To define alterations early in tumor formation, we studied nerve tumors in neurofibromatosis 1 (NF1), a tumor predisposition syndrome in which affected individuals develop plexiform neurofibroma (PN). These benign tumors are driven by NF1 loss in Schwann cells (SC). By comparing normal nerve cells to PN cells using single cell and bulk RNA sequencing, we identified changes in five SC populations, including a de novo Schwann cell progenitor-like population. Long after Nf1 loss, SC populations developed PN-specific expression of Dcn, Postn, and CD74, and showed dramatic expansion of immune and stromal cell populations; in human PN, immune and stromal cells comprised 90% of cells. Label transfer enabled verification of each SC population and predicted tumor unique patterns of cell-cell communication in each SC population. We identified PROS-AXL, FGF-FGFR, and MIF-CD74 and its effector pathway NFkB as deregulated in NF1 SC populations, including SCP-like cells. Each receptor-ligand pair was predicted to influence surrounding cells in mouse and human. These findings highlight remarkable changes in all PN cells driven by loss of NF1 in multiple types of SCs and identify therapeutic targets for PN. Overall design: [Mouse] single cell mRNA profiles of paraspinal tumors (2 or 7 mo. Dhh-Cre;Nf1fl/fl) (n=6), and age-matched wild type dorsal root ganglia (DRG) with nerve roots [Human] single cell mRNA profiles of human plexiform neurofibromas (n=4) >>> Submitter declares that the human raw data will be deposited in dbGAP due to patient privacy concerns. <<<