Clusters of circulating tumor cells traverse capillary-sized vessels.
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.
Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;
Sam H
SH
Au
Olin College, Needham, MA 02492;
Brian D
BD
Storey
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129; Department of Molecular Pathology and Regenerative Medicine, Massachusetts General Hospital, Charlestown, MA 02129; Harvard Stem Cell Institute, Cambridge, MA 02138;
John C
JC
Moore
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129; Department of Molecular Pathology and Regenerative Medicine, Massachusetts General Hospital, Charlestown, MA 02129; Harvard Stem Cell Institute, Cambridge, MA 02138;
Qin
Q
Tang
Institute of Physics, Academia Sinica, Taipei 11529, Taiwan;
Yeng-Long
YL
Chen
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;
Sarah
S
Javaid
Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;
A Fatih
AF
Sarioglu
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114;
Ryan
R
Sullivan
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129;
Marissa W
MW
Madden
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129;
Ryan
R
O'Keefe
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; Howard Hughes Medical Institute, Bethesda, MD 20815;
Daniel A
DA
Haber
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129;
Shyamala
S
Maheswaran
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129; Department of Molecular Pathology and Regenerative Medicine, Massachusetts General Hospital, Charlestown, MA 02129; Harvard Stem Cell Institute, Cambridge, MA 02138;
David M
DM
Langenau
Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; mehmet_toner@hms.harvard.edu sstott@mgh.harvard.edu.
Shannon L
SL
Stott
Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114; Shriners Hospital for Children, Boston, MA 02114 mehmet_toner@hms.harvard.edu sstott@mgh.harvard.edu.
Mehmet
M
Toner
D002196:Capillaries / Q000473:pathology*; D002465:Cell Movement; D006801:Humans; D009360:Neoplastic Cells, Circulating
CTC clusters; cancer metastasis; capillary microhemodynamics; circulating tumor cell cluster microemboli; microfluidics