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

Abstract

Increased mTORC1 signaling from <i>TSC1/TSC2</i> 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 <i>Tsc2</i> in craniofacial and limb bud mesenchymal progenitors. Tsc2cKO^Prrx1-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 with <i>TSC1</i>/<i>TSC2</i> mutations in the TCGA database. Signature component <i>Lgals3</i> encoding galectin-3 was increased in Tsc2-deficient cells and serum of Tsc2cKO^Prrx1-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 <i>Lgals3</i> relevant for human disease of <i>TSC1/TSC2</i> inactivation and mTORC1 hyperactivity.