Regenerative medicine such as stem cell based therapy holds great promise towards addressing many diseases that afflict millions of Canadians, including many forms of cancer, muscular and neurological degenerative disorders, diabetes, and arthritis. However, this promise has yet to be fully realized. Despite the many advances in stem cell biology, little is known on the mechanisms governing stem cell identity and on how this identity can be effectively changed and applied towards its target function. The lack of understanding in basic stem cell biology not only has hindered the proper application of stem cell therapy, but has also led to the proliferation of unproven and potentially unsafe applications in many private Canadian clinics.
My research aims to bridge this gap by studying how embryonic stem cells are able to self-maintain indefinitely, while retaining the ability to differentiate into any cell type of the body. Using cutting edge technologies such as gene editing, genomics, and single molecule imaging, our group plans to dissect the molecular underpinnings that make stem cells such versatile therapeutic agents.
Cancer is a complex disease with many factors which determine how rapidly cancer cells can grow and spread throughout the body. Significant differences exist within the cancer cell population of a patient. These differences shape the interaction of cancer cells with the surrounding healthy tissue, with dramatic variation between patients. This so called cancer heterogeneity has profound implication for patient prognosis, and is one of the primary challenges to developing effective cancer treatments. Recent technological advances now allow for the measurement of multiple aspects of individual cells within a cancer. This has created an opportunity to precisely characterize the set of mutations in each cancer cell, along with their functional consequences and how they impact interactions with surrounding cells. My group will develop statistical machine learning approaches to analyze the complex datasets generated by these technologies.
Working alongside clinicians and biologists at BC Cancer, part of the Provincial Health Services Authority (BC Cancer), we will apply these computational methods to study the evolution of metastatic breast cancer and the mechanisms of relapse in follicular lymphoma. Ultimately this research will provide important insights that can guide the development of better strategies for the diagnosis and treatment of these cancers.
A defining characteristic of cancer cells is their ability to grow and replicate in an uncontrolled manner. Cancer cells have altered signaling pathways that allow them to bypass checkpoints that would normally prevent their rapid growth. STAT3 protein is a master regulator of cancer cell signaling and is found to be overactive in 70 % of cancers. While healthy cells can survive without STAT3, cancer cells become addicted to overactive STAT3 and are sensitive to disruptions in this pathway.
As a result, several drug-like molecules have been explored for their ability to inhibit STAT3 signaling in cancer cells. While some have shown promising anti-cancer effects, issues with selectivity and toxicity have prevented their clinical use. With the goal of identifying better STAT3 inhibitors, my research program uses cutting-edge techniques to determine how STAT3 inhibitors function in cells. We investigate what exactly the inhibitor binds to inside a cancer cell and how that affects STAT3 signaling. We also use these techniques to develop our own STAT3 inhibitors which we then explore as novel anti-cancer agents. Our ultimate goal is to produce new medicines that can help patients win their battle against cancer.
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer related deaths mostly due to the absence of symptoms as the cancer develops. This leads to diagnosis after the tumor has already become widely invasive and cannot be surgically removed. Unfortunately, surgical removal of early stage tumors is the most effective treatment option and other treatments, such as chemotherapy, are woefully ineffective.
Thus, there are two major fronts where research could improve the outcomes of pancreatic cancer patients:
- early detection and
- more effective treatments. Early detection requires knowledge of the events associated with tumor development, while improving treatments requires a thorough understanding of pancreatic cancer. It is clear that a 'one-size-fits-all' strategy has largely been ineffective for pancreatic cancer. We hypothesize that this is partly because PDAC is a 'catch-all' diagnosis for tumors that look the same, but may have different properties due to differences during their development. Our research program seeks to identify these differences and ultimately leverage the differences to improve patient outcomes through the development of personalized treatments.
One million Canadian women are affected by endometriosis annually. There is little investment in research, and socioeconomic cost, >$4 billion annually in Canada, continue to climb owing to lost productivity, sick days, treatments for frequent pain, infertility and depression. Most critically, affected women may have up to a 10-fold increased risk of developing specific types of ovarian cancer. There are no biological features that predict if endometriosis will result in severe or chronic pain, infertility, or cancer.
In 2017, my work identified cancer mutations in the DNA of endometriosis, a feature seen only in cancer.
Since then, I have established a research program with two goals:
- to examine association between specific mutations and types of endometriosis.
- to understand how other biological features, such as the immune-system, may be affected by mutations and contribute to the establishment of endometriosis, and progression to cancer. Cancer mutations are present in all types of endometriosis, including those with no risk of cancer. Additional work is needed to understand how these mutations influence the biology and symptoms of both endometriosis and their associated cancers, as well as establish management strategies.
