What do a telescope capturing detailed pictures of space and a newly funded team of cancer researchers leading an innovative project on metabolites and our immune system have in common?
Both are using high-end, state-of-the-art visual imaging technologies to capture pictures that will give them clues to the origin of things: in the first instance the origin of the universe; in the other, the origins and behaviour of cancer.
Dr. Julian Lum, a distinguished scientist at the Deeley Cancer Centre in Victoria who is leading a newly awarded Terry Fox New Frontiers Program Project Grant, uses the Hubble telescope analogy to explain the work his world-class team is undertaking for their spatial metabolome “hubble” project. The first PPG to be based in Victoria, British Columbia, the program aims to decipher tumour-driven immunosuppression to understand how different nutrients, called metabolites, function in, on and around cancer tumours, and explore solutions to overcome it. The project title stems from a video he was watching of the new James Webb telescope.
“Our mass spectrometry imaging or MSI ‘telescopes’ will allow us to create maps of where metabolites are found and help us determine if those metabolites are changing how the immune system is trying to fight the tumour,” Dr. Lum explains. “We are the only team in Canada that has the newest collection of MSI instruments to look at metabolites with high-spatial resolution (near single cell) and with high specificity. No one else in Canada is applying MSI in the way we are going to and there are, maybe, only one or two groups in the world doing this.”
The team is focused on metabolites because they’ve learned that cancer cells adapt to nutrient deficits, and this alters the normal function of cancer-fighting immune cells. Our immune system protects our cells and defends our body against harmful invaders. But cancer cells can evade this natural defense system, change it and avoid detection. Immunotherapy, which was developed to combat this, has revolutionized cancer treatment by strengthening the patient’s own immune system to fight the disease. However, these treatments are often ineffective – and not all benefit.
“The biggest challenge is that existing technologies cannot distinguish the metabolites of the cancer and immune cells or their precise location. This is like having a picture of space without information about where the stars and planets are located,” says Dr. Lum, whose team comprises Canadian pioneers in metabolomic research. “Our goal is to create high-resolution, metabolic cancer images that allow us to visualize metabolomes just like the stars in space. By creating these metabolic maps, we will gain a new fundamental level of richness about how cancers hijack metabolism to disarm the immune system.” They hope their work leads to new therapeutic opportunities that could radically improve the effectiveness of immunotherapy.
Over the next four years, with $2.4 million in PPG funding, the team’s synergistic approach will take advantage of their combined expertise in cancer biology, immunology and high-end, mass spectrometry imaging infrastructure to achieve their program goals, with details outlined below:
Project 1, led by Dr. Shoukat Dedhar, centres on understanding the harsh environment around pancreatic cancer cells. By altering their metabolism, pancreatic cancer cells create a build-up of substances that fights or suppresses the body’s immune response and resists immunotherapy. Using advanced imaging techniques and testing on various cell and mouse models, the project aims to identify the major metabolic changes and create a detailed map of the metabolites in and around the cancer cells.
Project 2, led by Drs. Julian Lum and Robert Rottapel, focuses on ovarian cancer, in which the tumour's immediate environment can create a “metabolic wall” to prevent the immune system from doing its job. One metabolite they have found, methionine, and a related family of metabolites, seems to reduce the activity of immune cells, and blocking its consumption increases the effectiveness of an immunotherapy called CAR T-cell therapy. To improve the effectiveness of immunotherapy in ovarian cancer, they will study how this group of metabolites are distributed within the tumour, how they affect immune response and how to block these metabolites or modify CAR-T cells so they aren't affected by them.
Project 3, led by Drs. Poul Sorensen and Seth Parker, focuses on studying how tumour cells cope with metabolic stress in specific types of cancer, like pancreatic cancer and Ewing sarcoma, and how this can prevent CAR-T cells from being effective. Using advanced mass spectrometry imaging techniques, the researchers will measure changes in the tumour's nutrient composition and how this affects surrounding immune cells within the tumour.
The Spatial Metabolomics Hub is a pioneering initiative, led by Drs. David Goodlett and Kyle Duncan, using advanced imaging technology to explore metabolic profiles within different areas of tumour tissues. This core centre aims to understand why certain immune cells, specifically tumour-infiltrating lymphocytes, are more or less active in some parts of a tumour – a detail that is crucial to a patient's survival.
“While we are exploring a relatively new and small space in -omics research, we hope our success will inspire other groups across Canada to dream big, like Terry himself, and come together to propose groundbreaking research that will fundamentally change the paradigms of how we approach cancer as a disease,” concludes Dr. Lum.
Funding for this New Frontiers Program Project on The Spatial Metabolome Hubble Project to Decipher Tumour-Driven Immunosuppression (MetaboHUB) is provided equally by the Terry Fox Foundation and the Lotte & John Hecht Memorial Foundation.