title: Melanoma cell invasiveness is promoted at least in part by the epidermal growth factor-like repeats of tenascin-C.
abstract: Tenascin-C (TNC), overexpressed in invasive growths, has been implicated in progression of melanoma, but the source and function of this molecule are not well defined. We found TNC expression at the front of invading melanoma cells, and that adding TNC to matrices enhances individual melanoma cell migration. As TNC is a multidomain protein, we examined the role of the TNC EGF-like (EGFL) repeats as these activate motogenic signaling cascades. We overexpressed a TNC fragment containing the assembly and EGFL domains of TNC (TNCEGFL). TNCEGFL-expressing melanoma cells had lower speed and persistence in 2D migration assays due to a shift in the adhesion-contractility balance, as expression of TNCEGFL delayed melanoma cell attachment and spreading. The less adhesive phenotype was due, in part, to increased Rho-associated kinase (ROCK) signaling concomitant with myosin light chain 2 and MYPT phosphorylation. Inhibition of ROCK activity, which drives transcellular contractility, restored adhesion of TNCEGFL-expressing melanoma cells and increased their migration in 2D. In contrast to the diminished migration in 2D, TNCEGFL-expressing melanoma cells had higher invasive potential in Matrigel invasion assays, with cells expressing TNCEGFL having amoeboid morphology. Our findings suggest that melanoma-derived TNCEGFL exert a role in melanoma invasion by modulating ROCK signaling and cell migration.
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Jelena
authors.initials: J
authors.lastname: Grahovac
authors.forename: Dorothea
authors.initials: D
authors.lastname: Becker
authors.forename: Alan
authors.initials: A
authors.lastname: Wells
mesh_terms: D024722:Cardiac Myosins / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D018994:Myosin Light Chains / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010446:Peptide Fragments / Q000096:biosynthesis; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology*; D019063:Tenascin / Q000096:biosynthesis* / Q000235:genetics; D054460:rho-Associated Kinases / Q000096:biosynthesis
chemical_list: D018994:Myosin Light Chains; D010446:Peptide Fragments; D019063:Tenascin; C107184:myosin light chain 2; D004815:Epidermal Growth Factor; D054460:rho-Associated Kinases; D024722:Cardiac Myosins