In vitro study of TSC1 deficiency in preadipocytes: insights into development and treatment options for tuberous sclerosis related lipomatosis

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Abstract Background Tuberous sclerosis complex (TSC) is a rare genetic neurocutaneous disorder resulting from mutations in the TSC1 or TSC2 genes, characterized by overgrowth and lesions in multiple organs. While renal angiomyolipomas are commonly seen, lipomas located elsewhere are rarely reported in these patients. Results We identified a heterozygous TSC1 mutation in a pediatric patient, who developed a lipoma in the gluteal region, which recurred after surgical resection. We observed a loss of heterozygosity in the lipoma tissue, resulting in TSC1 deficiency and subsequent activation of the mechanistic target of rapamycin (mTOR) signaling pathway. Further in vitro experiments showed that silencing TSC1 in adipocyte progenitors led to increased cell proliferation, supporting the hypothesis that TSC1 deficiency contributes to lipoma formation. Treatment with mTOR inhibitors, such as sirolimus and torin-1, as well as the phosphoinositide 3-kinase (PI3K) inhibitor alpelisib reduced cell proliferation and pathway activation in TSC1-deficient cells. Conclusions This study highlights the need for further investigation into the efficacy of pathway inhibitors in managing TSC-related lipomas in vivo and offers a potential treatment avenue for patients suffering from recurrent lipomatosis.

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