title: Association of RHAMM with E2F1 promotes tumour cell extravasation by transcriptional up-regulation of fibronectin.
abstract: Dissemination of cancer cells from primary to distant sites is a complex process; little is known about the genesis of metastatic changes during disease development. Here we show that the metastatic potential of E2F1-dependent circulating tumour cells (CTCs) relies on a novel function of the hyaluronan-mediated motility receptor RHAMM. E2F1 directly up-regulates RHAMM, which in turn acts as a co-activator of E2F1 to stimulate expression of the extracellular matrix protein fibronectin. Enhanced fibronectin secretion links E2F1/RHAMM transcriptional activity to integrin-β1-FAK signalling associated with cytoskeletal remodelling and enhanced tumour cell motility. RHAMM depletion abolishes fibronectin expression and cell transmigration across the endothelial layer in E2F1-activated cells. In a xenograft model, knock-down of E2F1 or RHAMM in metastatic cells protects the liver parenchyma of mice against extravasation of CTCs, whereas the number of transmigrated cells increases in response to E2F1 induction. Expression data from clinical tissue samples reveals high E2F1 and RHAMM levels that closely correlate with malignant progression. These findings suggest a requirement for RHAMM in late-stage metastasis by a mechanism involving cooperative stimulation of fibronectin, with a resultant tumourigenic microenvironment important for enhanced extravasation and distant organ colonization. Therefore, stimulation of the E2F1-RHAMM axis in aggressive cancer cells is of high clinical significance. Targeting RHAMM may represent a promising approach to avoid E2F1-mediated metastatic dissemination.
authors.affiliation: Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Centre, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Meier
authors.forename: Alf
authors.initials: A
authors.lastname: Spitschak
authors.forename: Kerstin
authors.initials: K
authors.lastname: Abshagen
authors.forename: Shailendra
authors.initials: S
authors.lastname: Gupta
authors.forename: Joel M
authors.initials: JM
authors.lastname: Mor
authors.forename: Olaf
authors.initials: O
authors.lastname: Wolkenhauer
authors.forename: Jörg
authors.initials: J
authors.lastname: Haier
authors.forename: Brigitte
authors.initials: B
authors.lastname: Vollmar
authors.forename: Vijay
authors.initials: V
authors.lastname: Alla
authors.forename: Brigitte M
authors.initials: BM
authors.lastname: Pützer
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005353:Fibronectins / Q000096:biosynthesis*; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D064593:Heterografts; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D047468:Immunoprecipitation; D051379:Mice; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D050687:E2F1 Transcription Factor; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D018960:Hyaluronan Receptors; C098946:hyaluronan-mediated motility receptor
keywords: E2F1 transcription factor; RHAMM; docking analyses; extravasation; feed-forward loop; fibronectin; human tissues