ICAT, Inhibitor of β-catenin and TCF4, a new modulator of melanoma cells motility and invasiveness
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels la protéine ICAT régule la motilité des cellules métastatiques de mélanome
ICAT (inhibitor of β-catenin and TCF-4) negatively regulates β-catenin co-transcriptional activity by competing with LEF/TCF factors. Deregulation of β-catenin signaling is frequently implicated in melanoma, a highly invasive skin cancer. We observed that high ICAT levels in a panel of human melanoma cell lines correlated with their capacity to form metastases in nude mice. To address the role of ICAT in melanoma, we ectopically expressed ICAT in metastatic and non-metastatic melanoma cell lines. This had no effect on melanoma cell proliferation but increased in vitro cell motility in 2D and matrigel invasion in 3D. These in vitro effects required stable protein interaction between ICAT and β-catenin. At the cellular level, ICAT promoted switching of metastatic Lu1205 and WM852 melanoma cells from an elongated/mesenchymal towards a round/amoeboid phenotype but did not affect the elongated morphology of non-metastatic Mel501 and Skmel3 melanoma cells. Transition from a mesenchymal to an amoeboid movement was associated in Lu1205 cells with decreased production of the scaffold protein NEDD9 and decreased levels of Rac1-GTP, a positive regulator of mesenchymal movement. In vivo, ectopic ICAT expression increased lung colonization by Lu1205 melanoma cells in nude mice, suggesting that it increases the metastatic potential of such cells. Our results indicate that ICAT-induced down-regulation of Rac signaling can increase motility and invasiveness of metastatic cells by promoting morphological variability allowing tumor cells to adapt to their microenvironment. We show, for the first time, that ICAT is a new potential modulator of melanoma cell invasion.