A UCLouvain team is working to “scramble” the instructions received by metastases to develop. © Adobe Stock
Every year, 27,000 people die of cancer in Belgium, including some 24,000 due to the presence of metastases. In recent years, researchers at the Institute for Experimental and Clinical Research at UCLouvain have taken decisive steps in identifying a particular mechanism: certain cancer cells have the ability to leave their original tumor and implant in other tissues and organs to form metastases there. It was known that these cells “migrated” from the primary tumor in the event of threatened survival (lack of oxygen, deficiency in nutrients and/or accumulation of metabolic waste). But these cells, qualified as “metastatic progenitors”, still need to be informed of the inhospitable nature of their environment.
A drug candidate
Under the direction of Professor Pierre Sonveaux, FRS-FNRS research director, investigator at the WEL Research Institute (WELBIO), UCLouvain researchers have shown that metastatic progenitors have mitochondria (their “power plants”) whose structure is aberrant and abnormally increased activity. They then demonstrated that these mitochondria behave like metabolic sensors, detectors of the hostility of the tumor microenvironment. They then emit a signal to encourage cancer cells to migrate to an environment more conducive to their survival. What signal? The production of a free radical: superoxide.
Pierre Sonveaux and his team wondered how to prevent the migration of metastatic progenitors by deactivating superoxide. “We succeeded in preventing the appearance of metastases in mice brought to develop a form of human breast cancer with a strong propensity to cause secondary cancerous foci”, reports Professor Sonveaux. Good news, the substance administered, MitoQ, is a low-toxic drug candidate currently being tested in patients suffering from Parkinson’s, Alzheimer’s or hepatitis C. The path to clinical trials in oncology therefore seems to have been mapped out. Especially since Pierre Sonveaux brings an important precision: “We tested in vitro the combination of MitoQ with all the chemotherapies used in hospital in patients suffering from breast cancer. We observed no drug interference, which was confirmed in mice.“In addition, the scientists observed in mice that MitoQ also prevented recurrences of human breast tumors after surgery. And very recently, they obtained in pancreatic cancer results similar to those obtained in breast cancer. However, MitoQ does not eliminate metastases that have already formed.
On September 8, 2022, the journal Cancers published the results of another study by Pierre Sonveaux’s team. Work that allowed him to come full circle. Because another question tormented researchers: why do metastatic progenitors colonize certain organs and not others to generate metastases there? Breast cancer metastasizes to the brain, lungs, liver or bones, but never to the earlobe or fingers. The researchers postulated that metastatic progenitors have a predilection for organs capable of meeting their needs. Thus, a lack of glucose or lipids in the primary tumor (of the breast, for example) could lead them to establish themselves preferentially in the brain, rich in these elements, while a lack of oxygen could cause them to settle. implant in the lung. The question then was: how, once in the bloodstream, do metastatic progenitors know where to stop? The UCLouvain researchers have suggested the existence of sensors that would inform the cell that it has arrived at its destination.
Cox7b, the stationmaster
Professor Sonveaux and his collaborators validated their hypothesis on mice developing a human form of breast cancer. They observed that metastatic progenitors selected to metastasize only in the brain differed from the others by the presence, in their mitochondria, of a protein called Cox7b. Better still, if this protein was removed from these cells, the number of cerebral metastases recorded in the mice fell by more than 90%, and the other organs were spared. “In the absence of Cox7b, these metastatic progenitors lack a “brain sensor” and no longer manage to leave the circulatory stream and die there.”, says Pierre Sonveaux. In contrast, when the researchers added Cox7b into cancer cells that originally metastasized sparsely to mouse brains, they went there en masse and nowhere else.
Scientists believe that several families of sensors allow the arrest of metastatic progenitors in one or more specific organs. They therefore expect the discovery of various proteins controlling the choice of the destination site according to the characteristics of the primary tumor, in particular the type of deficiencies that the metastatic progenitors encounter there and which push them to leave. To avoid metastases, a solution could therefore be to “jam the radar” by exposing the sensors to a blockage through therapeutic molecules. Strategies aimed at inhibiting superoxide, on the one hand, and destination sensors, on the other hand, appear to be complementary. In fact, metastatic progenitors that escape the action of MitoQ and nevertheless succeed in leaving the primary tumor could be condemned to wander and die in the circulatory torrent thanks to the inactivation of a destination sensor. Which would be a major step forward.