Deciphering cellular and molecular signatures of malignant progression in Neurofibromatosis type 1 using single-cell transcriptomic analysis

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with currently no effective treatment. While half of MPNSTs arise sporadically, the others are due to the malignant progression of neurofibromas (NFs) in patients with neurofibromatosis type 1 (NF1). NFs are benign nerve sheath tumors due to bi-allelic loss of NF1, encoding a negative regulator of Ras pathway, in the Schwann cell (SC) lineage. We have conceived an Nf1-KO mouse model in which NFs spontaneously transform into MPNSTs To decipher the step-by-step evolution of the cellular composition and biological activities of tumor cells and their microenvironment during the transformation process, we performed single-cell transcriptomic profiling of pNFs, dyNFs and MPNSTs, all issued from Prss56Cre, Nf1fl/fl cohort, using 10x Chromium platform. We discovered that malignant transformation is initiated by a molecular transition of tumor SCs from glial to mesenchymal identity (GMT).