Elife 2017 07 11;6. Epub 2017 Jul 11.
Department of Dermatology, Uniformed Services University of the Health Sciences, Bethesda, United States.
Increased mTORC1 signaling from inactivation is found in cancer and causes tuberous sclerosis complex (TSC). The role of mesenchymal-derived cells in TSC tumorigenesis was investigated through disruption of in craniofacial and limb bud mesenchymal progenitors. Tsc2cKO mice had shortened lifespans and extensive hamartomas containing abnormal tortuous, dilated vessels prominent in the forelimbs. Abnormalities were blocked by the mTORC1 inhibitor sirolimus. A Tsc2/mTORC1 expression signature identified in Tsc2-deficient fibroblasts was also increased in bladder cancers with / mutations in the TCGA database. Signature component encoding galectin-3 was increased in Tsc2-deficient cells and serum of Tsc2cKO-cre mice. Galectin-3 was increased in TSC-related skin tumors, angiomyolipomas, and lymphangioleiomyomatosis with serum levels in patients with lymphangioleiomyomatosis correlating with impaired lung function and angiomyolipoma presence. Our results demonstrate Tsc2-deficient mesenchymal progenitors cause aberrant morphogenic signals, and identify an expression signature including relevant for human disease of inactivation and mTORC1 hyperactivity.