Therapeutic options are limited for Neurofibromatosis type 1 (NF1) associated malignant peripheral nerve sheath tumours(MPNSTs) and clinical trials using drug agents have so far been unsuccessful. This lack of clinical success is likely attributed to high levels of intratumoural molecular heterogeneity and variations in signal transduction within MPNSTs. To better explore the variance of malignant signalling properties within heterogeneous MPNSTs, four MPNST cell lines (ST8814, S462, S1844.1 and S1507.2) were used. The data demonstrate that small molecule inhibition of the MET proto-oncogene and mTOR had variable outcome when preventing wound healing, cell migration and invasion, with the S462 cells being highly resistant to both. Of interest, targeted inhibition of the STAT3 transcription factor suppressed wound healing, cell migration, invasion and tumour formation in all four MPNST lines, which demonstrates that unlike MET and mTOR, STAT3, functions as a common driver of tumourigenesis in NF1-MPNSTs. Of clinical importance, STAT3 knockdown was sufficient to block the expression of HIF-1alpha, HIF-2alpha and VEGF-A in all four MPNST lines. Finally, the data demonstrates that wound healing, cell migration, invasion and tumour formation through STAT3 is highly dependent on HIF signalling, where knockdown of HIF-1alpha ablated these oncogenic facets of STAT3. IMPLICATIONS: This research reveals that aberrant STAT3 and HIF-1a activity drives tumour progression in MPNSTs, indicating that inhibition of the STAT3/HIF-1alpha/VEGF-A signalling axis is a viable treatment strategy.