[PDF][PDF] Programming of Schwann cells by Lats1/2-TAZ/YAP signaling drives malignant peripheral nerve sheath tumorigenesis

LMN Wu, Y Deng, J Wang, C Zhao, J Wang, R Rao… - Cancer Cell, 2018 - cell.com
LMN Wu, Y Deng, J Wang, C Zhao, J Wang, R Rao, L Xu, W Zhou, K Choi, TA Rizvi…
Cancer Cell, 2018cell.com
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 …
Summary
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.
cell.com