Antibiotics revolutionized our medicine against pathogen infection. However, pathogenic bacteria have recently evolved resistance to multiple antibiotics, becoming a global health care risk. We urgently need to develop novel strategies to combat antibiotic resistance and develop evolution-proof antibiotics.
Dr. Han’s research will study and engineer enzymes that could be used as potential antibiotic reagents to degrade a key chemical molecule that bacteria utilize to develop virulence and resistance to antibiotics (biofilm formation). Specifically, Dr. Han will look to discover novel enzymes and perform detailed profiles of these enzymes to interpret their molecular mechanisms. Using state-of-the-art enzyme engineering and laboratory evolution techniques, he will engineer these enzymes for higher stability and functionality and demonstrate anti-virulence and anti-biofilm capabilities of these engineered enzymes, crucial for biotechnological and pharmaceutical applications.
This research program will provide the first mechanistic study of enzymes that disrupt the virulence of diverse pathogenic bacteria, and could have significant impact in the field. Most importantly, this research could provide novel and effective tools to control bacterial population and infection, crucial in the fight against the development of antibiotic resistance.
Prostate cancer is the second leading cause of cancer death. Comprehensive analysis of genomes has the potential to inform precise prostate cancer treatments. However, a major challenge of prostate cancer genomic analysis is the inaccessibility of metastatic tissue. Circulating tumour cells (CTCs) offer great potential as an alternative source of genetic material, which would enable the identification of the relevant mutations and aberrations that define prostate cancer subtypes.
Despite the tremendous potential of CTC genomics, there has been little progress in genotyping CTCs. This is due to the rarity of CTCs and their genetically heterogeneous population. Current methodologies have overcome this limitation by performing single-cell sequencing. However, existing methods for single-cell isolation require precise manipulations using contaminant-free tools, which are either extremely difficult to perform or are associated with unacceptable cell loss.
Dr. Choi’s research will look to develop a new method to rapidly target and select single CTCs based on their phenotypic profile. This method would enable both in situ immunostaining and single cell sequencing, which would provide important insights when interpreting data from genetic analysis.
The results of this research could be significantly beneficial in the development of personalized therapy, evaluation of anti-cancer drugs, and surveillance for disease recurrence.
Epilepsy is one of the most common brain disorders. The condition is characterized by uncoordinated brain electrical activity and recurrent seizures. Epilepsy patients may die unexpectedly with unknown cause, a phenomenon termed “sudden unexpected death in epilepsy” (SUDEP). SUDEP accounts for about 50% of deaths in individuals suffering from drug-resistant epilepsy in which severe seizures are followed by alterations in respiratory and cardiac functions.
The underlying mechanisms triggering SUDEP remain unknown. Using animal models of human disease and live brain imaging, Dr. Thouta’s research will work to define the specific brain regions that promote brain inactivity during SUDEP-like seizures. This will include testing novel anti-epileptic drugs as a potential preventative SUDEP agent.
The results of this research will provide an understanding of the cause of SUDEP and could have a significant impact on epilepsy drug development efforts, potentially leading to the discovery of novel therapeutics for SUDEP prevention.
The dispersal of tumour cells within malignant tissue relies on a process called chemotaxis, where tumour cells migrate in response to chemical signals in the local microenvironment. There has been longstanding interest in using chemotaxis assays to deduce how invasive a tumour is, and how it might respond to drug therapy. However, current chemotaxis assays are prone to extreme inter-assay variability, due to the inherent instability of the chemical gradient. Additionally, existing assays require a large number of cells, making it impossible to test primary patient tissue, which typically only yields a few hundred tumour cells.
Dr. Park’s research will work towards developing a microfluidic platform to generate highly stable and uniform chemical gradients for the chemotaxis assay of a small number of tumour cells. She will validate the technology by examining the response of cultured tumour cells to chemotherapy. Cells from murine tumour xenograft will further establish the relationship between migration with disease progression and drug-efficacy.
The results of this research could provide a reliable means to evaluate the migratory potential of patient tumour cells both before and in response to therapy, ultimately guiding clinical decisions in practice and within personalized clinical trials.
Diarrheal disease affects 1.7 billion people every year, killing around 760,000 children. A leading cause of this disease are bacteria like enteropathogenic Escherichia coli (EPEC). EPEC’s ability to cause disease relies entirely on creating an environment in which it can thrive. EPEC achieves this by secreting “effector” proteins directly into human host cells, which rewire the human cell, allowing EPEC to take control of cell immune signalling. One way effectors work is by chemically modifying host proteins with phosphate groups (phosphorylation), which may alter how proteins interact with one another.
Dr. McCoy’s research will develop a method for studying the interaction between bacteria like EPEC and their human hosts. His preliminary data has shown that a group of drugs called bumped kinase inhibitors (BKIs) can block this interaction. Expanding on this, he will aim to reveal how EPEC uses phosphorylation to manipulate the human host and establish infection.
