NF1 genetic background in the tumor micro-environment governs transcriptomic landscape of tumor cells in malignant peripheral nerve sheath tumors

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Onfroy, Audrey | Coulpier, Fanny | Radomska, Katarzyna, J. | Thieffry, Denis | Topilko, Piotr

Edité par CCSD -

International audience. Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas for which there is no effective treatment to date. They usually arise in the context of the genetic disease neurofibromatosis type I (NF1) or sporadically. While in both types of MPNSTs, the tumor Schwann cells exhibit biallelic loss of NF1, their cellular microenvironment is NF1 heterozygous (NF1+/-) and wild-type (wt), respectively.In this study, we address the impact of NF1 heterozygosity in the tumor microenvironment on tumor cell progression in NF1-induced and sporadic MPNSTs. We designed and characterized an Nf1 mouse model with simultaneous biallelic loss of Nf1 and Tomato reporter expression in boundary cap cells and their derivatives (Radomska et al., 2019). Mutants were generated on an NF1 heterozygous (Prss56-Nf1KO, NF1+/-) and wt (Prss56-Nf1KO) genetic background. Both types of mutants develop cutaneous and plexiform neurofibromas. Interestingly, in about 70% of the mutants, pNFs evolve spontaneously, between 7 and 12 months, into true MPNSTs.We performed extensive scRNAseq analysis (10x Genomics) of 16 Prss56-Nf1KO and 5 Prss56-Nf1KO, NF1+/- tumors. We annotated 10 distinct cell populations, including tumor (Tom+) cells, various immune populations, fibroblasts, and endothelial cells in each dataset. Analyses of the proportions and transcriptomic signatures of each cell population in relation to the tumor genetic background led us to the following observations: (i) among tumor cells, we distinguished two distinct subpopulations, either with a glial or with a mesenchymal profile, without cells sharing both signatures, suggesting a rapid glial-to-mesenchymal switch, (ii) while on NF1+/- background, both types of tumor cells (glial and mesenchymal) co-exist in the same tumor; on wt background, virtually all tumor cells are either glial or mesenchymal, in the same sample, (iii) differential expression analysis reveal that tumor cells on NF1+/- background over-express a panel of pro-fibrotic genes, compared to wt background. Such pro-fibrotic profile may be related to over-activation of pro-inflammatory signaling observed pathways-related genes in NF1+/- versus wt micro-environment cells.

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