I think you present a really nice overview of current considerations in the field. I think the discussion of MET-dependent versus MET-independent metastatic pathways, possibly reflecting differing levels of genomic instability or different cells of origin, is a particularly well-made point.
One thing possibly missing is a discussion of the role of EpCAM (ESA) as an epithelial marker that may be retained in the partial EMT state and enable discrimination of a partial from a full EMT in studies assessing ‘stemness’. To my knowledge, this method was first used by John Stingl to sort EpCAM+ multipotent breast stem cells from lineage-restricted EpCAM- myoepithelial cells (Stingl et al., 1998). In the seminal Al-Hajj paper, they noted that only those CD44+CD24- cells that also retained EpCAM expression were able to seed tumours (Al-Hajj et al., 2003). This suggested that retention of epithelial markers in the CD44+CD24- EMT sub-population was essential for tumour-initiating ability. Finally, our own work (Biddle et al., 2011) demonstrated that the ability to undergo MET was only exhibited by those cells in the EMT sub-population that retained EpCAM expression. In combination with the other studies you’ve cited demonstrating that ability to undergo MET is essential for carcinoma metastasis (Ocana et al., 2012; Tsai et al., 2012), these findings indicate that retention of the epithelial marker EpCAM (indicative of a partial EMT) is essential to the ability to seed metastases through an MET-dependent pathway.
Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J., and Clarke, M. F. (2003). Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 100, 3983-3988.
Biddle, A., Liang, X., Gammon, L., Fazil, B., Harper, L. J., Emich, H., Costea, D. E., and Mackenzie, I. C. (2011). Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative. Cancer Res 71, 5317-5326.
Ocana, O. H., Corcoles, R., Fabra, A., Moreno-Bueno, G., Acloque, H., Vega, S., Barrallo-Gimeno, A., Cano, A., and Nieto, M. A. (2012). Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22, 709-724.
Stingl, J., Eaves, C. J., Kuusk, U., and Emerman, J. T. (1998). Phenotypic and functional characterization in vitro of a multipotent epithelial cell present in the normal adult human breast. Differentiation 63, 201-213.
Tsai, J. H., Donaher, J. L., Murphy, D. A., Chau, S., and Yang, J. (2012). Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22, 725-736.