Researchers have revealed a novel process by which cancer cells can repair fatal membrane injuries by macropinocytosis.
Repairing plasma membrane damage
The plasma membrane protects all cells from the extracellular space and maintains the intracellular environment. Membrane injuries can be lethal, as they lead to cell lysis and leakage of cytosolic components. To avoid this death sentence, cells have developed mechanisms to repair membrane damage within seconds. These mechanisms involve intact parts of the cell membrane coming together to seal holes in under a minute. After repair, the membrane still needs to be restructured to restore cellular homeostasis. However, the mechanisms of membrane restructuring are currently poorly understood.
A recent study conducted at the Danish Cancer Society Research Centre and published in Science Advances, revealed a new mechanism by which cancer cells re-establish membrane integrity after injury. The team behind this study termed the mechanism light chain 3 (LC3)-associated macropinocytosis (LAM). In cells, macropinocytosis is a process whereby fluids and membranes are taken up into large intracellular vesicles. Internal contents are then degraded after the vesicles fuse with lysosomes.
In this study, the team induced membrane damage in breast carcinoma cells by ablation laser. Exposure to the laser activated macropinocytosis-associated proteins specifically at the site of injury. Macropinocytosis is then triggered minutes after initial membrane repair in order to remove and degrade damaged membrane constituents.
Blocking macropinocytosis with inhibitors prevented vesicle formation after membrane injury and led to cell death. This suggests that the internalisation of damaged membranes by macropinocytosis is crucial for membrane restructuring and cell survival.
The researchers further observed a substantial accumulation of LC3 around the injury site. LC3 accumulation is also seen in LC3-associated phagocytosis, the engulfment of extracellular pathogens triggered by cell surface receptor activation. However, the mechanism of LC3-associated phagocytosis is distinct to the process of macropinocytosis observed in this study. This indicates that LAM is a unique process required for membrane restructuring.
Implications for cancer
Critically, this work has also shed new light into cancer biology. Cancer cells are prone to membrane damage during metastasis. Nevertheless, some aggressive forms of cancer still manage to spread. Jesper Nylandsted, leader of the research group, said:
“Our research provides very basic knowledge about how cancer cells survive. In our experiments, we have also shown that cancer cells die if the process is inhibited, and this points towards macropinocytosis as a target for future treatment. It is a long-term perspective, but it is interesting.”
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