title: Proteomic screening identifies a YAP-driven signaling network linked to tumor cell proliferation in human schwannomas.
abstract: BACKGROUND
  Inactivation of the NF2 gene predisposes to neurofibromatosis type II and the development of schwannomas. In vitro studies have shown that loss of NF2 leads to the induction of mitogenic signaling mediated by receptor tyrosine kinases (RTKs), MAP kinase, AKT, or Hippo pathways. The goal of our study was to evaluate the expression and activity of these signaling pathways in human schwannomas in order to identify new potential therapeutic targets.
  
  
  METHODS
  Large sets of human schwannomas, totaling 68 tumors, were analyzed using complementary proteomic approaches. RTK arrays identified the most frequently activated RTKs. The correlation between the expression and activity of signaling pathways and proliferation of tumor cells using Ki67 marker was investigated by reverse-phase protein array (RRPA). Finally, immunohistochemistry was used to evaluate the expression pattern of signaling effectors in the tumors.
  
  
  RESULTS
  We showed that Her2, Her3, PDGFRß, Axl, and Tie2 are frequently activated in the tumors. Furthermore, RRPA demonstrated that Ki67 levels are linked to YAP, p-Her3, and PDGFRß expression levels. In addition, Her2, Her3, and PDGFRß are transcriptional targets of Yes-associated protein (YAP) in schwannoma cells in culture. Finally, we observed that the expression of these signaling effectors is very variable between tumors.
  
  
  CONCLUSIONS
  Tumor cell proliferation in human schwannomas is linked to a signaling network controlled by the Hippo effector YAP. Her2, Her3, PDGFRß, Axl, and Tie2, as well as YAP, represent potentially valuable therapeutic targets. However, the variability of their expression between tumors may result in strong differences in the response to targeted therapy.
authors.affiliation: Centre National de la Recherche Scientifique, Institut Curie, Paris, France (A.B., C.C., D.Lo., D.La.); Institut National de la Santé et de la Recherche Médicale, Paris, France (I.B., P.H.); Mines ParisTech, Fontainebleau, France (P.H.); Breast Cancer Biology Group, Institut Curie, Paris, France (T.D.); Reverse Phase Protein Array Platform, Institut Curie, Paris, France (C.D., L.D.K.); Centre National de la Recherche Scientifique, Institut Curie, Paris, France (D.F.); Department of Neurosurgery, Assistance Publique-Hôpitaux de Paris, Hopital Beaujon, Clichy, France (M.K.); Unité Institut National de la Santé et de la Recherche Médicale, Fondation Jean Dausset, Paris, France (M.K.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Bichat, Paris, France (A.C.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (A.C.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Beaujon, Clichy, France (P.B.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (M.K.).
authors.forename: Alizée
authors.initials: A
authors.lastname: Boin
authors.affiliation: Centre National de la Recherche Scientifique, Institut Curie, Paris, France (A.B., C.C., D.Lo., D.La.); Institut National de la Santé et de la Recherche Médicale, Paris, France (I.B., P.H.); Mines ParisTech, Fontainebleau, France (P.H.); Breast Cancer Biology Group, Institut Curie, Paris, France (T.D.); Reverse Phase Protein Array Platform, Institut Curie, Paris, France (C.D., L.D.K.); Centre National de la Recherche Scientifique, Institut Curie, Paris, France (D.F.); Department of Neurosurgery, Assistance Publique-Hôpitaux de Paris, Hopital Beaujon, Clichy, France (M.K.); Unité Institut National de la Santé et de la Recherche Médicale, Fondation Jean Dausset, Paris, France (M.K.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Bichat, Paris, France (A.C.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (A.C.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Beaujon, Clichy, France (P.B.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (M.K.).
authors.forename: Anne
authors.initials: A
authors.lastname: Couvelard
authors.affiliation: Centre National de la Recherche Scientifique, Institut Curie, Paris, France (A.B., C.C., D.Lo., D.La.); Institut National de la Santé et de la Recherche Médicale, Paris, France (I.B., P.H.); Mines ParisTech, Fontainebleau, France (P.H.); Breast Cancer Biology Group, Institut Curie, Paris, France (T.D.); Reverse Phase Protein Array Platform, Institut Curie, Paris, France (C.D., L.D.K.); Centre National de la Recherche Scientifique, Institut Curie, Paris, France (D.F.); Department of Neurosurgery, Assistance Publique-Hôpitaux de Paris, Hopital Beaujon, Clichy, France (M.K.); Unité Institut National de la Santé et de la Recherche Médicale, Fondation Jean Dausset, Paris, France (M.K.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Bichat, Paris, France (A.C.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (A.C.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Beaujon, Clichy, France (P.B.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (M.K.).
