title: SRC kinase is a novel therapeutic target in lymphangioleiomyomatosis.
abstract: Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease affecting some women with tuberous sclerosis complex (TSC). Sporadic LAM can develop in women without TSC, owing to somatic mutations in the TSC2 gene. Accumulating evidence supports the view of LAM as a low-grade, destructive, metastasizing neoplasm. The mechanisms underlying the metastatic capability of LAM cells remain poorly understood. The observed behavior of LAM cells with respect to their infiltrative growth pattern, metastatic potential, and altered cell differentiation bears similarity to cells undergoing epithelial-mesenchymal transition. Here, we report increased levels of active Src kinase in LAM lungs and in TSC2(-/-) cells, caused by a reduction of autophagy. Furthermore, increased Src kinase activation promoted migration, invasion, and inhibition of E-cadherin expression in TSC2(-/-) cells by upregulating the transcription factor Snail. Notably, Src kinase inhibitors reduced migration and invasion properties of TSC2(-/-) cells and attenuated lung colonization of intravenously injected TSC2(-/-) cells in vivo to a greater extent than control TSC2(+/+) cells. Our results reveal mechanistic basis for the pathogenicity of LAM cells and they rationalize Src kinase as a novel therapeutic target for treatment of LAM and TSC.
authors.affiliation: Authors' Affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas.
authors.forename: Alexey
authors.initials: A
authors.lastname: Tyryshkin
authors.forename: Abhisek
authors.initials: A
authors.lastname: Bhattacharya
authors.forename: N Tony
authors.initials: NT
authors.lastname: Eissa
mesh_terms: D000818:Animals; D001343:Autophagy; D002465:Cell Movement; D002478:Cells, Cultured; D004789:Enzyme Activation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D018192:Lymphangioleiomyomatosis / Q000201:enzymology / Q000209:etiology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000502:physiology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D050796:STAT3 Transcription Factor; C000624654:Tsc2 protein, mouse; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D019061:src-Family Kinases