Team from Duke-NUS Medical School, Singapore have discovered that a well-known signalling pathway helps cancers grow by blocking the pro-growth signals from a second major cancer pathway.
Excessive cell growth is a known result of the hallmarks of cancer. When cells grow in an uncontrolled manner, it can cause a type of cellular ageing that results in arrested growth. Cancer cells are able to proliferate excessively is through the hallmark known as sustained proliferative signaling. Many cancers are driven by activating mutations in the RAS-MAPK signalling pathway which triggers a cascade of proteins that directs cells to grow, divide and migrate. Mutations in proteins involved in this cascade can turn on genes that make this process go into overdrive, causing cells to grow out of control and aggressively invade other parts of the body. However, increased RAS-MAPK signalling causes cancer cells to prematurely age, and eventually stop growing — a process called cellular senescence.
Publishing their findings in the journalCancer Research, the Duke-NUS research team found that another important and well-known biochemical pathway, the Wnt signalling pathway, allows some cancers to grow by dampening RAS-MAPK signalling.
The team made the discovery while investigating how Wnt proteins regulate pancreatic cancers. Scientists have long observed that genetic mutations causing Wnt proteins to be hyperactive drive many common cancers and cause excessive cell proliferation. The new findings from this study suggest that this idea needs re-evaluation.
Ensuring a balance in RAS-MAPK signalling, Wnt signalling enables cancers to grow steadily instead of heading towards the premature ageing that can be caused by excessive RAS-MAPK signalling. These findings support a growing awareness that cancers need a certain level of RAS-MAPK signalling. Disrupting modulating signals like Wnt can cause cancers to stop growing by forcing them to undergo cellular senescence, similar to just getting old.
Assistant Professor Babita Madan, from Duke-NUS Cancer and Stem Cell Biology (CSCB) Programme, a senior co-author of the study, explained, “Using an experimental drug, ETC-1591, to stop Wnts in multiple models of human pancreatic and colorectal cancer, we found that, unexpectedly, Wnt signalling turns off as many genes as it turns on.”
Upon further analysis, the team made the connection between Wnt signalling and the diminished activity of the RAS-MAPK pathway. Inhibiting Wnt signalling with ETC-159 and other anti-cancer drugs actually activated RAS-MAPK signalling, while inhibiting cancer growth at the same time.
“This makes sense; while activating mutations in the RAS-MAPK pathway are common in cancer, in isolation, they cause cells to stop growing by causing senescence, a form of ageing-induced arrested cell growth,” said Professor David Virshup, Director of the CSCB Programme, and also a senior co-author of the study.
“By reining in RAS-MAPK signalling, Wnt signalling achieves Goldilocks’ goal of getting it not too hot, not too cold, but just right.” Professor Virshup added.
The results of this research open up potentially new methods of tackling a number of cancers. The traditional way is to kill cancer cells; however, this new study shows that stopping cancer cell growth can be achieved by inducing senescence.