# 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.

## Key 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.