ROCK inhibition promotes microtentacles that enhance reattachment of breast cancer cells

Abstract

The presence of circulating tumor cells (CTCs) in blood predicts poor patient outcome and CTC frequency is correlated with higher risk of metastasis. Recently discovered, novel microtubule-based structures, microtentacles, can enhance reattachment of CTCs to the vasculature. Microtentacles are highly dynamic membrane protrusions formed in detached cells and occur when physical forces generated by the outwardly expanding microtubules overcome the contractile force of the actin cortex. Rho-associated kinase (ROCK) is a major regulator of actomyosin contractility and Rho/ROCK over-activation is implicated in tumor metastasis. ROCK inhibitors are gaining popularity as potential cancer therapeutics based on their success in reducing adherent tumor cell migration and invasion. However, the effect of ROCK inhibition on detached cells in circulation is largely unknown. In this study, we use breast tumor cells in suspension to mimic detached CTCs and show that destabilizing the actin cortex through ROCK inhibition in suspended cells promotes the formation of microtentacles and enhances reattachment of cells from suspension. Conversely, increasing actomyosin contraction by Rho over-activation reduces microtentacle frequency and reattachment. Although ROCK inhibitors may be effective in reducing adherent tumor cell behavior, our results indicate that they could inadvertently increase metastatic potential of non-adherent CTCs by increasing their reattachment efficacy.

Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis

“…Additionally, priming with Fasudil may decrease cell survival in the bloodstream via impaired tolerance to shear stress (97). Whereas previous studies have reported conflicting findings on the effects of ROCK inhibition on cell invasion (98-100), short-term treatment with Fasudil did not show adverse effects, unlike chronic ROCK targeting. We also reveal that Fasudil priming impairs the ability of metastasized cells to create a fibrotic refuge, potentially enhancing their vulnerability to subsequent chemotherapy (67).…”

ROCK Inhibition Promotes Attachment, Proliferation, and Wound Closure in Human Embryonic Stem Cell–Derived Retinal Pigmented Epithelium

“…42 Recent studies have shown that ROCK inhibition can promote the reattachment of breast cancer cells in circulation, which correlates with our conclusions. 43 …”

Rho Kinases in Health and Disease: From Basic Science to Translational Research

“…Several studies described the inhibitory effects of ROCK blockers on in vitro adherent tumor cell migration and invasion (Gutjahr et al, 2005;Torka et al, 2006;Patel et al, 2014), although recent data showed that ROCK inhibition increases the metastatic potential of nonadherent breast tumor cells by increasing their reattachment efficacy (Bhandary et al, 2015). ROCKs have been implicated in the pathogenesis of cancer and several aspects of human tumor progression (Rath and Olson, 2012).…”