TSC2-Mutant Yucatan Minipig Cardiac Rhabdomyoma Model Reveals mTORC1 Activation and MITF/TFE Expression Signature

Tuberous sclerosis complex (TSC) is an inherited tumor predisposition syndrome caused by pathogenic variants in TSC1 or TSC2 , yet no animal model faithfully recapitulates the cardiac rhabdomyomas (CR) that are among its earliest manifestations. We generated a heterozygous TSC2 -mutant Yucatan minipig carrying the recurrent pathogenic TSC2 p.Arg505* variant and characterized its cardiac phenotype using histopathology, immunohistochemistry, and RNA sequencing. TSC2 -mutant minipigs consistently developed multiple CR that closely resembled human lesions, including enlarged glycogen-rich spider cells and activation of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Comparative transcriptomic analyses demonstrated enrichment of a conserved TSC-associated gene expression program and activation of microphthalmia/transcription factor E (MITF/TFE)-regulated lysosomal pathways in both human and minipig tumors. Although other manifestations of TSC were not observed during the first year of life, this large-animal model faithfully reproduced the principal histopathologic and molecular features of human CR. These findings have established the TSC2-mutant Yucatan minipig as what we believe to be the first large-animal model of TSC-associated CR and provide a physiologically relevant platform for investigating tumor pathogenesis, mechanisms of spontaneous regression, and therapeutic strategies targeting mTORC1- and MITF/TFE-dependent signaling.