The cell surface proteome of malignant peripheral nerve sheath tumors reveals therapeutic targets.

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas and the most common cause of disease-associated death for Neurofibromatosis type 1 (NF1) patients. In the context of NF1, MPNSTs develop from benign premalignant precursors. The transition to malignancy is usually accompanied by loss of the polycomb repressive complex 2 (PRC2), leading to aberrant upregulation of many genes. There is a significant gap in our knowledge of which cell-surface targets become derepressed and therapeutically actionable following PRC2 loss, contributing to the current lack of effective targeted therapies for MPNSTs. Methods: This study uses cell-surface capture technology with mass spectrometry to profile MPNST models. We define PRC2-dependent effects on the cell surface proteome by profiling models with and without PRC2 activity and comparing surface protein profiles. We also create an MPNST cell-surface protein compendium comprised of proteins that are highly expressed across a variety of well-defined MPNST models. Results: Comparisons of PRC2-active to PRC2-inactive samples revealed a host of pathways dysregulated at the surface protein level, including epithelial-mesenchymal transition and interferon response. An MPNST cell surface protein compendium was defined with multiple previously known and unknown surface antigens. These markers made tumor-derived cell lines vulnerable to therapeutic assault and showed significant presence in immunostaining of primary MPNST samples. Conclusion: Results reveal PTK7 as a novel and promising target for MPNST. In total, these efforts represent a step toward addressing the knowledge gap in MPNST genesis and identifying new therapeutic targets for further testing.