Canadian research teams, including several from BC Cancer, will receive a total of $2.4 million to advance cancer research and treatment following new awards in the 2023 Terry Fox New Frontiers Program Project Grant (PPG) competition.
Dr. Julian Lum, distinguished scientist at the Deeley Lab at BC Cancer – Victoria, is working with fellow BC Cancer collaborators Drs. Shoukat Dedhar and Poul Sorensen and research colleagues Drs. David Goodlett (University of Victoria), Kyle Duncan (Vancouver Island University), Seth Parker (BC Children’s Hospital Research Institute) and Robert Rottapel (University of Toronto) as part of a world-class team undertaking a collaborative spatial metabolome “hubble” project. The program aims to decipher how different nutrients, called metabolites, function in, on and around cancer tumours to shut down the immune system, and explore solutions to overcome it. The project title stems from the Hubble telescope analogy used to explain the work and a video Dr. Lum 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. The immune system protects cells and defends bodies 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 can be ineffective, especially in hard-to-treat cancers like ovarian cancer, pancreatic cancer and ewing sarcoma.
“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:
Led by Dr. Shoukat Dedhar, Project 1 centres on understanding the harsh, low oxygen environment that surrounds pancreatic cancer cells. Tumour cells residing in areas of low oxygen have to adapt to hypoxia by altering their metabolic state and energy consumption. 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. Dr. Dedhar and group are aiming to understand the molecular and metabolic nature of this build up and reverse it by targeting key proteins responsible for metabolic alteration to improve immune cell response.
The group found that by targeting the tumour proteins responsible for blockade, they could activate the immune cells to kill tumour cells. In partnership with the other projects, Dr. Dedhar and group plan to identify and image the metabolites that are involved in the immuno-suppressive barriers in pancreatic cancer. This insight will lead to the identification of new and novel therapeutic targets designed to improve immunotherapy treatment options for pancreatic cancer.
Led by Drs. Julian Lum and Robert Rottapel, Project 2 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. Drs. Lum and Rottapel are working to understand how methionine, an amino acid found in protein-based foods, affects the immune system’s response to ovarian cancer. Their initial findings indicate methionine can reduce the activity of T-cells, the main immune cell that is responsible for detecting and destroying cancer cells. By using innovative spatial metabolomics technology “telescopes,” they can pin-point exactly which T-cells are exposed to methionine and being disarmed.
“Coincidentally, when cells take up and use methionine, several important products are generated including another metabolite called adenosine,” says Dr. Lum. “Adenosine is a key feature of pancreatic cancers that will link our work to the outcomes and findings from Project 1, led by Dr. Dedhar. Methionine is also crucial in producing detoxifying molecules that combat toxic products that tumour cells generate linking our work to the work in Project 3, led by Drs. Sorensen & Parker.
Project 3, led by Drs. Poul Sorensen and Seth Parker, focuses on studying how pancreatic and Ewing sarcoma cancer cells cope with metabolic stress and how this stress can prevent immunotherapy from being effective. Project 3 will work to better understand if tumour cells can create a metabolic crisis for immune cells, by either producing anti-immune cell metabolites, or by consuming metabolites that immune cells need in order to function properly.
Drs. Sorensen and Parker believe that these studies will provide a blueprint for studying the effects of metabolite shifts and could reprogram tumour cells on the immune response within the tumour microenvironment. They believe that by interfering with how tumour cells orchestrate such metabolic rewiring, they can enhance anti-tumour immune responses to help make treatments more effective.
“Since metabolic pathways are very interconnected, we expect that there will be strong synergies between our project and Project 1, since the metabolite, adenosine, is a key feature of pancreatic cancers that will link our work to the work of the Dedhar group. There will also be strong synergies to Project 2, led by Drs. Lum and Rottapel,” says Dr. Sorensen.
Project 3 will also utilize the Core “telescope” extensively for spatial imaging of the various metabolites that Dr. Sorensen and group plan to study.