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

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-Rachamimov, Jianqiang Wu, Yi Zheng, Mei Xin, Nancy Ratner, Q. Richard Lu

Research output: Contribution to journalArticle

13 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Pages (from-to)292-308.e7
JournalCancer Cell
Volume33
Issue number2
DOIs
StatePublished - Feb 12 2018

Fingerprint

Schwann Cells
Neurilemmoma
Peripheral Nerves
Carcinogenesis
Platelet-Derived Growth Factor Receptors
Neoplasms
Penetrance
Cell Lineage
Growth
Tumor Burden
Sarcoma
Cell Proliferation
Genome
Phenotype

Keywords

  • hippo signaling
  • Lats1/2
  • MPNST
  • murine models
  • PDGF signaling
  • peripheral nerve sheath tumor
  • Schwann cells
  • TAZ
  • tumor suppressor
  • YAP

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

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

In: Cancer Cell, Vol. 33, No. 2, 12.02.2018, p. 292-308.e7.

Research output: Contribution to journalArticle

Wu, LMN, Deng, Y, Wang, J, Zhao, C, Wang, J, Rao, R, Xu, L, Zhou, W, Choi, K, Rizvi, TA, Remke, M, Rubin, JB, Johnson, RL, Carroll, TJ, Stemmer-Rachamimov, AO, Wu, J, Zheng, Y, Xin, M, Ratner, N & Lu, QR 2018, 'Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis', Cancer Cell, vol. 33, no. 2, pp. 292-308.e7. https://doi.org/10.1016/j.ccell.2018.01.005
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. / Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis. In: Cancer Cell. 2018 ; Vol. 33, No. 2. pp. 292-308.e7.
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AU - Wu, Lai Man Natalie

AU - Deng, Yaqi

AU - Wang, Jincheng

AU - Zhao, Chuntao

AU - Wang, Jiajia

AU - Rao, Rohit

AU - Xu, Lingli

AU - Zhou, Wenhao

AU - Choi, Kwangmin

AU - Rizvi, Tilat A.

AU - Remke, Marc

AU - Rubin, Joshua B.

AU - Johnson, Randy L.

AU - Carroll, Thomas J.

AU - Stemmer-Rachamimov, Anat O.

AU - Wu, Jianqiang

AU - Zheng, Yi

AU - Xin, Mei

AU - Ratner, Nancy

AU - Lu, Q. Richard

PY - 2018/2/12

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N2 - 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. 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.

AB - 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. 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.

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KW - tumor suppressor

KW - YAP

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