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

• DOI: 10.1016/j.ccell.2018.01.005
• Publication Date: 2018-02-12T16:38:45Z
• Authors: Lai Man Natalie Wu; Yaqi Deng; Jincheng Wang; Chuntao Zhao; Jiajia Wang; Rohit Rao; Lingli Xu; Wenhao Zhou; Kwangmin Choi; Tilat A. Rizvi; Marc Remke; Joshua B. Rubin; Randy L. Johnson; Thomas J. Carroll; Anat O. Stemmer-R...; Jianqiang Wu; Yi Zheng; Mei Xin; Nancy Ratner; Q. Richard Lu
• Keywords: Schwann cell

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.