by SILAC-based quantitative proteomic approach

      Sirvent A, Urbach S, Roche S.

      Med Sci (Paris). 30:558-66. Pubmed

    • 2014

      SLAP displays tumour suppressor functions in colorectal cancer via destabilization of the SRC substrate EPHA2.

      Naudin C, Sirvent A, Leroy C, Larive R, Simon V, Pannequin J, Bourgaux JF, Pierre J, Robert B, Hollande F,[...]

      Nat Commun. 5:3159. Pubmed

    • 2014

      Antagonistic functions of LMNA isoforms in energy expenditure and lifespan.

      Lopez-Mejia IC, de Toledo M, Chavey C, Lapasset L, Cavelier P, Lopez-Herrera C, Chebli K, Fort P, Beranger G, Fajas[...]

      EMBO Rep. 15:529-39 Pubmed

    • 2014

      Suppressor of cytokine signaling 1 modulates invasion and metastatic potential of colorectal cancer cells.

      David M, Naudin C, Letourneur M, Polrot M, Renoir JM, Lazar V, Dessen P, Roche S, Bertoglio J, Pierre J.

      Mol Oncol. 8:942-55. Pubmed

    • 2014

      Wolbachia divergence and the evolution of cytoplasmic incompatibility in Culex pipiens.

      Atyame CM, Labbé P, Dumas E, Milesi P, Charlat S, Fort P, Weill M.

      PLoS One. 9:e87336. Pubmed

    • 2013

      The short form of RON is expressed in acute myeloid leukemia and sensitizes leukemic cells to cMET inhibitors.

      Fialin C, Larrue C, Vergez F, Sarry JE, Bertoli S, Mansat-De Mas V, Demur C, Delabesse E, Payrastre B, Manenti[...]

      Leukemia. 27(2):325-35. Pubmed

    • 2012

      Analysis of SRC oncogenic signaling in colorectal cancer by stable isotope labeling with heavy amino acids in mouse xenografts.

      Sirvent A, Vigy O, Orsetti B, Urbach S, Roche S.

      Mol Cell Proteomics. 11(12):1937-50. Pubmed

    • 2012

      Oncogenic signaling by tyrosine kinases of the SRC family in advanced colorectal cancer.

      Sirvent A, Benistant C, Roche S.

      Am J Cancer Res. 2(4):357-71. Pubmed

    • 2011

      Quantitative phosphoproteomics revealed interplay between Syk and Lyn in the resistance to nilotinib in chronic myeloid leukemia cells.

      Gioia R, Leroy C, Drullion C, Lagarde V, Etienne G, Dulucq S, Lippert E, Roche S, Mahon FX, Pasquet JM.

      Blood. 118(8):2211-21. Pubmed

    • 2011

      Specific oncogenic activity of the Src-family tyrosine kinase c-Yes in colon carcinoma cells.

      Sancier F, Dumont A, Sirvent A, Paquay de Plater L, Edmonds T, David G, Jan M, de Montrion C, Cogé[...]

      PLoS One. 6(2):e17237. Pubmed

    • 2010

      Src family tyrosine kinases-driven colon cancer cell invasion is induced by Csk membrane delocalization.

      Sirvent A, Bénistant C, Pannequin J, Veracini L, Simon V, Bourgaux JF, Hollande F, Cruzalegui F, Roche S.

      Oncogene. 29(9):1303-15. Pubmed

    • 2010

      A non-catalytic function of the Src family tyrosine kinases controls prolactin-induced Jak2 signaling.

      García-Martínez JM, Calcabrini A, González L, Martín-Forero E, Agulló-Ortuño MT, Simon V, Watkin H, Anderson SM, Roche S, Martín-Pérez J.

      Cell Signal. 22(3):415-26. Pubmed

    • 2009

      Alternative splicing modulates autoinhibition and SH3 accessibility in the Src kinase Fyn.

      Brignatz C, Paronetto MP, Opi S, Cappellari M, Audebert S, Feuillet V, Bismuth G, Roche S, Arold ST, Sette C,[...]

      Mol Cell Biol. 29(24):6438-48. Pubmed

    • 2009

      Quantitative phosphoproteomics reveals a cluster of tyrosine kinases that mediates SRC invasive activity in advanced colon carcinoma cells.

      Leroy C, Fialin C, Sirvent A, Simon V, Urbach S, Poncet J, Robert B, Jouin P, Roche S.

      Cancer Res. 69(6):2279-86. Pubmed

    • 2008

      Evidence that resistance to nilotinib may be due to BCR-ABL, Pgp, or Src kinase overexpression.

      Mahon FX, Hayette S, Lagarde V, Belloc F, Turcq B, Nicolini F, Belanger C, Manley PW, Leroy C, Etienne G,[...]

      Cancer Res. 68(23):9809-16 Pubmed

    • 2008

      Cytoplasmic signalling by the c-Abl tyrosine kinase in normal and cancer cells.

      Sirvent A, Benistant C, Roche S.

      Biol Cell. 100(11):617-31. Pubmed

    • 2008

      The Src-like adaptor protein regulates PDGF-induced actin dorsal ruffles in a c-Cbl-dependent manner.

      Sirvent A, Leroy C, Boureux A, Simon V, Roche S.

      Oncogene. 27(24):3494-500. Pubmed

    • 2008

      The Csk-binding protein PAG regulates PDGF-induced Src mitogenic signaling via GM1.

      Veracini L, Simon V, Richard V, Schraven B, Horejsi V, Roche S, Benistant C.

      J Cell Biol. 182(3):603-14. Pubmed

    Selected publications

    Chevalier et al. TOM1L1 drives membrane delivery of MT1-MMP to promote ERBB2-induced breast cancer cell invasion. (2016) Nature Commun 7:10765

    Maffei et al. The SH3 Domain Acts as a Scaffold for the N-Terminal Intrinsically Disordered Regions of c-Src. (2015) Structure 23, 893-902

    Naudin et al. SLAP displays tumor suppression function in colorectal cancer via destabilization of the SRC substrate EPHA2. (2014) Nature Commun 5 :3159

    Fialin et al. The short form of RON is expressed in Acute Myeloid Leukemia and sensitizes leukemic cells to cMET inhibitors. (2013) Leukemia 27(2):325-35

    Sirvent et al. Analysis of Src oncogenic signalling in colorectal cancer by Stable Isotope Labeling in mouse Xenografts. (2012) Mol Cell & Proteomics 11:1937-1950

    Sirvent et al. Src family tyrosine kinases-driven colon cancer cell invasion is induced by Csk membrane delocalization. (2010) Oncogene 29; 1303-1315

    Leroy et al. Quantitative phosphoproteomics reveals a cluster of tyrosine kinases that mediates Src invasive activity in advanced colon carcinoma cells. Cancer Res (2009) 69;2279-2296

    Veracini et al. The Csk binding protein PAG regulates PDGF-induced Src mitogenic signalling via GM1. J Cell Biol (2008) 182; 603-614