Oncogene-like induction of cellular invasion from centrosome amplification

Godinho S.A., Picone R., Burute M., Dagher R., Su Y., Leung C.T., Polyak K., Brugge J.S., Thery M., and Pellman D. Nature. (2014) 510, 167-171.

Speaker: Yin-Ping Wang (王尹平)                               Time: 15:00~16:00, Dec. 17, 2014

Commentator: Dr. Cheng-Chan Lu (呂政展 教授)     Place: Room 601

Abstract:

Centrosome is the microtubule-organizing center (MTOC) regulating cell adhesion, motility and mitosis in animal cells. Increasing evidence suggests that centrosome abnormalities are highly correlated with tumorigenesis (Zyss and Gergely, 2009), especially with invasive phenotypes. Centrosome amplification has long been observed in tumors, but the detailed mechanism is unclear. There is a possibility that extra centrosomes may provide favorable features which lead to tumorigenesis. By a three-dimensional model system, the authors found that centrosome amplification induced by Polo-like kinase 4 (PLK4) overexpression exhibits invasiveness in non-transformed human mammary epithelial cell line, MCF10A. This invasive manner resembles the effects induced by the breast cancer oncogene ERBB2 (Levental et al., 2009). Both of them express E-cadherin, and epithelial-to-mesenchymal transition (EMT) is not responsible for the cellular invasion. Further investigation reveals that increased number of centrosome causes defects in cell-cell adhesion and improper Rac1 activation. Rac1 is a small GTPase which is associated with oncogenic signaling, invasiveness and metastasis. The activity of RhoA, another small GTPase, which is antagonistic to Rac1, is accordingly decreased. The authors further reveal that Rac1 activation induced by centrosome amplification is through centrosomal microtubule nucleation. But how microtubules activate Rac1 remains unclear. In summary, centrosome amplification activates Rac1 by increasedcentrosomal microtubule nucleation, which disrupts cell-cell adhesion and promotes invasion of the cancer cells.

References:

1. Levental K.R., Yu H., Kass L., Lakins J.N., Egeblad M., Erler J.T., Fong S.F., Csiszar K., Giaccia A., Weninger W., Yamauchi M., Gasser D.L., Weaver V.M. (2009). Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891-906.

2. Zyss D., and Gergely F. (2009). Centrosome function in cancer: guilty or innocent? Trends in cell biology 19, 334-346.