J Pathol. 2014 Nov;234(3):351-64.

Association of RHAMM with E2F1 promotes tumor cell extravasation by transcriptional upregulation of fibronectin.

Meier C, Spitschak A, Abshagen K, Gupta S, Mor JM, Wolkenhauer O, Haier J, Vollmar B, Alla V, Pützer BM.

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 tumor cells cphCTCs) relies on a novel function of the hyaluronan-mediated motility receptor RHAMM. E2F1 directly upregulates 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 signaling associated with cytoskeletal remodeling and enhanced tumor cell motility. RHAMM depletion abolishes fibronectin expression and cell transmigration across the endothelial layer in E2F1-activated cells. In a xenograft model, knockdown 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 tumorigenic 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.