Microtentacles tip the balance of cytoskeletal forces in circulating tumor cells

Abstract

Detection of circulating tumor cells (CTC) is advancing as an effective predictor of patient outcome and therapeutic response. Unfortunately, our knowledge of CTC biology remains limited, and the impact of drug treatments on CTC metastatic potential is currently unclear. Improved CTC imaging in vivo and analysis of free-floating tumor cells now show that cytoskeletal regulation in CTCs contrasts starkly with tumor cells attached to extracellular matrix. In this review, we examine how persistent microtubule stabilization promotes the formation of microtentacles on the surface of detached breast tumor cells and enhances metastatic potential.

Figure 1. Microtubule stabilization in McTNs and metastasis

(A) In detached epithelial cells [1], microtubules (green) outwardly expanding from the cell center are counterbalanced by contraction of the cortical actin cytoskeleton (red). Such cells die by apoptosis or fragmentation in capillaries [2] when circulating. In breast tumor cells [3], McTNs overcome the restrictive forces of the actin cortex by associating with tau. Similarly, removal of the COOH-terminal tyrosine of Tyr-tubulin by TCP yields Glu-tubulin that associates with vimentin until it is retyrosinated by TTL. Microtubule-stabilizing drugs [4], like paclitaxel, increase McTNs and tumor cell reattachment. (B) Confocal microscopy of live GFP-labeled breast tumor cells shows that McTNs stimulate aggregation by encircling adjacent cells labeled with a red lipophillic dye (B, white arrow). McTNs also promote tumor cell reattachment to mCherry-labeled endothelial cell layers (C, black arrows). Movies of 3-D reconstructions from the imaged time point in (B) and (C) are available as supplementary data (rendered with Bitplane Imaris6.4).