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

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.

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.

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.

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.