Investigating the role of TAM family receptors in Merlin deficient tumours

NF2 mutation causes development of multiple benign tumours of the nervous system such as schwannomas, meningiomas and ependymomas. Conventional chemotherapy is ineffective for this group of tumours, and surgery/radiosurgery... [ view full abstract ]

NF2 mutation causes development of multiple benign tumours of the nervous system such as schwannomas, meningiomas and ependymomas. Conventional chemotherapy is ineffective for this group of tumours, and surgery/radiosurgery carries significant risk due to tumour multiplicity and location, thus effective drug therapy is urgently needed. TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases are upregulated in several tumours including schwannomas and are shown to be under negative control of a tumour suppressor protein Merlin, encoded by Neurofibromatosis type II (NF2) gene. Our group has also previously shown that AXL contributes to tumour development by increasing cell-proliferation and cell-matrix adhesion in schwannomas. In this study, we’re investigating the role of TYRO3 and MERTK in development of schwannomas and all three receptors in development meningiomas using human primary cells and tissues. Our current data demonstrates that in human primary schwannoma cells, AXL expression is dependent on expression of TYRO3 and MERTK. Confocal microscopy showed co-localisation of AXL, TYRO3 and MERTK in schwannoma cells. However, co-immunoprecipitation experiments revealed the direct interaction only between AXL and TYRO3, and TYRO3 and MERTK. In addition to interact with own members, shRNA knock down experiments confirmed that TYRO3 and MERTK can also cross-talk with other group of receptors such as integrin β1, EGFR and PDGFR in schwannoma. In addition, Western blot experiments with tumour tissue lysates showed overexpression of all three TAM members in grade-I meningiomas, compared to grade II and III meningiomas. High expression and activation/phosphorylation of TYRO3, AXL and MERTK has been also found in NF2-/- grade-I meningioma primary cells and Merlin reintroduction in NF2-/- meningioma primary cells confirmed TAM receptors are negatively regulated by Merlin in meningiomas. Investigating the role of TAM family receptors in pathobiology of schwannoma and meningioma will help to determine the best molecule to target therapeutically for NF2 tumours.