authors.forename: Christophe
authors.initials: C
authors.lastname: Couderc
authors.affiliation: Centre National de la Recherche Scientifique, Institut Curie, Paris, France (A.B., C.C., D.Lo., D.La.); Institut National de la Santé et de la Recherche Médicale, Paris, France (I.B., P.H.); Mines ParisTech, Fontainebleau, France (P.H.); Breast Cancer Biology Group, Institut Curie, Paris, France (T.D.); Reverse Phase Protein Array Platform, Institut Curie, Paris, France (C.D., L.D.K.); Centre National de la Recherche Scientifique, Institut Curie, Paris, France (D.F.); Department of Neurosurgery, Assistance Publique-Hôpitaux de Paris, Hopital Beaujon, Clichy, France (M.K.); Unité Institut National de la Santé et de la Recherche Médicale, Fondation Jean Dausset, Paris, France (M.K.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Bichat, Paris, France (A.C.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (A.C.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Beaujon, Clichy, France (P.B.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (M.K.).
authors.forename: Isabel
authors.initials: I
authors.lastname: Brito
authors.affiliation: Centre National de la Recherche Scientifique, Institut Curie, Paris, France (A.B., C.C., D.Lo., D.La.); Institut National de la Santé et de la Recherche Médicale, Paris, France (I.B., P.H.); Mines ParisTech, Fontainebleau, France (P.H.); Breast Cancer Biology Group, Institut Curie, Paris, France (T.D.); Reverse Phase Protein Array Platform, Institut Curie, Paris, France (C.D., L.D.K.); Centre National de la Recherche Scientifique, Institut Curie, Paris, France (D.F.); Department of Neurosurgery, Assistance Publique-Hôpitaux de Paris, Hopital Beaujon, Clichy, France (M.K.); Unité Institut National de la Santé et de la Recherche Médicale, Fondation Jean Dausset, Paris, France (M.K.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Bichat, Paris, France (A.C.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (A.C.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Beaujon, Clichy, France (P.B.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (M.K.).
authors.forename: Dan
authors.initials: D
authors.lastname: Filipescu
authors.affiliation: Centre National de la Recherche Scientifique, Institut Curie, Paris, France (A.B., C.C., D.Lo., D.La.); Institut National de la Santé et de la Recherche Médicale, Paris, France (I.B., P.H.); Mines ParisTech, Fontainebleau, France (P.H.); Breast Cancer Biology Group, Institut Curie, Paris, France (T.D.); Reverse Phase Protein Array Platform, Institut Curie, Paris, France (C.D., L.D.K.); Centre National de la Recherche Scientifique, Institut Curie, Paris, France (D.F.); Department of Neurosurgery, Assistance Publique-Hôpitaux de Paris, Hopital Beaujon, Clichy, France (M.K.); Unité Institut National de la Santé et de la Recherche Médicale, Fondation Jean Dausset, Paris, France (M.K.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Bichat, Paris, France (A.C.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (A.C.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Beaujon, Clichy, France (P.B.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (M.K.).
authors.forename: Michel
authors.initials: M
authors.lastname: Kalamarides
authors.affiliation: Centre National de la Recherche Scientifique, Institut Curie, Paris, France (A.B., C.C., D.Lo., D.La.); Institut National de la Santé et de la Recherche Médicale, Paris, France (I.B., P.H.); Mines ParisTech, Fontainebleau, France (P.H.); Breast Cancer Biology Group, Institut Curie, Paris, France (T.D.); Reverse Phase Protein Array Platform, Institut Curie, Paris, France (C.D., L.D.K.); Centre National de la Recherche Scientifique, Institut Curie, Paris, France (D.F.); Department of Neurosurgery, Assistance Publique-Hôpitaux de Paris, Hopital Beaujon, Clichy, France (M.K.); Unité Institut National de la Santé et de la Recherche Médicale, Fondation Jean Dausset, Paris, France (M.K.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Bichat, Paris, France (A.C.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (A.C.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Beaujon, Clichy, France (P.B.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (M.K.).
authors.forename: Pierre
authors.initials: P
authors.lastname: Bedossa
authors.affiliation: Centre National de la Recherche Scientifique, Institut Curie, Paris, France (A.B., C.C., D.Lo., D.La.); Institut National de la Santé et de la Recherche Médicale, Paris, France (I.B., P.H.); Mines ParisTech, Fontainebleau, France (P.H.); Breast Cancer Biology Group, Institut Curie, Paris, France (T.D.); Reverse Phase Protein Array Platform, Institut Curie, Paris, France (C.D., L.D.K.); Centre National de la Recherche Scientifique, Institut Curie, Paris, France (D.F.); Department of Neurosurgery, Assistance Publique-Hôpitaux de Paris, Hopital Beaujon, Clichy, France (M.K.); Unité Institut National de la Santé et de la Recherche Médicale, Fondation Jean Dausset, Paris, France (M.K.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Bichat, Paris, France (A.C.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (A.C.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Beaujon, Clichy, France (P.B.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (M.K.).
