TY - JOUR AU - Kershner, Leah J. AU - Choi, Kwangmin AU - Wu, Jianqiang AU - Zhang, Xiyuan AU - Perrino, Melissa AU - Salomonis, Nathan AU - Shern, Jack F. AU - Ratner, Nancy T1 - Multiple Nf1 Schwann cell populations reprogram the plexiform neurofibroma tumor microenvironment PY - 2022/09/22/ AB - 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.154513 VL - 7 IS - 18 UR - https://doi.org/10.1172/jci.insight.154513 PB - The American Society for Clinical Investigation ER -