Blocking the protein Munc13-4 could stop the spread of cancer.
Cancer cells are known to release tiny fluid-filled bags, or vesicles, called exosomes.
These are packed with powerful proteins and other molecules that make tissue conditions more favorable for tumor progression in numerous ways.
The molecules can remodel the environment of the cancer cells, for instance, and they can insert cancer genes into other cells and signal the immune system not to mount attacks.
These changes make it easier for tumors to grow and for the cancer to invade nearby tissue and spread to other parts of the body.
Cancer invasion and spread is a complex process called metastasis and is the main reason for it being such a serious disease.
Now, University of Wisconsin-Madison researchers have discovered a protein that controls the release of exosomes from cancer cells to promote tumor progression and metastasis.
They report their findings in a paper published in the Journal of Cell Biology.
Protein triggers exosome secretion
The protein is known as Munc13-4 and it is often found in abundance in lung, breast, and pancreatic tumors.
Led by senior study author Thomas F. J. Martin — a professor in biochemistry at the University of Wisconsin-Madison — the team observed that as pancreatic and lung cancer cells became more aggressive, they raised their levels of Munc13-4 and secreted more exosomes.
Munc13-4 is activated by binding to calcium, levels of which are known to be frequently heightened in cancer cells.
The researchers found that calcium triggered exosome secretion in aggressive breast cancer cells. But, when they removed Munc13-4 in the breast cancer cells, calcium no longer caused the cells to secrete exosomes.
This was also the case when they replaced Munc13-4 with a mutant form that cannot bind to calcium.
Increasing knowledge of exosome biology
Scientists first found out about exosomes some 50 years ago. But for decades, they thought that all they did was get rid of cell waste.
But, in the past 10 years or so, “interest in exosomes has exploded,” as evidenced by a huge rise in published studies.
Yet despite the renewed interest and much enlarged body of knowledge, we still do not know very much about the “basics of exosome biology.”
One thing we do know is that exosomes form inside of the cell in structures called “multivesicular bodies.” These release the exosomes by fusing with the “plasma membrane,” or cell wall.
Prof. Martin and colleagues discovered that the mechanism that triggers this process in cancer cells involves Munc13-4 working with another protein called Rab11.
They also showed that depleting Munc13-4 in breast cancer cells reduced the release of exosomes containing an enzyme that makes the tissue environment more favorable for cancer cell dispersion and spread.
The enzyme is called MT1-MMP and it breaks down the “extracellular matrix.” This is known to make it easier for cancer to metastasize and form secondary tumors.
“Overall, we think that increased expression of Munc13-4, combined with elevated calcium levels, drives enhanced exosome release by highly aggressive cancer cells, and that Munc13-4 is a potential target for therapeutic intervention.”
Prof. Thomas F. J. Martin