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Multiple Nf1 Schwann cell populations reprogram the plexiform neurofibroma tumor microenvironment
Leah J. Kershner, … , Jack F. Shern, Nancy Ratner
Leah J. Kershner, … , Jack F. Shern, Nancy Ratner
Published September 22, 2022
Citation Information: JCI Insight. 2022;7(18):e154513. https://doi.org/10.1172/jci.insight.154513.
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Research Article Cell biology Oncology

Multiple Nf1 Schwann cell populations reprogram the plexiform neurofibroma tumor microenvironment

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Abstract

To define alterations early in tumor formation, we studied nerve tumors in neurofibromatosis 1 (NF1), a tumor predisposition syndrome. Affected individuals develop neurofibromas, benign tumors driven by NF1 loss in Schwann cells (SCs). By comparing normal nerve cells to plexiform neurofibroma (PN) cells using single-cell and bulk RNA sequencing, we identified changes in 5 SC populations, including a de novo SC progenitor–like (SCP-like) population. Long after Nf1 loss, SC populations developed PN-specific expression of Dcn, Postn, and Cd74, with sustained expression of the injury response gene Postn and showed dramatic expansion of immune and stromal cell populations; in corresponding human PNs, the immune and stromal cells comprised 90% of cells. Comparisons between injury-related and tumor monocytes/macrophages support early monocyte recruitment and aberrant macrophage differentiation. Cross-species analysis verified each SC population and unique conserved patterns of predicted cell-cell communication in each SC population. This analysis identified PROS1-AXL, FGF-FGFR, and MIF-CD74 and its effector pathway NF-κB as deregulated in NF1 SC populations, including SCP-like cells predicted to influence other types of SCs, stromal cells, and/or immune cells in mouse and human. These findings highlight remarkable changes in multiple types of SCs and identify therapeutic targets for PN.

Authors

Leah J. Kershner, Kwangmin Choi, Jianqiang Wu, Xiyuan Zhang, Melissa Perrino, Nathan Salomonis, Jack F. Shern, Nancy Ratner

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Figure 1

Immune and stromal cell increases in PNs occur long after SC loss of Nf1.

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Immune and stromal cell increases in PNs occur long after SC loss of Nf1...
(A) Schematic of the analysis of control and PN cells by scRNA-seq showing analyzed cell numbers. (B) UMAPs of PNs (7-month Dhh-Cre;Nf1fl/fl), pretumor (2-month Dhh-Cre;Nf1fl/fl), and corresponding 7-month and 2-month Nf1fl/fl littermate controls, generated using Seurat. (C) Cell type frequencies across sample types showing all cell types (left); immune cells (middle), and stromal cells (right), showing enrichment of immune and stromal cell clusters in PNs. UMAP cluster numbers (from B) are shown in parentheses for each annotated cell type. (D) Left: Heatmap showing scRNA-seq gene fold changes in 7-month PN cells versus controls, generated using cellHarmony. Right: Differential expression of the same genes in bulk RNA-seq, analyzed as fold changes in 7-month PNs versus controls. The changes were independent of PN growth rate (fast/slow). Broad patterns of differential gene expression across cell types and cell type specific changes are evident.

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ISSN 2379-3708

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