Analysis of Hippo pathway signalling in schwannoma and meningioma

Abstract

This project focuses on two tumours of the nervous system, schwannoma and meningioma. A large group of schwannomas and meningiomas display the inactivation of the NF2 gene. The NF2 gene codes for the tumour suppressor protein Merlin and its loss is associated with a multitude of pro-tumourigenic mechanisms leading to the occurrence of schwannomas and meningiomas. The loss of Merlin function causes augmented Hippo signaling i.e. interaction of YAP and TAZ, both co-activators of gene expression and the two main effectors of the Hippo signalling pathway, and TEAD, a group of transcription factors binding to YAP and TAZ. There resulting gene expression is associated with increased proliferation and evasion of cell death. This makes the YAP/TAZ-TEAD complex an excellent therapeutic target.

Since therapy options for schwannomas and meningiomas are limited to surgery and radiosurgery, both carrying additional risks for the patient, new therapy approaches are desperately needed. Therefore, we explored if a schwannoma mouse model and cell culture and primary meningioma cells would be suitable systems to allow the testing of two potential new therapy options.

Macrophages, especially tumour associated macrophages (TAMs), have been shown to promote tumour growth in various ways. Therefore, macrophage depletion is considered a promising therapy option. To see whether elimination of macrophages could be effective in our chosen schwannoma mouse model, a connection between increased TAM numbers and equally heightened proliferation within the developing schwannomas would need to be and was established. Additionally, Nf2 gene knockout and the additional knockout of either Yap or Taz genes also had distinct effects on proliferation, TAM numbers and overall schwannoma structure and cell numbers.

Macrophage infiltration and resulting support of tumour growth has also been shown to be partly YAP/TAZ-TEAD signaling dependent. Therefore, in order to simultaneously reduce TAM-derived growth support and directly impair tumour cell proliferation, the second approach targets the Hippo signaling pathway using TEAD S-autopalmitoylation inhibitors by Vivace Therapeutics which interfere with YAP/TAZ-TEAD interaction. I could show that these TEAD palmitoylation inhibitors efficiently inhibit cell proliferation of human meningioma cell lines and primary human meningioma cells.