Increased type III TGF-β receptor shedding decreases tumorigenesis through induction of epithelial-to-mesenchymal transition

• Published in: Oncogene Vol. 38; no. 18; pp. 3402 - 3414
• Main Authors: Huang, Jennifer J., Corona, Armando L., Dunn, Brian P., Cai, Elise M., Prakken, Jesse N., Blobe, Gerard C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.05.2019; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/109; 13/31; 13/51; 13/95; 14/63; 38/44; 59/5; 631/67/1612/1350; 631/67/327; 631/67/395; 631/80/304; 631/80/86/2368; 64/60; A549 Cells; Animals; Apoptosis; Carcinogenesis - metabolism; Carcinogenesis - pathology; Cell adhesion; Cell Biology; Cell culture; Cell Line; Cell Line, Tumor; Cell migration; Cell Movement - physiology; Cell surface; Disease Progression; Drug Resistance, Neoplasm - physiology; Epithelial-Mesenchymal Transition - physiology; Female; Gemcitabine; Gene Expression Regulation, Neoplastic - physiology; Growth rate; HEK293 Cells; Human Genetics; Humans; Internal Medicine; Invasiveness; Ligands; Lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medicine; Medicine & Public Health; Mesenchyme; Mice; Mice, Nude; Oncology; Proteoglycans - metabolism; Receptors, Transforming Growth Factor beta - metabolism; Signal Transduction - physiology; Tumorigenesis; Tumorigenicity
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0672-7

The type III TGF-β receptor (TβRIII) is a TGF-β co-receptor that presents ligand to the type II TGF-β receptor to initiate signaling. TβRIII also undergoes ectodomain shedding to release a soluble form (sTβRIII) that can bind ligand, sequestering it away from cell surface receptors. We have previously identified a TβRIII extracellular mutant that has enhanced ectodomain shedding (“super shedding (SS)”—TβRIII-SS). Here, we utilize TβRIII-SS to study the balance of cell surface and soluble TβRIII in the context of lung cancer. We demonstrate that expressing TβRIII-SS in lung cancer cell models induces epithelial-to-mesenchymal transition (EMT) and that these TβRIII-SS (EMT) cells are less migratory, invasive and adhesive and more resistant to gemcitabine. Moreover, TβRIII-SS (EMT) cells exhibit decreased tumorigenicity but increased growth rate in vitro and in vivo. These studies suggest that the balance of cell surface and soluble TβRIII may regulate a dichotomous role for TβRIII during cancer progression.