Upregulation of acid ceramidase contributes to tumor progression in tuberous sclerosis complex

• DOI: 10.1172/jci.insight.166850
• Publication Date: 2023-03-16T16:00:53Z
• Authors: Aristotelis Astri...; Chenggang Li; Erik Y. Zhang; Xueheng Zhao; Shuyang Zhao; Minzhe Guo; Tasnim Olatoke; Ushodaya Mattam; Rong Huang; Alan G. Zhang; Lori Pitstick; Elizabeth J. Kopras; Nishant Gupta; Roman Jandarov; Eric P. Smith; Elizabeth Fugate; Diana Lindquist; Maciej M. Markiewski; Magdalena Karbown...; Kathryn A. Wikenh...; Kenneth D. R. Set...; Francis X. McCormack; Yan Xu; Jane J. Yu
• Keywords: TSC2; Sphingolipid; TSC1

Tuberous sclerosis complex (TSC) is characterized by multisystem, low-grade neoplasia involving the lung, kidneys, brain, and heart. Lymphangioleiomyomatosis (LAM) a progressive pulmonary disease affecting almost exclusively women. TSC LAM are both caused mutations in TSC1 TSC2 that result mTORC1 hyperactivation. Here, we report single-cell RNA sequencing of lungs identified activation genes sphingolipid biosynthesis pathway. Accordingly, expression acid ceramidase (ASAH1) dihydroceramide desaturase (DEGS1), key enzymes controlling ceramide metabolism, was significantly increased TSC2-null cells. negatively regulated tumorigenic sphingolipids, suppression ASAH1 shRNA or inhibitor ARN14976 (17a) resulted markedly decreased cell viability. In vivo, 17a growth cell-derived mouse xenografts short-term lung colonization Combined rapamycin treatment synergistically inhibited renal cystadenoma Tsc2+/- mice, consistent with activity being insensitive. Collectively, present study identifies rapamycin-insensitive upregulation cells tumors provides evidence targeting aberrant pathways has potential therapeutic value mechanistic target 1-hyperactive neoplasms, including LAM.