Why is our research important?
Despite our understanding of the genetics of colorectal cancer (CRC), current treatments are still based on cytotoxic regimens with significant side effects, and patients with advanced diseases have few therapeutic options. The good news is that colorectal cancer may be effectively prevented through diet. Among all types of cancer, CRC is most tightly linked with diet. Indeed, diet and nutrition are estimated to explain as much as 30-70% of the worldwide incidence of colorectal cancer. The important question is which diets, foods or nutrients are linked to colorectal cancer. Epidemiological studies have suggested that we should restrict our consumption of red meats while eating lots of vegetables to reduce the risk of colorectal cancer. But is that really true? If so, what are the molecular mechanisms? What are other nutrients linked to colorectal cancer?
The most common approach used in the field of nutrition is the human epidemiological study. Unfortunately, epidemiology can never prove causation; it can only show the association between the nutrient and the disease. Also, it is hard to control one’s diet or lifestyle strictly, confounding the dietary factors in question and often leading to mixed results in epidemiological studies. Moreover, epidemiological studies don’t tell us the molecular mechanisms of the relationship between the nutrient and the disease. Our team's mission is to create a new domain of nutrition and cancer research using our multidisciplinary approach ('What?') and experimental model systems and technologies ('How?').
In the end, we aim to achieve three things:
- Identification of nutrients that can affect colorectal cancer development
- Understanding the molecular mechanisms linking nutrients and colorectal cancer development
- Applications of our discovery to make the world a better place
What is our approach?
Our multidisciplinary approach
Our research goals are to understand the molecular mechanisms behind the interactions of diet and cells in the intestines. The intestine has many different types of cells including, but not limited to, intestinal stem cells, immune cells, microbiota, neural cells and cancer cells. The complex communications between diets and various cells in the intestines have profound effects on the development of chronic disease including colorectal cancer. Traditional monodisciplinary and reductionist approaches have limited potential for fulfilling our goals. To overcome these limitations, we apply multidisciplinary and systems biology to unravel these complex and dynamic interrelationships. We believe that discoveries from our research will have the direct and profound impact on our daily lives.
How do we do the research?
Our model systems
Our lab uses three preclinical model systems:
- in vivo (mouse model)
- ex vivo (3D organoids)
- in vitro (cell lines).
All three systems have their pros and cons; however, they are interdependent and complementary approaches to studying human disease and understanding complex biological phenomena. Our team maximizes the benefits of our model systems to rigorously address our questions and hypotheses. Nevertheless, it remains true that human disease is best studied in human subjects. Thus, whenever we discover new findings using our model systems, we verify them in human samples or human populations. Additionally, the opposite case can occur where we test observational studies from human (i.e. epidemiological studies) using our model systems to understand causality and mechanisms. Ultimately, our goal is to provide the solid preclinical results that warrant investigation in therapeutic and preventative human clinical trials.
In vivo mouse models
Our lab uses various mouse models of colorectal cancer depending on the purpose. This includes genetically engineered mouse models (APC, KRAS, BRAF, PIK3CA, p53), xenografts, PDX (patient-derived xenografts), orthotopic organoid transplantation in mice, and chemically induced mice models such as Azoxymethane (AOM) mice.
Ex vivo organoids
Three-dimensional (3D) cultures of organoids from normal cells or tumor cells are emerging model systems that hold great promise to mimic better the biology found in vivo. To complement our mouse models, we utilize this surrogate organoid ex vivo approach to facilitate the molecular characterization and functional assays using powerful genetic approaches such as shRNA or CRISPR in a time and cost-effective manner. Furthermore, utilizing an organoid system allows us to discern the direct effect of nutrients on normal intestinal cells or tumor cells from cell non-autonomous effects caused by nutrient-host interactions. Our lab uses both healthy intestinal and tumor organoids derived from mice and humans.
In vitro cell lines
Monolayer cancer cell lines derived from cancer patients have been a pillar of cancer research and gave us many significant insights in the field of cancer biology despite their limitations (e.g. the adaptation of cell lines to monolayer culture conditions.) Our lab continues to exploit the benefits of in vitro cell line systems to address our research questions.
Technologies that we use
To unravel the complex relationship between diets and intestinal cells, we need tools that can measure our biological changes in high-throughput and systematic manners. Thankfully, we have many cutting-edge technologies that enable us to explore these diverse and dynamic interactions. Our laboratory utilizes –omics technologies such as next-generation sequencing (genomics, transcriptomics, microbiome), proteomics, and metabolomics together with traditional molecular, genetic and biochemical assays. We integrate these -omics data to understand the role of diets in our body and disease progress in holistic and comprehensive ways.