Genetically engineered mouse models shed new light on the pathogenesis of neurofibromatosis type I-related neoplasms of the peripheral nervous system

Abstract

Neurofibromatosis type 1 (NF1), the most common genetic disorder affecting the human nervous system, is characterized by the development of multiple benign Schwann cell tumors in skin and large peripheral nerves. These neoplasms, which are termed dermal and plexiform neurofibromas respectively, have distinct clinical courses; of particular note, plexiform, but not dermal, neurofibromas often undergo malignant progression to form malignant peripheral nerve sheath tumors (MPNSTs), the most common malignancy occurring in NF1 patients. In recent years, a number of genetically engineered mouse models have been created to investigate the molecular mechanisms driving the pathogenesis of these tumors. These models have been designed to address key questions including: 1) whether NF1 loss in the Schwann cell lineage is essential for tumorigenesis; 2) what cell type(s) in the Schwann cell lineage gives rise to dermal neurofibromas, plexiform neurofibromas and MPNSTs; 3) how the tumor microenvironment contributes to neoplasia; 4) what additional mutations contribute to neurofibroma-MPNST progression; 5) what role different neurofibromin-regulated Ras proteins play in this process and 6) how dysregulated growth factor signaling facilitates PNS tumorigenesis. In this review, we summarize the major findings from each of these models and their limitations as well as how discrepancies between these models may be reconciled. We also discuss how information gleaned from these models can be synthesized to into a comprehensive model of tumor formation in peripheral nervous system and consider several of the major questions that remain unanswered about this process.

Genomic MET amplification occurs early in NF1-related malignant peripheral nerve sheath tumor (MPNST) progression and is a potent therapeutic target

“…The RAS signaling node activates multiple kinase effector cascades, including the RAF-MEK-ERK pathway. NF1-related MPNSTs have been shown to arise from NF1-null myelinating Schwann cells where neurofibromin deficiency results in RAS deregulation (10)(11)(12)(13)(14)(15). Plexiform neurofibromas are the benign precursor of NF1-related MPNSTs and are formed by a recruited admixture of NF1 haploinsufficient cells (fibroblasts, mast cells, and perineurial cells) following an initial NF1-loss-of-heterozygosity event in a peripheral nerve Schwann cell (16)(17)(18).…”

Preclinical assessments of the MEK inhibitor PD-0325901 in a mouse model of neurofibromatosis type 1

“…In Nf1 mouse models, including the Nf flox/flox ;DhhCre mouse model, all mice form neurofibromas which are histologically identical to human neurofibromas. Thus, neurofibromas are comprised of Schwann cells, axons, fibroblasts, perineurial cells, mast cells, macrophages, and blood vessels . Mouse tumors can, like human neurofibromas, be monitored using volumetric measurement after MRI imaging …”

“…Thus, neurofibromas are comprised of Schwann cells, axons, fibroblasts, perineurial cells, mast cells, macrophages, and blood vessels. [16][17][18] Mouse tumors can, like human neurofibromas, be monitored using volumetric measurement after MRI imaging. [14,19] Because the NF1 protein encodes a Ras-GAP protein, NF1 loss results in high Ras-GTP.…”

Whole Exome Sequencing Reveals the Order of Genetic Changes during Malignant Transformation and Metastasis in a Single Patient with NF1-plexiform Neurofibroma

“…While NF1 loss is required for MPNST development, it is not sufficient for malignant transformation. As such, genetically-engineered mice with conditional Nf1 gene inactivation in Schwann cell precursors do not develop MPNSTs (9–13): MPNST formation requires the acquisition of additional genetic mutations that cooperate with loss of NF1 gene function to promote malignant transformation. In mouse and human tumors, alterations in the TP53, CDKN2A , and EGFR genes contribute to MPNST pathogenesis (14, 15).…”