Tsc2 disruption in mesenchymal progenitors results in tumors with vascular anomalies overexpressing Lgals3.

Abstract

Increased mTORC1 signaling from TSC1/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 of Tsc2 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 with TSC1/TSC2 mutations in the TCGA database. Signature component Lgals3 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 including Lgals3 relevant for human disease of TSC1/TSC2 inactivation and mTORC1 hyperactivity.

• Authors: Peter J Klover, Rajesh L Thangapazham, Jiro Kato, Ji-An Wang, Stasia A Anderson, Victoria Hoffmann, Wendy K Steagall, Shaowei Li, Elizabeth McCart, Neera Nathan, Joshua D Bernstock, Matthew D Wilkerson, Clifton L Dalgard, Joel Moss, Thomas N Darling
• Journal: eLife (Elife) Vol. 6 (07 11 2017) ISSN: 2050-084X [Electronic] England
• PMID: 28695825 (Publication Type: Journal Article)

Chemical References

• Blood Proteins
• Galectin 3
• Galectins
• LGALS3 protein, human
• Lgals3 protein, mouse
• TSC2 protein, human
• Tsc2 protein, mouse
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins
• Mechanistic Target of Rapamycin Complex 1

Topics

• Animals
• Blood Proteins
• Galectin 3 (metabolism)
• Galectins
• Humans
• Mechanistic Target of Rapamycin Complex 1 (metabolism)
• Mesenchymal Stem Cells (physiology)
• Mice
• Mice, Knockout
• Skin Neoplasms (physiopathology)
• Tuberous Sclerosis Complex 2 Protein
• Tumor Suppressor Proteins (deficiency, metabolism)