An in vivo functional screen identifies ST6GalNAc2 sialyltransferase as a breast cancer metastasis suppressor.
Murugaesu N., Iravani M., van Weverwijk A., Ivetic A., Johnson DA., Antonopoulos A., Fearns A., Jamal-Hanjani M., Sims D., Fenwick K., Mitsopoulos C., Gao Q., Orr N., Zvelebil M., Haslam SM., Dell A., Yarwood H., Lord CJ., Ashworth A., Isacke CM.
To interrogate the complex mechanisms involved in the later stages of cancer metastasis, we designed a functional in vivo RNA interference (RNAi) screen combined with next-generation sequencing. Using this approach, we identified the sialyltransferase ST6GalNAc2 as a novel breast cancer metastasis suppressor. Mechanistically, ST6GalNAc2 silencing alters the profile of O-glycans on the tumor cell surface, facilitating binding of the soluble lectin galectin-3. This then enhances tumor cell retention and emboli formation at metastatic sites leading to increased metastatic burden, events that can be completely blocked by galectin-3 inhibition. Critically, elevated ST6GALNAC2, but not galectin-3, expression in estrogen receptor-negative breast cancers significantly correlates with reduced frequency of metastatic events and improved survival. These data demonstrate that the prometastatic role of galectin-3 is regulated by its ability to bind to the tumor cell surface and highlight the potential of monitoring ST6GalNAc2 expression to stratify patients with breast cancer for treatment with galectin-3 inhibitors.