Invasiveness‐triggered state transition in malignant melanoma cells

Abstract

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 epithelialmesenchymal 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.

A Strategy Utilizing Protein–Protein Interaction Hubs for the Treatment of Cancer Diseases

“…Mathematical methods and hypotheses, as well as computational modeling to describe PPI and gene regulatory networks, are also constantly improving [134][135][136][137][138]. The philosophical underpinning of how the transition from a normal state to a malignant state can be accurately described in mathematical terms is a subject that merits contemplation [139][140][141]. Furthermore, there is a gradual integration of other molecular entities, such as non-coding RNAs (ncRNAs), into these networks [142,143].…”