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Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis.

Cancer cell | 2018

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell (SC)-lineage-derived sarcomas. Molecular events driving SC-to-MPNST transformation are incompletely understood. Here, we show that human MPNSTs exhibit elevated HIPPO-TAZ/YAP expression, and that TAZ/YAP hyperactivity in SCs caused by Lats1/2 loss potently induces high-grade nerve-associated tumors with full penetrance. Lats1/2 deficiency reprograms SCs to a cancerous, progenitor-like phenotype and promotes hyperproliferation. Conversely, disruption of TAZ/YAP activity alleviates tumor burden in Lats1/2-deficient mice and inhibits human MPNST cell proliferation. Moreover, genome-wide profiling reveals that TAZ/YAP-TEAD1 directly activates oncogenic programs, including platelet-derived growth factor receptor (PDGFR) signaling. Co-targeting TAZ/YAP and PDGFR pathways inhibits tumor growth. Thus, our findings establish a previously unrecognized convergence between Lats1/2-TAZ/YAP signaling and MPNST pathogenesis, revealing potential therapeutic targets in these untreatable tumors.

Pubmed ID: 29438698 RIS Download

Mesh terms: Adaptor Proteins, Signal Transducing | Animals | Cell Differentiation | Cell Proliferation | Cell Transformation, Neoplastic | Humans | Mice | Phosphoproteins | Protein-Serine-Threonine Kinases | Schwann Cells | Signal Transduction

Associated grants

  • Agency: NINDS NIH HHS, United States
    Id: R01 NS072427
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS078092
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS075243
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS028840
  • Agency: NHLBI NIH HHS, United States
    Id: R01 HL132211
  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM063483
  • Agency: NINDS NIH HHS, United States
    Id: R37 NS096359
  • Agency: NINDS NIH HHS, United States
    Id: R01 NS086219

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