A preclinical University of Toronto study is revealing new insights into the molecular machinery that drives the aggressiveness of pancreatic cancer.
This cancer's ability to invade and spread to other parts of the body is a major factor in its poor prognosis. Once a pancreatic tumour has metastasized to other organs, it becomes much more challenging to target and eradicate the cancer.
"Pancreatic cancer cells are known to be very metastatic and that's a big problem," says Leonardo Salmena, an associate professor of pharmacology and toxicology at the Temerty Faculty of Medicine .
Salmena is the senior author of a study that investigates the role of a gene called INPP4B in pancreatic cancer's ability to spread, recently published in the Journal of Cell Biology .
The researchers, led by postdoctoral fellow Golam Saffi and former master's student Lydia To, found that INPP4B exerts its tumour-promoting effects via a cellular organ called the lysosome.
"Classically, the lysosome is a garbage disposal organelle where old and tired proteins and other organelles get degraded to be used for energy and other building blocks for the cell," says Salmena.
In most cells, lysosomes typically cluster around the nucleus. But in pancreatic cancer cells, the researchers found that INPP4B drove the lysosomes from the cell interior to the periphery, where these organelles fuse with the cell's outer membrane. In doing so, the enzymes and other lysosomal factors responsible for breaking down cellular waste are dumped into the space surrounding the tumour cells.
This space contains a network of proteins and molecules that provides crucial structural support to cells and tissues while also restricting a cell's ability to move. The release of the lysosome's protein-degrading contents into this extracellular space causes the stabilizing network to fall apart, thus making it easier for pancreatic cancer cells to migrate and invade other tissues.
Crucially, Salmena and his team also identified the signalling pathway by which INPP4B drives the movement of lysosomes to the cell edge. INPP4B works with two other proteins — PIKfyve and TRPML-1 — to modify the lysosome's surface structure and alter local calcium levels, such that the organelle is propelled to the cell periphery.
Based on these findings, the researchers are testing two experimental drugs that target TRPML-1 and PIKfyve in a mouse model of pancreatic cancer. They are also studying how the release of lysosomal contents can change the immunological environment of the cancer cells, and what effects that might have on the immune system's ability to respond to the tumour.
Salmena first became interested in INPP4B when, during his postdoctoral fellowship, he found that it was involved in breast cancer. Since then, he and his team have shown that the effects of INPP4B vary depending on the context.
For example, in some breast cancer types, INPP4B behaves as a tumour suppressor whereas it has an activating role in other aggressive cancers like pancreatic cancer.
Salmena and his colleagues later showed that among all cancers, INPP4B levels are highest in pancreatic tumours, and that high levels of the protein are associated with decreased overall survival in people with pancreatic cancer.
Pancreatic cancer, with an overall five-year survival rate of less than 10 per cent, is considered one of the most difficult to treat cancers. According to the Canadian Cancer Society, it is expected to be the third leading cause of cancer death in Canada in 2024, with an estimated 6,100 people dying from the disease.
The current study was a collaboration between Salmena's group, Roberto Botelho, a professor of chemistry and biology at Toronto Metropolitan University, and Steven Gallinger, a hepatobiliary and pancreatic surgical oncologist and clinician-scientist at Princess Margaret Cancer Centre , part of the University Health Network .
Gallinger is also a professor of surgery and laboratory medicine and pathobiology at Temerty Medicine and director of the PanCuRx Translational Research Initiative at the Ontario Institute for Cancer Research.
The study was supported by the Cancer Research Society and the Canadian Institutes of Health Research.
