Spatiotemporal Loss of NF1 in Schwann Cell Lineage Leads to Different Types of Cutaneous Neurofibroma Susceptible to Modification by the Hippo Pathway.
Zhiguo ChenJuan MoJean-Philippe BrosseauTracey ShipmanYong WangChung-Ping LiaoJonathan M CooperRobert J AllawaySara J C GoslineJustin GuinneyThomas J CarrollLu Q LePublished in: Cancer discovery (2018)
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.This article is highlighted in the In This Issue feature, p. 1.
Keyphrases
- signaling pathway
- mouse model
- lps induced
- pi k akt
- nuclear factor
- oxidative stress
- endothelial cells
- induced apoptosis
- single cell
- inflammatory response
- end stage renal disease
- risk factors
- newly diagnosed
- ejection fraction
- chronic kidney disease
- immune response
- transcription factor
- induced pluripotent stem cells
- heavy metals
- prognostic factors
- stem cells
- cell death
- cell therapy
- risk assessment
- mesenchymal stem cells
- patient reported outcomes
- smoking cessation
- neural network
- wild type
- lymph node metastasis
- squamous cell