Edited by Konstantinos Konstantopoulos, The Johns Hopkins University, Baltimore, MD, and accepted by the Editorial Board February 26, 2016 (received for review December 12, 2015)
Metastasis is responsible for 90% of cancer-related deaths and is driven by tumor cells circulating in blood. However, it is believed that only individual tumor cells can reach distant organs because multicellular clusters are too large to pass through narrow capillaries. Here, we collected evidence by examining clusters in microscale devices, computational simulations, and animals, which suggest that this assumption is incorrect, and that clusters may transit through capillaries by unfolding into single-file chains. This previously unidentified cell behavior may explain why previous experiments reported that clusters were more efficient at seeding metastases than equal numbers of single tumor cells, and has led to a strategy that, if applied clinically, may reduce the incidence of metastasis in patients.
Multicellular aggregates of circulating tumor cells (CTC clusters) are potent initiators of distant organ metastasis. However, it is currently assumed that CTC clusters are too large to pass through narrow vessels to reach these organs. Here, we present evidence that challenges this assumption through the use of microfluidic devices designed to mimic human capillary constrictions and CTC clusters obtained from patient and cancer cell origins. Over 90% of clusters containing up to 20 cells successfully traversed 5- to 10-μm constrictions even in whole blood. Clusters rapidly and reversibly reorganized into single-file chain-like geometries that substantially reduced their hydrodynamic resistances. Xenotransplantation of human CTC clusters into zebrafish showed similar reorganization and transit through capillary-sized vessels in vivo. Preliminary experiments demonstrated that clusters could be disrupted during transit using drugs that affected cellular interaction energies. These findings suggest that CTC clusters may contribute a greater role to tumor dissemination than previously believed and may point to strategies for combating CTC cluster-initiated metastasis.
Author contributions: S.H.A., B.D.S., J.C.M., Q.T., D.A.H., S.M., D.M.L., S.L.S., and M.T. designed research; S.H.A., B.D.S., J.C.M., Q.T., Y.-L.C., S.J., R.S., M.W.M., and R.O. performed research; S.H.A., B.D.S., J.C.M., Q.T., Y.-L.C., S.J., and A.F.S. contributed new reagents/analytic tools; S.H.A., B.D.S., J.C.M., Q.T., S.L.S., and M.T. analyzed data; and S.H.A. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. K.K. is a guest editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1524448113/-/DCSupplemental.
Freely available online through the PNAS open access option.
