Best Of Best Poster Oral Clinical Oncology Society of Australia Annual Scientific Meeting 2017

Can ERBB4 induce nuclear YAP in High Grade Glioma? (#135)

Samad Raza 1 2 , Wishva Herath 1 , Sameer Greenall 1 , Terrance Johns 1
  1. Oncogenic Signalling Laboratory, Hudson Institute of Medical Research, Melbourne, Victoria, Australia
  2. Monash University, Melbourne, Victoria, Australia

ERBB4, the fourth member of the EGFR family of receptor tyrosine kinases, is a promising therapeutic target in several cancers. However, its significance in high grade glioma (HGG) is yet to be elucidated. Recent studies in breast cancer have shown that ERBB4-s80, the intracellular fragment generated by ligand-dependent cleavage of ERBB4, bypasses the tumour-suppressive Hippo pathway, acting as a nuclear chaperone for the oncogenic transcription factor YAP and thereby promoting carcinogenesis. We speculated whether ERBB4 is a regulator of YAP in the setting of HGG. Western blots were employed to assess the phosphorylation and cleavage of ERBB4 in response to its principal ligand, neuregulin-1β (NRG-1β), in a panel of ERBB4-positive HGG cell lines. Immunofluorescence was then used to examine the effect of NRG-1β treatment on nuclear ERBB4 and YAP localisation in the same cell lines. Whilst in the conventional HGG cell line SF767, NRG-1β treatment lead to ERBB4 activation and nuclear ERBB4 and YAP co-localisation, these findings were not replicated in patient-derived cell lines maintained at low passage (PR1.1, RR2 and GBM-L1). In these cells, ERBB4 remained underphosphorylated in response to ligand treatment, suggesting the presence of a yet-unknown inhibitory mechanism preventing its activation. Furthermore, immunofluorescence showed no relationship between NRG-1β treatment and nuclear YAP localisation. Lastly, the ERBB4-s80 fragment was not demonstrated in any of the cell lines. Collectively, these findings suggest that ERBB4 is not a key orchestrater of nuclear YAP in HGG. We are planning further experiments to explain the cause and significance of non-responsive ERBB4 in patient-derived HGG cell lines.