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Proteomic screening identifies a YAP-driven signaling network linked to tumor cell proliferation in human schwannomas
Alizée Boin1, Anne Couvelard1, Christophe Couderc1
1Centre 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.).
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.
Insights
Inactivation of the NF2 gene causes schwannomas, driven by signaling pathways like Hippo. Targeting YAP and specific receptor tyrosine kinases (RTKs) may offer new therapies, but tumor variability poses challenges.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Neurofibromatosis type II (NF2) gene inactivation leads to schwannomas.
- Loss of NF2 activates mitogenic signaling via receptor tyrosine kinases (RTKs), MAP kinase, AKT, and Hippo pathways.
- Understanding these pathways is crucial for identifying therapeutic targets in schwannomas.
Purpose of the Study:
- To evaluate the expression and activity of key signaling pathways in human schwannomas.
- To identify potential therapeutic targets for schwannoma treatment.
Main Methods:
- Proteomic analysis of 68 human schwannomas.
- RTK arrays to identify activated RTKs.
- Reverse-phase protein array (RRPA) to correlate signaling pathways with proliferation (Ki67).
- Immunohistochemistry to assess signaling effector expression patterns.
Main Results:
- Her2, Her3, PDGFRß, Axl, and Tie2 were frequently activated.
- Ki67 levels correlated with YAP, p-Her3, and PDGFRß expression.
- Her2, Her3, and PDGFRß are YAP transcriptional targets in schwannoma cells.
- Significant variability in signaling effector expression was observed between tumors.
Conclusions:
- Schwannoma proliferation is linked to a YAP-controlled signaling network.
- YAP, Her2, Her3, PDGFRß, Axl, and Tie2 are potential therapeutic targets.
- Tumor expression variability may impact targeted therapy response.
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