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The outside of a cancer cell is bombarded by signals, they come from the immune system, supporting tissues and other structures. There is a connection between the cancer cell ‘swallowing’ certain molecules and its ability to activate tumor suppressor genes,” says study author Sofia Merajver, M.D., Ph.D., professor of internal medicine and epidemiology at the University of Michigan.
Merajver’s lab at the Rogel Cancer Center worked with a Michigan Engineering team led by Allen Liu, Ph.D., and postdoctoral researcher Luciana Rosselli-Murai, Ph.D. They focused on a protein called clathrin, which impacts how metabolites, hormones and other proteins enter into a cell. Clathrin-coated pits form little indentations inwards on the surface of cells that fold in on themselves and internalize these molecules.
Researchers looked at breast cancer cells that did not express PTEN, a protein known to be mutated or deleted in about a third of breast cancers. PTEN played a role in the dynamics of clathrin-coated pits. Changing these dynamics by deleting PTEN resulted in shorter-lived pits.
The clathrin-coated pits that don’t live longer than 20 seconds have historically been thought to be non-important but those are the ones important for bringing signals from outside the cell into the cell.
Many cancers develop because of cell signaling problems. Signals must get from outside the cell into its nucleus to produce proteins. If the signal is altered, it alters what the cell makes, which then alters how the cell grows. This study finds that the short-lived clathrin-coated pits are used to help control the signals that enter the cell. Additionally, PTEN alters the signaling of the clathrin-coated pits that make cancer more aggressive.
Challenges the current paradigm that short-lived clathrin-coated pits are abortive structures, finding that instead they can be capable of driving signaling. PTEN and other tumor suppressor genes are desirable targets for cancer therapy, but they have proven elusive: no drugs have yet been found to restore function of these mutated or deleted genes.
The researchers hope that by understanding the role of PTEN at a mechanistic level – what are the steps that cause PTEN to modulate how cancer cells communicate with the outside – it could provide a new approach to targeting the consequences of decreased function of this critical tumor suppressor.
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