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

• Published in: Cancer cell Vol. 33; no. 2; pp. 292 - 308.e7
• Main Authors: Wu, Lai Man Natalie, Deng, Yaqi, Wang, Jincheng, Zhao, Chuntao, Wang, Jiajia, Rao, Rohit, Xu, Lingli, Zhou, Wenhao, Choi, Kwangmin, Rizvi, Tilat A., Remke, Marc, Rubin, Joshua B., Johnson, Randy L., Carroll, Thomas J., Stemmer-Rachamimov, Anat O., Wu, Jianqiang, Zheng, Yi, Xin, Mei, Ratner, Nancy, Lu, Q. Richard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.02.2018
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Animals; Cell Cycle Proteins; Cell Differentiation - genetics; Cell Proliferation - genetics; Cell Transformation, Neoplastic; hippo signaling; Humans; Lats1/2; Mice; MPNST; murine models; PDGF signaling; peripheral nerve sheath tumor; Phosphoproteins - genetics; Protein-Serine-Threonine Kinases - genetics; Schwann cells; Schwann Cells - cytology; Signal Transduction - genetics; TAZ; Transcription Factors; tumor suppressor; YAP; murine models; Schwann cells; Lats1/2; tumor suppressor; YAP; TAZ; MPNST; peripheral nerve sheath tumor; hippo signaling; PDGF signaling
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2018.01.005

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. [Display omitted] •Human MPNSTs exhibit elevated HIPPO-TAZ/YAP expression•TAZ/YAP hyperactivity in Schwann cells potently induces high-grade nerve tumors•Lats1/2 dysregulation activates oncogenic programs, including PDGFR signaling•Co-targeting TAZ/YAP and PDGFR pathways inhibits MPNST tumor growth Wu et al. find that HIPPO-TAZ/YAP expression is elevated in malignant peripheral nerve sheath tumors (MPNST). Lats1/2 deficiency in Schwann cells induces hyperactivation of TAZ/YAP and increased PDGFR signaling, leading to the development of MPNST in mice. Inhibition of TAZ/YAP and PDGFR reduces MPNST growth.