Tsc2 disruption in mesenchymal progenitors results in tumors with vascular anomalies overexpressing < i > Lgals3 < /i >

Increased mTORC1 signaling fromTSC1/TSC2 inactivation is found in cancer and causes tuberous sclerosis complex (TSC). The role of mesenchymal-derived cells in TSC tumorigenesis was investigated through disruption ofTsc2 in craniofacial and limb bud mesenchymal progenitors. Tsc2cKOPrrx1-cre 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 withTSC1/TSC2 mutations in the TCGA database. Signature componentLgals3 encoding galectin-3 was increased in Tsc2-deficient cells and serum of Tsc2cKOPrrx1-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 includingLgals3 relevant for human disease ofTSC1/TSC2 inactivation and mTORC1 hyperactivity.
Source: eLife - Category: Biomedical Science Tags: Cancer Biology Human Biology and Medicine Source Type: research