Cell Solved a 50-year-old Riddle: Why Certain Cells Repel One Another

The cells in the connective tissue would be mutually exclusive in the event of a collision--people discovered this phenomenon as early as fifty years ago. However, only recently researchers at the University of Basel have clarified the molecular basis of this process, whose study results was published in the journal Developmental Cell.

Fibroblasts are motile constituents of the connective tissue and responsible for the regulation of connective tissue stiffness. These cells play an important role in malignant skin (such as melanoma), and are also used as a model system for the study of cell migration.

In 1950's, the British researcher Michael Abercrombie found colliding fibroblasts repel one another, and change their direction of movement in this process. He called this phenomenon of contact inhibition of locomotion. Although researchers have identified a number of key factors, the molecular basis of this process is still a mystery. For example, it is unclear which rejection signals this process involves, how these signals get into the cell, and how they influence cytoskeleton and thus affect the regulation of cell motility.

Olivier Pertz, a professor of the University of Basel, now gives detailed answers to these questions in the paper. He led the research team, and identified a signaling axis that are composed of three proteins separately named Slit2, Robo4 and srGAP2.

The study has shown that the repulsion factor receptor Slit2 binds to the receptor Robo4, thus signal enter into the interior of the cell and activate srGAP2. Then srGAP2 inhibits cytoskeletal regulation Rac1, and the Rac1 inactivation leads to cell contraction, so the two cells are mutually exclusive. If Slit2, Robo4 or srGAP2 are inactivated, the cells will adhere to each other and it can not so easily separated.

Interestingly, this repulsion mechanism is always at the front of the cell. By assembling such "molecular bumper", cells are preparing for collisions with others. In many cancers, the spread of cancer cell is the most deadly threat. People often successfully treat the primary tumor by surgery, drugs, chemotherapy or radiation therapy, but once the cancer cells spread to other organs of the body it is difficult to be curbed.

Scientists have been trying to block the transfer pathway of cancer cells, but the effect is not ideal. Researchers noted that cellular rejection may have an important role in cancer metastasis. The new finding could have important implications for cancer research.

Reference:

SrGAP2-Dependent Integration of Membrane Geometry and Slit-Robo-Repulsive Cues Regulates Fibroblast Contact Inhibition of Locomotion, Developmental Cell.