Tumor malignancy and treatment resistance are often attributed to cellular plasticity and heterogeneity that result from activation of the epithelial-to-mesenchymal transition (EMT) program, which endows benign tumor cells with malignant traits such as migration, invasion, and chemoresistance ( 8). SC and their precursors (SCPs) can be transformed from benign slow-growing nerve sheath tumors such as plexiform neurofibromas (PNFs) to MPNST ( 7). SCs in peripheral nerves are highly quiescent yet show remarkable cellular plasticity following injury ( 6). Together, our studies reveal the underlying principles of tumor cell-state evolution and their regulatory circuitries during NF-to-MPNST transformation, highlighting a hitherto unrecognized mesenchymal stem-like subpopulation in MPNST disease progression. Targeting key epithelial-mesenchymal transition and stemness regulators including ZEB1 and ALDH1A1 impedes MPNST growth. Integrative multiomics profiling further identifies unique regulatory networks and druggable targets against the malignant subpopulations in MPNST. We uncover a nestin-negative mesenchymal neural crest-like subpopulation as a previously unknown malignant stem-like state common to murine and human MPNSTs, which correlates with clinical severity. Nestin + cells have been implicated as tumor stem cells in MPNST unexpectedly, single-cell profiling of human NF and MPNST and their animal models reveal a broad range of nestin-expressing SC lineage cells and dynamic acquisition of discrete cancer states during malignant transformation. Malignant peripheral nerve sheath tumor (MPNST), a highly aggressive Schwann cell (SC)–derived soft tissue sarcoma, arises from benign neurofibroma (NF) however, the identity, heterogeneity and origins of tumor populations remain elusive. Richard Lu +18 authors +16 authors +11 authors fewer Authors Info & Affiliations Belcher, Zaili Luo, , Sean Ogurek, Colleen Reilly, Xin Zhou, Li Zhang, Joshua Rubin, Long-sheng Chang, Mei Xin, Jiyang Yu, Mario Suva, Christine A. Lai Man Natalie Wu, Feng Zhang, , Rohit Rao, Mike Adam, , Kai Pollard, Sara Szabo, Xuezhao Liu, Katie A.
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