Like a bicycle messenger weaving through busy city streets, cancer cells are skilled at maneuvering through microenvironments. Researchers know they use complex signalling pathways to move through and sense their surroundings, but exactly how these pathways worked was unclear. Now, researchers from the Konstantinos Konstantopoulos laboratory at Johns Hopkins University have determined that both calcium and the cell protein myosin play a role in a cooperative feedback loop that makes cancer cells champions of motility even in a tight squeeze Their work appears in the May 17, 2016 journal Cell Reports, and an artist’s interpretation of the study graces the journal’s cover.
Wei-Chien Hung was the lead author on a study that used microfabricated growth chambers featuring narrow channels that the cells had to move through. As the cancer cells migrated through the device, they had to squeeze and stretch to fit into confined spaces. As the cell membrane stretched, it caused special stretch-activated channels (called Piezo1 channels) to open. When the channels opened, calcium ions could flow through the cell membrane into the cell. The additional calcium ions set off a cascade of biochemical events leading to the activation of myosin.
As a molecular motor, myosin drove the cancer cells to move forward. Myosin also served as a sensor that directly responded to external force and stretched the membrane. This opened the channels, allowing more calcium ions to flow in; myosin in turn was further activated and so on. This feedback system maximized the signaling output of the two sensors.
Konstantopoulos, professor and chair of Department of Chemical and Biomolecular Engineering and an affiliated faculty member of Johns Hopkins Institute for NanoBioTechnology, says that the two ways of sensing the environment and signaling movement in a microenvironment makes the motility of cancer cells extremely efficient and highly effective in confined spaces, such as what might be found inside of a tumor cell mass. These two pathways also present two potential targets on which cancer researchers can focus further investigation in order to prevent cancer cell migration.
Other authors on the paper include Jessica Yang, Christopher Yankaskas, Joy T. Yang and Jin Zhang. The research was funded in part by the NIH and the American Heart Association.
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