For patients with neuroblastoma, one of the most common solid tumours in children, disease outcomes can vary widely. Some children face a fairly good prognosis with survival rates in excess of 80 per cent. However, some neuroblastoma have genetic characteristics that make the disease particularly aggressive and prone to metastatic spread. The survival rate for these high-risk cancers is drastically lower, approximately 30 per cent.
Now, researchers at the University of British Columbia and BC Cancer have identified a previously unknown gene that drives the aggressive behaviour of high-risk neuroblastoma. The findings, recently published in Science Advances, could offer new possibilities for the development of more effective treatments.
“Neuroblastoma is responsible for 13 per cent of all pediatric cancer-related deaths,” said Dr. Poul Sorensen, professor of pathology and laboratory medicine at UBC, distinguished scientist at BC Cancer, and the Johal Chair in Childhood Cancer Research. “Understanding why some forms of this cancer are so aggressive and fast-spreading is critical for developing better, targeted treatments that improve outcomes for the most high-risk children.”
Unravelling the genetics of cancer
Neuroblastoma arises from young nerve cells and is commonly found in the adrenal glands which sit on top of the kidneys, in addition to the neck, chest and near the spine. It typically affects babies and children under the age of five.
For years, scientists have known that a particular gene, called MYCN, is a defining feature of high-risk neuroblastoma. Tumours that carry a large number of copies of the MYCN gene overproduce proteins that enable the cancer to spread to other tissues. Doctors will often run tests to determine if a child’s tumour has these genetic characteristics and tailor treatment plans accordingly.
For the new study, Dr. Sorensen and his team wanted to know if there are other genes that also contribute to this aggressive behaviour.
“It has been largely assumed that the MYCN gene was the sole genetic driver of aggressive neuroblastoma carrying excessive copies of MYCN. We set out to find if there was more to this story,” said Dr. Haifeng Zhang, staff scientist in the Sorensen lab and the study’s first author.
The analysis revealed that another gene, called GREB1, which neighbours the MYCN gene, also plays a critical role in high-risk neuroblastoma. The researchers found that GREB1 is frequently co-expressed with MYCN and triggers its own independent pathway that enables neuroblastoma to aggressively grow, invade nearby tissue and spread to other parts of the body.
“These genes are like partners in crime, they are expressed together and each of them triggers their own molecular pathway that fuels aggressive behaviour,” said Dr. Sorensen. “It was surprising to find that these two genes, located on different but nearby parts of the same chromosome, influence each other’s expression, leading to this unexpected and previously unknown connection.”
A potential new treatment target
When they looked deeper, the researchers uncovered a series of complex cellular changes that are controlled by GREB1. Notably, GREB1 triggers the expression of another gene called Myosin 1B (MYO1B), which promotes the tumour’s ability to invade nearby cells and metastasize. Furthermore, MYO1B promotes the secretion of proteins from the tumour that promote cancer growth, blood vessel formation and metastatic spread to other tissues.
“Metastatic disease is widely associated with poor patient outcomes because current treatment strategies are often ineffective at controlling the growth of metastatic lesions,” said Dr. Karla Williams, assistant professor in the faculty of pharmaceutical sciences at UBC and Canada Research Chair in Oncology. “Understanding how tumour cells spread and develop into deadly metastatic lesions is critical for the development of new therapeutic strategies to improve patient outcomes.”
With a better understanding of the mechanisms that drive aggressive neuroblastoma, the researchers hope to apply the findings toward the development of new therapies that target the pathway.
“This discovery is significant because it provides a potential target for the development of treatments,” said Dr. Zhang. “It opens up brand new possibilities to target the GREB1 pathway and the secretory pathway it controls, which could offer new approaches for treating patients with this challenging cancer.”
The findings could also have applications beyond neuroblastoma. The study showed that similar genetic mechanisms are at work in medulloblastoma, a childhood brain tumour, and previous research has shown that GREB1 drives the aggressive nature of other cancers, mainly sex hormone-related cancers, including breast, ovarian, prostate and endometrial cancer.
For Dr. Sorensen, it highlights what an exciting time it is to be involved in cancer research.
“Every day, we’re learning something new about how genes influence cancer’s behavior and the complex interplay between those genes. What was once a perplexing puzzle is becoming a decipherable code, and that’s opening doors for better treatments and better outcomes for patients.”
This study was funded by a National Institutes of Health (NIH) Joe Biden Cancer Moonshot grant, a St. Baldrick’s Foundation/American Association for Cancer Research/Stand Up to Cancer grant, and generous funds from the BC Cancer Foundation.