Alizée Boin1, Anne Couvelard1, Christophe Couderc1, Isabel Brito1, Dan Filipescu1, Michel Kalamarides1, Pierre Bedossa1, Leanne De Koning1, Carine Danelsky1, Thierry Dubois1, Philippe Hupé1, Daniel Louvard1, Dominique Lallemand1. 1. 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.).
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.
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 humanschwannomas in order to identify new potential therapeutic targets. METHODS: Large sets of humanschwannomas, 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 humanschwannomas 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: Helen Morrison; Tobias Sperka; Jan Manent; Marco Giovannini; Helmut Ponta; Peter Herrlich Journal: Cancer Res Date: 2007-01-15 Impact factor: 12.701
Authors: Jeffrey A Engelman; Kreshnik Zejnullahu; Tetsuya Mitsudomi; Youngchul Song; Courtney Hyland; Joon Oh Park; Neal Lindeman; Christopher-Michael Gale; Xiaojun Zhao; James Christensen; Takayuki Kosaka; Alison J Holmes; Andrew M Rogers; Federico Cappuzzo; Tony Mok; Charles Lee; Bruce E Johnson; Lewis C Cantley; Pasi A Jänne Journal: Science Date: 2007-04-26 Impact factor: 47.728
Authors: Sany Hoxha; Alyssa Shepard; Scott Troutman; Huitian Diao; Joanne R Doherty; Michalina Janiszewska; Robert M Witwicki; Matthew E Pipkin; William W Ja; Michael S Kareta; Joseph L Kissil Journal: Cancer Res Date: 2020-05-14 Impact factor: 12.701
Authors: Jaishri O Blakeley; Xiaobu Ye; Dan G Duda; Chris F Halpin; Amanda L Bergner; Alona Muzikansky; Vanessa L Merker; Elizabeth R Gerstner; Laura M Fayad; Shivani Ahlawat; Michael A Jacobs; Rakesh K Jain; Christopher Zalewski; Eva Dombi; Brigitte C Widemann; Scott R Plotkin Journal: J Clin Oncol Date: 2016-03-14 Impact factor: 44.544
Authors: Alexander Schulz; Robert Büttner; Christian Hagel; Stephan L Baader; Lan Kluwe; Johannes Salamon; Victor-Felix Mautner; Thomas Mindos; David B Parkinson; Jeffrey R Gehlhausen; D Wade Clapp; Helen Morrison Journal: Acta Neuropathol Date: 2016-05-28 Impact factor: 17.088
Authors: Robert Allaway; Steve P Angus; Roberta L Beauchamp; Jaishri O Blakeley; Marga Bott; Sarah S Burns; Annemarie Carlstedt; Long-Sheng Chang; Xin Chen; D Wade Clapp; Patrick A Desouza; Serkan Erdin; Cristina Fernandez-Valle; Justin Guinney; James F Gusella; Stephen J Haggarty; Gary L Johnson; Salvatore La Rosa; Helen Morrison; Alejandra M Petrilli; Scott R Plotkin; Abhishek Pratap; Vijaya Ramesh; Noah Sciaky; Anat Stemmer-Rachamimov; Tim J Stuhlmiller; Michael E Talkowski; D Bradley Welling; Charles W Yates; Jon S Zawistowski; Wen-Ning Zhao Journal: PLoS One Date: 2018-06-13 Impact factor: 3.240