Invasiveness‐triggered state transition in malignant melanoma cells

• Published in: Journal of cellular physiology Vol. 234; no. 5; pp. 5354 - 5361
• Main Authors: Wang, Huan, Zhang, Yan‐Guo, Ma, Jing, Li, Jun‐Chang, Zhang, Jian, Yu, Yao‐Qing
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.05.2019
• Subjects: Acetylcholine receptors (muscarinic); Antigens, CD - metabolism; Cadherins - metabolism; Cancer; Cell Line, Tumor; Cell Movement; Cell Shape; E-cadherin; Epithelial cells; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Heterogeneity; Humans; Immunoprecipitation; invasion; Invasiveness; Melanoma; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Mesenchyme; Metastases; Migration; Molecular modelling; Morphology; Neoplasm Invasiveness; Nerve Tissue Proteins - metabolism; p75NTR; Receptor, Muscarinic M3 - genetics; Receptor, Muscarinic M3 - metabolism; Receptors, Nerve Growth Factor - metabolism; Ribonucleic acid; RNA; Signal Transduction; siRNA; Skin cancer; Skin Neoplasms - genetics; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; state transition; Tissues; Vimentin; Vimentin - metabolism; p75NTR; melanoma; invasion; M3; state transition
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.27405

Cancer cells are considered to have high morphological heterogeneity in human melanoma tissue. Here, we report that epithelial cancer cells are dominant in different development stages of human melanoma tissues. The cellular and molecular mechanisms that maintain melanoma cells in the epithelial state are further investigated in the A2058 cell line. We find that micropore (8 µm) transwell invasion, but not superficial migration in the scratch assay, can induce remarkable morphological changes between epithelial and mesenchymal melanoma cells within 4 days. The morphological switch is associated with dynamic changes of epithelial–mesenchymal transition (EMT) hallmarks E‐cadherin and vimentin. Further immunoflurencent staining and co‐immunoprecipitation assay showed the uncoupling of the M3 muscarinic acetylcholine receptor (mAChR) and the p75 neurotrophin receptor (p75NTR) in epithelial melanoma cells. Specific knockdown of M3 mAChR by small interfering RNA (siRNA) significantly abrogates the transition of spindle‐shaped mesenchymal cells to epithelial cells. Collectively, we report a cellular model of invasiveness‐triggered state transition (ITST) in which melanoma cell invasion can induce morphological changes between epithelial and mesenchymal cells. ITST is one of the biological basis for maintaining metastatic melanoma cells in the epithelial state. Furthermore, M3 mAChR receptor‐mediated ITST provides a novel therapeutic strategy to inhibit the development of malignant melanoma.