Autophagy is required for the migration and invasion of metastatic tumor cells •Autophagy promotes the degradation of paxillin and focal adhesion turnover •Paxillin interacts with LC3B through a conserved LIR in a Src-regulated manner •Autophagy is required for Src-regulated tumor cell motility
Inhibiting autophagy effectively blocks tumor cell migration and breast cancer metastasis in tumor models. They demonstrate that the process is essential for tumor metastasis and describe the mechanisms that connect autophagy to cell migration. Metastasis is responsible for 90% of cancer deaths.
2 MD/PhD students working in MacLeod’s laboratory, Marina Sharifi and Erin Mowers, noticed that when they placed metastatic breast cancer cells on a dish and monitored them with time-lapse microscopy, the control cells were “active, constantly moving around the dish,” MacLeod said. But cancer cells that the team had altered, by knocking down autophagy-related genes Atg5 and Atg7, “didn’t move at all. They appeared to be stuck.” When they injected these gene-altered cancer cells into the mammary fat pad of female mice, the cells multiplied, forming large primary breast tumors, but these cancer cells were unable to metastasize to the usual distant sites, the lungs, liver or bone. A closer look showed that these cells were morphologically very different. Their focal adhesions, large structures at the edge of the cell that are crucial for cell movement, were more numerous and abnormally large.
“Focal adhesions function like tank tracks,” MacLeod explained. These large protein complexes are assembled at the front of the cell. They extend through the periphery of the cell and connect to the extra-cellular matrix. The cell uses them for traction to push or pull itself over the matrix. As the cell travels forward, focal adhesions form at the front of the cell and establish dynamic connections to the extracellular matrix. As the cell passes over them, these adhesions drift back to the trailing edge of the cell. Then autophagy intervenes, disassembling the focal adhesion, breaking down its contents and allowing the back edge of the cell to disengage from the extracellular matrix and be pulled forward by traction from the front end. So if autophagy is inhibited, these metastatic tumor cells cannot move. Adhesions that don’t get turned over grow larger and larger. They anchor the cell in place.
A closer look at the process revealed the biochemical connection between autophagy and focal adhesions. A protein called paxillin, found in focal adhesions, is used to link the internal components of cellular protrusions to cell migration. When the cell needs to disassemble a focal adhesion, the autophagy process uses LC3, a key protein in the autophagy system, to engulf paxillin and transport it to a lysosome, where it is degraded. The interaction between LC3 and paxillin is regulated by SRC which promotes cell migration and metastasis (first defined oncogene). It’s ability to promote metastasis depends on autophagy.
There are approved drugs, some now being evaluated in clinical trials, that can disrupt autophagy. One of them, hydroxychloroquine, is FDA approved to prevent and treat malaria and is currently being tested in clinical trials as a way to slow tumor growth. The researchers saw the same phenomenon in metastatic melanoma cells besides breast cancer etc. http://www.eurekalert.org/pub_releases/2016-05/uocm-sci050916.php
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