Reduced expression of the WAVE subunit CYFIP1 (cytoplasmic FMR1 interacting protein 1) causes the loss of epithelial cell adhesion and promotes tumor progression.
The WAVE complex regulates cytoskeletal dynamics by activating the Arp2/3 complex, which induces actin nucleation. WAVE-mediated actin reorganization has also been linked to cell adhesion. Gregory Hannonand colleagues now show that reduced expression of the WAVE subunit cytoplasmic FMR1 interacting protein 1 (CYFIP1) causes loss of epithelial cell adhesion and promotes tumour progression, which implicates CYFIP1 as a suppressor of invasion in epithelial cancers.
The authors assessed human cancers and cancer cell lines for recurrent chromosomal focal deletions (<2 Mb). Some of the deleted regions that were identified do not contain a known tumour suppressor gene, which suggests that they harbour novel tumour suppressors. Silva et al. therefore analysed the impact of silencing the genes located in these regions, by short hairpin RNA (shRNA), in an organotypic model of mammary epithelial morphogenesis. Interestingly, cells depleted of CYFIP1 generate abnormal acini structures. Furthermore, CYFIP1 is frequently found in larger deletions in human tumours and loss of CYFIP1 expression correlates with tumour progression and a poor clinical outcome, suggesting that CYFIP1 might be a tumour suppressor. As silencing other WAVE complex components causes the same phenotype as CYFIP1 depletion, CYFIP1 probably regulates epithelial morphology as part of the WAVE complex.
So, how does aberrant WAVE activity alter epithelial morphology and promote tumorigenesis? The disruption of epithelial tissue architecture that is associated with tumorigenesis is, in part, induced by defects in cell adhesion. The authors therefore assessed the effect of depleting WAVE components, including CYFIP1, on cell–cell and cell–substratum adhesion. Epithelial cells expressing shRNA against WAVE components show reduced cell–cell adhesion and are unable to form efficient adherence junctions, which are necessary for normal epithelial architecture. The ability of these cells to adhere to various substrata is also impaired. WAVE depletion therefore reduces cell adhesion, which contributes to abnormal epithelial cell morphology and might promote tumorigenesis.
Finally, the effect of Cyfip1 depletion was assessed in vivo. In a mouse model of skin tumorigenesis, shRNA-mediated knockdown of Cyfip1 in the presence of the Ras oncogeneinduces the progression of squamous cell carcinoma. In addition, analysis of mouse epidermis from different stages of tumorigenesis reveals that CYFIP1 levels are reduced at the invasive edge of the primary tumour.
The authors propose "a model wherein depletion of WAVE components directly perturbs actin dynamics, which in turn reduces epithelial adhesion and leads to disorganization of tissue architecture." It is now important to determine whether the disruption of actin cytoskeletal dynamics in general, or only alterations in the WAVE pathway, can influence the invasive potential of epithelial cells.
Katharine H. Wrighton
References
Silva, J. M. et al. Cyfip1 is a putative invasion suppressor in epithelial cancers. Cell137, 1047–1061 (2009) | Article | PubMed |
Takenawa, T. et al. The WASP–WAVE protein network: connecting the membrane to the cytoskeleton. Nature Rev. Mol. Cell Biol.8, 37–48 (2007) | Article | PubMed |
