Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with limited therapeutic options. Here, we present a novel sporadic murine model of Nf1 wild-type MPNST, driven by conditional expression of oncogenic BrafV600E and loss of Pten in the glial lineage using the Plp1::CreERT2 driver. This model allows for highly penetrant and rapid tumor induction through spontaneous formation, localized initiation, or cell transplantation. Comparative analysis with Tyr::CreERT2-driven melanoma revealed striking phenotypic divergence despite shared genetic alterations, underscoring the importance of the cell of origin in shaping tumor identity. In this system, MPNST cells show refractory capacities to induce melanocytic trans-differentiation upon melanoma-promoting signaling cues, such as canonical Wnt signaling gain of function or increased of levels of the epigenetic mark H3K27Me3 upon Ezh2 gain of function. Our findings emphasize the significance of lineage context in tumor initiation and provide a foundation for future mechanistic and therapeutic studies.