Spatiotemporal Loss of NF1 in Schwann Cell Lineage Leads to Different Types of Cutaneous Neurofibroma Susceptible to Modification by the Hippo Pathway

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 n...

Full description

Saved in:
Bibliographic Details
Published in:Cancer discovery 2019-01, Vol.9 (1), p.114-129
Main Authors: Chen, Zhiguo, Mo, Juan, Brosseau, Jean-Philippe, Shipman, Tracey, Wang, Yong, Liao, Chung-Ping, Cooper, Jonathan M, Allaway, Robert J, Gosline, Sara J C, Guinney, Justin, Carroll, Thomas J, Le, Lu Q
Format: Article
Language:English
Subjects:
Animals
Cell Lineage
Disease Models, Animal
Female
Male
Mice
Mice, Knockout
Mutation
Neurofibroma - etiology
Neurofibroma - genetics
Neurofibroma - metabolism
Neurofibroma - physiopathology
Neurofibroma, Plexiform - etiology
Neurofibroma, Plexiform - genetics
Neurofibroma, Plexiform - metabolism
Neurofibroma, Plexiform - physiopathology
Neurofibromatosis 1 - complications
Neurofibromatosis 1 - genetics
Neurofibromatosis 1 - metabolism
Neurofibromatosis 1 - physiopathology
Neurofibromin 1 - genetics
Protein-Serine-Threonine Kinases - metabolism
Schwann Cells - metabolism
Schwann Cells - physiology
Signal Transduction
Skin Neoplasms - etiology
Skin Neoplasms - genetics
Skin Neoplasms - metabolism
Skin Neoplasms - physiopathology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 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. .
ISSN:2159-8274
2159-8290
DOI:10.1158/2159-8290.cd-18-0151