Spatiotemporal loss of NF1 in schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway

Zhiguo Chen, Juan Mo, Jean Philippe Brosseau, Tracey Shipman, Yong Wang, Chung Ping Liao, Jonathan M. Cooper, Robert J. Allaway, Sara J.C. Gosline, Justin Guinney, Thomas J. Carroll, Lu Q. Le

研究成果: 雜誌貢獻文章

9 引文 斯高帕斯(Scopus)

摘要

Neurofibromatosis type 1 (NF1) is a cancer predisposition disorder that results from inactivation of the tumor suppressor neurofibromin, a negative regulator of RAS signaling. Patients with NF1 present with a wide range of clinical manifestations, and the tumor with highest prevalence is cutaneous neurofibroma (cNF). Most patients harboring cNF suffer greatly from the burden of those tumors, which have no effective medical treatment. Ironically, none of the numerous NF1 mouse models developed so far recapitulate cNF. Here, we discovered that HOXB7 serves as a lineage marker to trace the developmental origin of cNF neoplastic cells. Ablating Nf1 in the HOXB7 lineage faithfully recapitulates both human cutaneous and plexiform neurofibroma. In addition, we discovered that modulation of the Hippo pathway acts as a “modifier” for neurofibroma tumorigenesis. This mouse model opens the doors for deciphering the evolution of cNF to identify effective therapies, where none exist today. SIGNIFICANCE: This study provides insights into the developmental origin of cNF, the most common tumor in NF1, and generates the first mouse model that faithfully recapitulates both human cutaneous and plexiform neurofibroma. The study also demonstrates that the Hippo pathway can modify neurofibromagenesis, suggesting that dampening the Hippo pathway could be an attractive therapeutic target.
原文英語
頁(從 - 到)114-129
頁數16
期刊Cancer Discovery
9
發行號1
DOIs
出版狀態已發佈 - 一月 2019
對外發佈Yes

ASJC Scopus subject areas

  • Oncology

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