4.8 Article

Single-cell multiomics identifies clinically relevant mesenchymal stem-like cells and key regulators for MPNST malignancy

Journal

SCIENCE ADVANCES
Volume 8, Issue 44, Pages -

Publisher

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abo5442

Keywords

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Funding

  1. Cincinnati Children's research foundation
  2. NIH [R37 NS096359]
  3. Department of Defense [W81WXH2010443]
  4. Pablove Foundation Childhood Cancer Research Seed Grant
  5. Sarcoma Foundation of America Zachary Cohen Memorial Research Award
  6. NTAP fund

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Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive soft tissue sarcoma derived from benign neurofibroma (NF). A novel nestin-negative malignant stem-like subpopulation has been identified in MPNST, which is common to both mouse and human MPNSTs and correlates with clinical severity. Unique regulatory networks and druggable targets have been identified in MPNST, and targeting key epithelial-mesenchymal transition and stemness regulators can impede MPNST growth. These studies reveal the underlying principles of tumor cell-state evolution during NF-to-MPNST transformation and highlight a previously unrecognized mesenchymal stem-like subpopulation in MPNST disease progression.
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. 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. 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. Integrative multiomics profiling further identifies unique regulatory networks and druggable targets against the malignant subpopulations in MPNST. Targeting key epithelial-mesenchymal transition and stemness regulators including ZEB1 and ALDH1A1 impedes MPNST growth. 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.

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