Metastatic cancer, in which cancer cells invade healthy distant tissue, is the leading cause of death in Canada. Epithelial breast, colon, and prostate cancer of the outermost tissue lining are the most prevalent forms of metastatic cancer and require better tools to prevent life-threatening outcomes. Treatments such as surgery and chemotherapy are either impractical for metastases, invasive, or toxic. The goal of this work is to develop a radioactive molecule that targets matriptase, an enzyme which supports tumor growth and metastasis. A set of molecules will be made, labelled with a radioactive tag, and screened for binding. Conveniently, the radioactive source is interchangeable for imaging or targeted radiotherapy. Using a specialized camera, tumor radioactivity can be noninvasively tracked to classify disease progression. Using a different radioactive tag, radiation can also be delivered to exclusively kill matriptase-positive tumor cells. The lead candidate is expected to enable tumor staging and improve patient outcomes by impeding tumor growth and spread. It may also be used to monitor response to therapy and guide clinical decisions, representing a major advance in the management of metastatic epithelial cancer.
Research Pillar: Biomedical Research
How do neurons in breast cancer tumours control anti-tumour immune responses?
Immune cells can be very effective at killing cancer cells, but tumours have the ability to suppress the immune system. This is why some of the best cancer therapies work by turning the immune system back on. To do this, it is key to understand what controls immune responses in the tumour. In inflammation, it has been shown that neurons can control the immune system. Interestingly, there is evidence that by removing neurons, cancer growth is reduced. We have discovered that when the “heat sensing” TRPV1 neurons are removed in mice, the tumor will grow much slower. We will looked at changes in immune cells using flow cytometry, which allows us to measure over 20 different immune cell types and discovered that these mice may have lower numbers of a rare cell type called ILC2. Next we are trying to understand how neurons are affecting these cells and the tumor growth. Finally, we will design a cell culture system where neurons and mini-cancers will be grown together to see if the tumors are secreting something that changes the expression of genes by neurons. This will lead to the development of novel therapies that activate the immune system by targeting neurons and provide new information on therapeutic avenues for breast cancer.
Impact of TSC2-deficient neural cells on microglial structure and function in an induced human pluripotent stem cell model of tuberous sclerosis complex
Tuberous sclerosis complex (TSC) is a rare genetic disease caused by mutations in the TSC2 gene. The TSC brain develops malformed tissue clusters called cortical tubers (CTs), which cause epilepsy and cognitive problems. CTs result from abnormal cell differentiation, where clusters of enlarged neural stem cells, astroglia, and hyperactive neurons form. CTs notably present markers of cell stress and inflammation, which are known to affect organelles, cell differentiation, and neuron function in CTs. CTs are surrounded by microglia, the resident immune cell of the brain, required for proper brain function and the main drivers of inflammation. Though known to be a feature of TSC brain lesions, the role of microglia in CT formation is completely unknown. Therefore, I will investigate if microglia contribute to CT formation and, study for the first time, how the interaction with TSC2 mutant cells affect microglial function. Using advanced molecular and imaging techniques, I will study if microglia affect CT formation in a co-culture model of human pluripotent stem cell-derived microglia and TSC2 mutant neural cells. Our results will finally elucidate the role of microglia in CTs, a critical advance to uncover novel treatments for TSC.
Cerebrovascular physiology of circulatory death in patients undergoing medical assistance in dying (MAiD)
Patients undergoing medical assistance in dying (MAiD) can qualify as organ donors. Donation commences after death, which is declared when blood pressure drops below a certain threshold. We believe that a low enough blood pressure means the brain is no longer receiving blood, which represents true death, after which donation can begin. The time it takes for blood pressure to become low enough (ischemic time) can cause damage to organs because of reduced blood flow. If it takes too long for blood pressure to reach the threshold, too much damage occurs, and organs are discarded. The threshold value of blood pressure is based on studies of critically ill patients in the intensive care unit. We are not sure if the same thresholds would apply to patients undergoing MAiD, as their underlying physiology is different. We think the threshold would be higher for patients undergoing MAiD. We will measure blood flow velocity to the brain in patients undergoing MAiD using transcranial doppler. If blood flow stops at higher blood pressure levels than currently used cutoffs, this would reduce ischemic time and reduce damage to potential donated organs. We will report our results in scientific journals and through organ donation organizations.
Addressing inter-individual variability in aging: linking lifestyle factors to the brain and behaviour
Cognitive decline is associated with a variety of neurodegenerative disorders and is increasingly prevalent in Canada’s aging population. One of the most effective means to counteract cognitive decline is to maintain or enhance cognitive reserve. Lifestyle factors have been shown to impact cognitive reserve, but this impact varies highly across individuals. Most investigations into the effects of lifestyle factors on behavior and neural function do not capture this inter-individual variability and produced mixed, difficult to reproduce findings. This research aims to reduce this variability by clustering the population into sub-types based on their susceptibility to lifestyle changes before investigating the causal relationships between lifestyle factors, behaviour and neural function. The identified causal relationships will serve as promising targets for future clinical interventions in sub-types of our aging population that can limit the effects of cognitive decline and lower the rates of neurodegenerative diseases. In addition to the classical means of knowledge translation, this research will be shared through public presentations held by the Institute of Neuroscience and Neurotechnology at Simon Fraser University.
