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

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

Author information

1
Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
2
Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China.
3
Departments of Pediatric Oncology, Neuropathology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf 40225, Germany; Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Düsseldorf 40225, Germany.
4
Departments of Pediatrics and Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA.
5
Department of Cancer Biology, MD Anderson Cancer Center, University of Texas, Houston, TX 77054, USA.
6
Departments of Internal Medicine and Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
7
Department of Pathology, Massachusetts General Hospital, Dana-Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
8
Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China. Electronic address: richard.lu@cchmc.org.

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

Comment in

PMID:
29438698
PMCID:
PMC5813693
[Available on 2019-02-12]
DOI:
10.1016/j.ccell.2018.01.005
[Indexed for MEDLINE]

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