Heterogeneous Effects of Src Inhibition on Determinants of Metastasis in Preclinical Models of Human Bladder Cancer

Abstract

BackgroundPast work in preclinical models of solid tumors have implicated SRC in invasion and metastasis, but also demonstrated it inhibited bladder cancer metastasis. ObjectiveDetermine if the role of SRC in metastasis is dependent on bladder cancer molecular subtype membership. MethodsWe analyzed large public datasets, performed in vitro invasion and migration assays using small-molecule and doxycycline inducible SRC knock-down constructs, and in vivo experimental metastasis assays. ResultsLooking at large public datasets, we found SRC is upregulated in luminal papillary muscle invasive bladder cancer. Using the consensus classifier on RNA expression from 30 cell lines, we demonstrated that chemical SRC antagonists inhibited migration in luminal papillary cells but had little effect in basal/squamous lines. Conditional SRC knockdown inhibited migration in luminal papillary RT112 cells, whereas it increased migration and reduced proliferation in luminal papillary UM-UC6 cells. Regardless, these effects did not affect levels or sites of experimental metastasis in vivo. ConclusionsThe results support the conclusion that SRCs biological effects in bladder cancer are not primarily involved in promoting invasion and metastasis. Further work is required to define SRCs roles in luminal papillary bladder cancers.