Autophagy Inhibition May Stop Cancer Development

A study published in Cell Reports discovered that inhibiting autophagy can successfully block tumor cell migration and breast cancer metastasis in tumor models.

Metastasis accounts for 90% of all cancer deaths, and autophagy is a process used by cells to degrade large intra-cellular cargo and is essential for tumor metastasis.

“Using genetic and chemical means, we showed that autophagy is required for the motility and invasion of highly metastatic tumor cells,” said team leader Kay MacLeod, PhD. “Our work suggests that inhibiting autophagy in the clinical setting may be an effective approach to block metastatic dissemination.”

Researchers sought to determine what would happen if autophagy was shut down in metastatic cancer cells. When metastatic breast cancer cells were placed on a dish and monitored with time-lapse microscopy, scientists noticed that the control cells were active.

However, when examining the altered cancer cells that took away the autophagy-related genes Atg5 and Atg7, the cells didn’t move at all and appeared to be stuck.

The altered cancer cells were injected into the mammary fat pad of female mice, where the cells multiplied and formed large primary breast tumors. However, the cancer cells were unable to metastasize to the lungs, liver or bone as normal.

Researchers found that the cells were morphologically different, their focal adhesions were abnormally large and there was a greater amount of them.

The results of the study revealed that if autophagy is inhibited, the metastatic tumor cells are unable to move and adhesions that don’t get turned over keep growing, which anchors the cell in place.

“They literally just get stuck,” MacLeod said. “Through the microscope, you can see the cell wobbling, trying to move, to put out new protrusions, to migrate. But it can't, because it is stuck, unable to dissolve the adhesions at the back end of the cell. Basically, autophagy-deficient tumor cells cannot migrate and as a result cannot travel to another location. This is why we think that inhibiting autophagy could block tumor metastasis.”

Upon further investigation, researchers found that the protein paxillin found in focal adhesions are used to link the internal components of cellular protrusions to cell migration. When a focal adhesion needs to be disassembled, the autophagy process uses the key protein LC3 to engulf paxillin and move it to a lysosome, where it is degraded.

“The interaction between LC3 and paxillin is regulated by SRC,” MacLeod said. “If you inhibit autophagy, SRC can no longer drive migration of metastatic tumor cells. This is a major finding.”

At this time, there are approved drugs being evaluated in clinical trials that are able to disrupt autophagy, one being hydroxychloroquine, which is used to treat malaria. However, these drugs are not being specifically evaluated as a way to prevent metastasis.

“We would like to see trials designed to evaluate the efficacy of hydroxychloroquine or related drugs at blocking the progression to metastasis,” MacLeod said. “We think that's where this approach of inhibiting autophagy will be most useful as an anticancer measure.”

The study authors noted that their findings only add to a growing body of evidence that links autophagy to tumor cell metastasis.

“Together with our work identifying a critical role for autophagy in focal adhesion disassembly through paxillin degradation and its requirement for escape from the primary tumor, these studies highlight the potential utility of inhibiting autophagy to block tumor metastasis,” the study authors concluded.