authors.forename: Leanne
authors.initials: L
authors.lastname: De Koning
authors.affiliation: Centre National de la Recherche Scientifique, Institut Curie, Paris, France (A.B., C.C., D.Lo., D.La.); Institut National de la Santé et de la Recherche Médicale, Paris, France (I.B., P.H.); Mines ParisTech, Fontainebleau, France (P.H.); Breast Cancer Biology Group, Institut Curie, Paris, France (T.D.); Reverse Phase Protein Array Platform, Institut Curie, Paris, France (C.D., L.D.K.); Centre National de la Recherche Scientifique, Institut Curie, Paris, France (D.F.); Department of Neurosurgery, Assistance Publique-Hôpitaux de Paris, Hopital Beaujon, Clichy, France (M.K.); Unité Institut National de la Santé et de la Recherche Médicale, Fondation Jean Dausset, Paris, France (M.K.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Bichat, Paris, France (A.C.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (A.C.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Beaujon, Clichy, France (P.B.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (M.K.).
authors.forename: Carine
authors.initials: C
authors.lastname: Danelsky
authors.affiliation: Centre National de la Recherche Scientifique, Institut Curie, Paris, France (A.B., C.C., D.Lo., D.La.); Institut National de la Santé et de la Recherche Médicale, Paris, France (I.B., P.H.); Mines ParisTech, Fontainebleau, France (P.H.); Breast Cancer Biology Group, Institut Curie, Paris, France (T.D.); Reverse Phase Protein Array Platform, Institut Curie, Paris, France (C.D., L.D.K.); Centre National de la Recherche Scientifique, Institut Curie, Paris, France (D.F.); Department of Neurosurgery, Assistance Publique-Hôpitaux de Paris, Hopital Beaujon, Clichy, France (M.K.); Unité Institut National de la Santé et de la Recherche Médicale, Fondation Jean Dausset, Paris, France (M.K.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Bichat, Paris, France (A.C.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (A.C.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Beaujon, Clichy, France (P.B.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (M.K.).
authors.forename: Thierry
authors.initials: T
authors.lastname: Dubois
authors.affiliation: Centre National de la Recherche Scientifique, Institut Curie, Paris, France (A.B., C.C., D.Lo., D.La.); Institut National de la Santé et de la Recherche Médicale, Paris, France (I.B., P.H.); Mines ParisTech, Fontainebleau, France (P.H.); Breast Cancer Biology Group, Institut Curie, Paris, France (T.D.); Reverse Phase Protein Array Platform, Institut Curie, Paris, France (C.D., L.D.K.); Centre National de la Recherche Scientifique, Institut Curie, Paris, France (D.F.); Department of Neurosurgery, Assistance Publique-Hôpitaux de Paris, Hopital Beaujon, Clichy, France (M.K.); Unité Institut National de la Santé et de la Recherche Médicale, Fondation Jean Dausset, Paris, France (M.K.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Bichat, Paris, France (A.C.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (A.C.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Beaujon, Clichy, France (P.B.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (M.K.).
authors.forename: Philippe
authors.initials: P
authors.lastname: Hupé
authors.affiliation: Centre National de la Recherche Scientifique, Institut Curie, Paris, France (A.B., C.C., D.Lo., D.La.); Institut National de la Santé et de la Recherche Médicale, Paris, France (I.B., P.H.); Mines ParisTech, Fontainebleau, France (P.H.); Breast Cancer Biology Group, Institut Curie, Paris, France (T.D.); Reverse Phase Protein Array Platform, Institut Curie, Paris, France (C.D., L.D.K.); Centre National de la Recherche Scientifique, Institut Curie, Paris, France (D.F.); Department of Neurosurgery, Assistance Publique-Hôpitaux de Paris, Hopital Beaujon, Clichy, France (M.K.); Unité Institut National de la Santé et de la Recherche Médicale, Fondation Jean Dausset, Paris, France (M.K.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Bichat, Paris, France (A.C.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (A.C.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Beaujon, Clichy, France (P.B.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (M.K.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Louvard
authors.affiliation: Centre National de la Recherche Scientifique, Institut Curie, Paris, France (A.B., C.C., D.Lo., D.La.); Institut National de la Santé et de la Recherche Médicale, Paris, France (I.B., P.H.); Mines ParisTech, Fontainebleau, France (P.H.); Breast Cancer Biology Group, Institut Curie, Paris, France (T.D.); Reverse Phase Protein Array Platform, Institut Curie, Paris, France (C.D., L.D.K.); Centre National de la Recherche Scientifique, Institut Curie, Paris, France (D.F.); Department of Neurosurgery, Assistance Publique-Hôpitaux de Paris, Hopital Beaujon, Clichy, France (M.K.); Unité Institut National de la Santé et de la Recherche Médicale, Fondation Jean Dausset, Paris, France (M.K.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Bichat, Paris, France (A.C.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (A.C.); Pathology Department Beaujon-Bichat, AP-HP, Hôpital Beaujon, Clichy, France (P.B.); Université Paris Diderot, Sorbonne Paris Cité, Paris, France (M.K.).
authors.forename: Dominique
authors.initials: D
authors.lastname: Lallemand
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism*; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D008297:Male; D009442:Neurilemmoma / Q000378:metabolism*; D016518:Neurofibromatosis 2 / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D040901:Proteomics; D015398:Signal Transduction; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human
keywords: Neurofibromatosis type 2; YAP; proteomic; schwannoma; signaling