Structure-function relationship of retinal guanylyl cyclase, a key enzyme in phototransduction
Light adaptation is the ability of visual system to adjust its performance to the ambient level of illumination. It is fundamentally vital for the normal functioning of the visual system. During the normal cycle of day and night, the illumination of the earth’s surface varies over 11 orders of magnitude. The daily cycle of sensitivity adjustment is managed by switching between rod and cone pathways of retina. These pathways involve retinal guanylyl cyclase (retGC), an enzyme encoded by the GUCY2D gene expressed in rod and cone photoreceptors. In the light-induced signal cascade, retGC restores cGMP levels in the dark in a calcium-dependent manner. Mutations in GUCY2D are associated with recessive Leber congenital amaurosis-1 (LCA1) as well as dominant and recessive forms of cone-rod dystrophy (CORD). Presently, the molecular structure of retinal GC has not been determined; thus, its mechanism, interaction with other regulators, and identity of crucial residues conferring the activity of this enzyme have been elusive. We aim to fill this gap in our knowledge by determining the molecular structure of retGC. This information will enhance our understanding of the role of retGC in photoreceptors and diseases.
Advancing Cardiovascular Research: Developing Vascularized Heart Organoids-on-Chips Integrating Immume Cells
Organoids, miniature organ models grown from stem cells, replicate the complexity of actual organs on a scale of about one millimeter. They exhibit similar morphology and functions but lack crucial elements like vasculature and immune response. In contrast, organs-on-chips, while providing dynamic microenvironments, typically use less sophisticated biological models. By combining these technologies, we can leverage the biological accuracy of organoids with the dynamic capabilities of organs-on-chips. This synergy aims to replicate in vivo physiology, enabling a more accurate study of disease characteristics and drug responses.
The project’s centerpiece is to engineer heart organoids-on-chips, with functional vascular and immune components, to investigate hypertrophic cardiomyopathy (HCM). We will evaluate the efficacy of drugs in mitigating hypertrophic responses. In addition, the study will include perfusion of immune cells to analyze the role of inflammation in HCM progression, investigating immune cell recruitment.
This initiative coincides with the U.S. FDA’s pivot from mandatory animal testing for new drugs, marking a significant shift towards more relevant human-based models in drug development.
Developing novel strategies to enhance CAR Treg manufacture and testing in transplantation
After organ transplantation, patients must take immunosuppressive drugs to prevent rejection of the organ by their immune system. However, these drugs have severe side-effects. In contrast, regulatory T cell (Treg) therapy, which uses naturally suppressive immune cells to produce immunosuppression, can avoid these side-effects. Tregs for therapy can be isolated from patients, genetically modified in the lab, and infused back into patients to block unwanted immune responses without broader effects. However, improvements are still needed to this therapy. This project takes two strategies to enhance Treg therapy. Firstly, I will test the effect of supplementing lactic acid during cell growth in order to identify an optimal media composition that promotes function. Secondly, I will develop a human organ-in-a-dish system to model complicated transplantation immune responses in a lab without using mouse models, which often don’t replicate events in humans. Overall, this work will produce Tregs that function and survive better when administered to patients and develop a new way to test and model Treg function in a complex human system.
Addressing antimicrobial resistance through the design and preclinical evaluation of a Klebsiella pneumoniae vaccine
Antibacterial resistance occurs when bacterial infections become resistant to treatment. It is a serious and growing threat to global health. Klebsiella pneumoniae (Kp) is a bacteria that causes a wide range of infections, particularly in vulnerable populations such as children and immunocompromised adults. Kp can develop multi-drug resistance, which makes finding treatments difficult and increases the risk of severe complications or death. Finding novel treatments for Kp infections is a priority for both the World Health Organization and the Canadian government. Our goal is to develop a vaccine against Kp, which would reduce the incidence of Kp infection for both treatable and untreatable cases, and limit the opportunities for this bacteria to develop even stronger resistance to treatments.
In this project, I will focus on developing a vaccine that targets drug-resistant Kp. First, I need to identify vaccine targets that are present in most drug-resistant Kp infections. Then, I will develop vaccines using those targets. In the next step I will test whether our different vaccines protect mice from lung, bloodstream, and urinary tract infections. With these data, we will move the best candidate vaccine forward to clinical trials.
A personalized approach to non-physical practice after stroke
Chronic motor impairments are experienced by 85% of stroke survivors. Recovery of these impairments can be facilitated by repetitive non-physical motor practice including kinaesthetic motor imagery (KMI; the mental rehearsal of movement), visual motor imagery (VMI; specific focus on a mental image) and action observation (AO; passive observation of movement). Yet, effectiveness of these different non-physical practice modes is varied due to highly individualized brain function after stroke. To improve effectiveness, we will assess brain and behaviour changes driven by KMI, VMI, and AO at the individual participant level. We will then design a personalized intervention to show that improvements in motor function are maximized when practice mode is tailored to the individual based on the brain’s response to each mode. This research informs the development of evidence-based interventions after stroke, representing an important step in improving the quality of life of stroke survivors in Canada. Integrated knowledge translation (KT) activities (including engaging key knowledge users), and end-study KT activities (including public lectures of findings) will be conducted.