gene fusion reciprocally regulates mTORC1 activity and induces lineage plasticity in a novel mouse model of renal tumorigenesis.

The MiT/TFE family gene fusion proteins, such as , drive both epithelial (eg, translocation renal cell carcinoma, tRCC) and mesenchymal (eg, perivascular epithelioid cell tumor, PEComa) neoplasms with aggressive behavior. However, no prior mouse models for -related tumors exist and the mechanisms of lineage plasticity induced by this fusion remain unclear. Here, we demonstrate that constitutive murine renal expression of human using Ksp Cadherin-Cre as a driver disrupts kidney development leading to early neonatal renal failure and death. In contrast, post-natal induction of in renal tubular epithelial cells using Pax8 ERT-Cre induces infiltrative epithelioid tumors, which morphologically and transcriptionally resemble human PEComas. As seen in MiT/TFE fusion-driven human tumors, expression is accompanied by the strong induction of mTORC1 signaling, which is partially amino acid-sensitive and dependent on increased -mediated transcription. Remarkably, expression is sufficient to induce lineage plasticity in renal tubular epithelial cells, with rapid down-regulation of the critical PAX2/PAX8 nephric lineage factors and tubular epithelial markers, and concomitant up-regulation of PEComa differentiation markers in transgenic mice, human cell line models and human tRCC. Pharmacologic or genetic inhibition of mTOR signaling downregulates expression of the fusion protein and rescues nephric lineage marker expression and transcriptional activity These data provide evidence of a potential epithelial cell-of-origin for -driven PEComas and highlight a reciprocal role for and mTOR in driving lineage plasticity in the kidney, expanding our understanding of the pathogenesis of MiT/TFE-driven tumors.