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

Area of Science:

• Oncology
• Cancer Biology
• Stem Cell Research

Background:

• Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas originating from Schwann cells (SCs) and neurofibromas (NF).
• The cellular origins and heterogeneity of MPNSTs remain poorly understood, hindering effective treatment strategies.

Purpose of the Study:

• To elucidate the cellular identity, heterogeneity, and origins of tumor populations in MPNSTs.
• To identify novel therapeutic targets for MPNST by understanding malignant transformation processes.

Main Methods:

• Single-cell profiling of human and animal models of NF and MPNST.
• Integrative multiomics analysis (genomics, transcriptomics, etc.).
• Functional studies targeting key regulatory molecules.

Main Results:

• Identified a broad spectrum of nestin-expressing SC lineage cells during malignant transformation.
• Discovered a novel nestin-negative mesenchymal stem-like subpopulation common to human and murine MPNSTs, correlating with clinical severity.
• Uncovered unique regulatory networks and identified ZEB1 and ALDH1A1 as druggable targets.

Conclusions:

• MPNST development involves dynamic evolution of cell states and regulatory circuits.
• A previously unrecognized mesenchymal stem-like subpopulation drives MPNST progression.
• Targeting epithelial-mesenchymal transition and stemness regulators shows therapeutic potential against MPNST.