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

Cancer Cell. 2018 Feb 12;33(2):292-308.e7. doi: 10.1016/j.ccell.2018.01.005.

Abstract

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.

Keywords: Lats1/2; MPNST; PDGF signaling; Schwann cells; TAZ; YAP; hippo signaling; murine models; peripheral nerve sheath tumor; tumor suppressor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Animals
  • Cell Cycle Proteins
  • Cell Differentiation / genetics
  • Cell Proliferation / genetics
  • Cell Transformation, Neoplastic
  • Humans
  • Mice
  • Phosphoproteins / genetics*
  • Protein-Serine-Threonine Kinases / genetics*
  • Schwann Cells / cytology*
  • Signal Transduction / genetics
  • Transcription Factors

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Phosphoproteins
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • Yap protein, mouse
  • LATS1 protein, human
  • Lats1 protein, mouse
  • Protein-Serine-Threonine Kinases