Single-cell tumor microenvironment profiling informs a circulating proteome test for the interception of malignant transformation in NF1 nerve sheath tumors

TL;DR

Researchers developed a non-invasive blood test to detect early signs of cancer in nerve tumors linked to neurofibromatosis type 1.

Contribution

A novel circulating proteome test for early detection of malignant transformation in NF1 nerve sheath tumors.

Findings

Fifty plasma proteins accurately distinguish MPNST from benign or premalignant tumors.

Single-cell analysis identified key cellular changes in the tumor microenvironment during malignant transformation.

Protein biomarkers correlate with mRNA signatures specific to MPNST cell populations.

Abstract

The most common cause of death in neurofibromatosis type 1 (NF1) is the development of malignant peripheral nerve sheath tumor (MPNST), a deadly sarcoma that can transform from benign plexiform neurofibromas (PN) or premalignant atypical neurofibromas (AN). We built a single-cell dataset of 55 NF1-associated PN, AN, and MPNST to define cellular changes in neurofibroma at-risk of malignant transformation. Integrative analysis of changes in the tumor microenvironment revealed the emergence of malignant tumor cells, regulatory T cells, and loss of activated macrophages in MPNST. Using this reference dataset, we validated findings using anchor-based label transfer in an additional 19 NF1 nerve sheath tumors profiled with single cell sequencing, and public datasets. We then defined protein biomarkers of malignant transformation from high-throughput proteomic analysis of plasma samples collected from 45 NF1 patients that correlated to mRNAs specific to MPNST cell populations. Fifty plasma proteins accurately and non-invasively distinguished patients with MPNST from those with premalignant tumors. These markers should improve the ability to identify high-risk neurofibromas for improved cancer surveillance and enable early detection of malignant transformation in NF1.

Single-cell tumor sequencing of the tumor microenvironment and high-throughput plasma proteomics of NF1 patients were used to accurately differentiate malignant peripheral nerve sheath tumors from their benign precursors.

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