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 Ph.D., Jonathan M. Cooper, Robert J. Allaway, Sara J.C. Gosline, Justin Guinney, Thomas J Carroll, Lu Q Le

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)114-129
Number of pages16
JournalCancer Discovery
Volume9
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

Neurofibroma
Neurofibromatosis 1
Schwann Cells
Cell Lineage
Skin
Plexiform Neurofibroma
Neoplasms
Neurofibromin 1
Tumor Burden
Carcinogenesis
Therapeutics

ASJC Scopus subject areas

  • Oncology

Cite this

Spatiotemporal loss of NF1 in schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway. / Chen, Zhiguo; Mo, Juan; Brosseau, Jean Philippe; Shipman, Tracey; Wang, Yong; Liao Ph.D., Chung Ping; Cooper, Jonathan M.; Allaway, Robert J.; Gosline, Sara J.C.; Guinney, Justin; Carroll, Thomas J; Le, Lu Q.

In: Cancer Discovery, Vol. 9, No. 1, 01.01.2019, p. 114-129.

Research output: Contribution to journalArticle

Chen, Zhiguo ; Mo, Juan ; Brosseau, Jean Philippe ; Shipman, Tracey ; Wang, Yong ; Liao Ph.D., Chung Ping ; Cooper, Jonathan M. ; Allaway, Robert J. ; Gosline, Sara J.C. ; Guinney, Justin ; Carroll, Thomas J ; Le, Lu Q. / Spatiotemporal loss of NF1 in schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway. In: Cancer Discovery. 2019 ; Vol. 9, No. 1. pp. 114-129.
@article{bde5734ccb7c456e8e7855f7b952fc1b,
title = "Spatiotemporal loss of NF1 in schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway",
abstract = "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.",
author = "Zhiguo Chen and Juan Mo and Brosseau, {Jean Philippe} and Tracey Shipman and Yong Wang and {Liao Ph.D.}, {Chung Ping} and Cooper, {Jonathan M.} and Allaway, {Robert J.} and Gosline, {Sara J.C.} and Justin Guinney and Carroll, {Thomas J} and Le, {Lu Q}",
year = "2019",
month = "1",
day = "1",
doi = "10.1158/2159-8290.CD-18-0151",
language = "English (US)",
volume = "9",
pages = "114--129",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "1",

}

TY - JOUR

T1 - Spatiotemporal loss of NF1 in schwann cell lineage leads to different types of cutaneous neurofibroma susceptible to modification by the hippo pathway

AU - Chen, Zhiguo

AU - Mo, Juan

AU - Brosseau, Jean Philippe

AU - Shipman, Tracey

AU - Wang, Yong

AU - Liao Ph.D., Chung Ping

AU - Cooper, Jonathan M.

AU - Allaway, Robert J.

AU - Gosline, Sara J.C.

AU - Guinney, Justin

AU - Carroll, Thomas J

AU - Le, Lu Q

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85059796340&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059796340&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-18-0151

DO - 10.1158/2159-8290.CD-18-0151

M3 - Article

C2 - 30348677

AN - SCOPUS:85059796340

VL - 9

SP - 114

EP - 129

JO - Cancer Discovery

JF - Cancer Discovery

SN - 2159-8274

IS - 1

ER -