Epithelial stem cell biology

Epithelia comprise a variety of differentiated cell types that ensure their diversity in functions. Adult stem cells – specialised tissue-specific cells – constantly self-renew and replace cells that are lost through terminal differentiation or tissue damage. A key challenge in epithelial biology is to understand how these stem cells maintain the balance between proliferation and differentiation, and how these programmes become corrupted in disease contexts such as cancer, inflammation and ageing. To target these questions, we will innovate research tools including cutting-edge genetic mouse models, single-cell spatial multiomics, and 3D organoid culture system.

Tracing epithelial stem cells in tumourigenesis

Deep sequencings with normal human tissues from different anatomical sites have revealed that cells frequently harbour somatic cancer mutations. These cells and tissues appear to be phenotypically normal, but surprisingly carry known cancer mutations. Identification of these cells has opened the question of how the tissues tolerate mutant cells initially, and how the mutant cells subsequently become tumorigenic. We aim to discover cellular/molecular mechanisms promoting such transformation, which holds the key to developing next-generation drugs to stop cancer even before it starts. This approach is based on our innovative animal model – Red2Onco – in which different oncogenes are coupled with the RFP, allowing mutant (red) clones to be mapped at single-cell resolution alongside wild-type (non-red: CFP, YFP and GFP) clones  (Nature Yum et al., 2021). 

Exploring tissue microenvironment

Recent advances in high-throughput single-cell sequencing technologies allows comparative analysis of tissue microenvironment (e.g. epithelial cells, immune cells, stromal cells, endothelial cells etc.) during homeostasis and disease.  We are actively collaborating with computational biologists and mathematicians to establish and analyse single-cell multi-omics datasets of the microenvironment. This approach is critical to explore both cellular/molecular mechanisms governing clonal fate behaviour of epithelial stem cells in normal and disease contexts such as colon cancer and inflammatory bowel disease (IBD).

Modelling disease with 3D organoid culture

Epithelial stem cells possess remarkable self-organising capability, which enables us to create an organotypic culture of small tissue-like structures in a laboratory dish, which is called organoids. Together with CRISPR/Cas9 technology, this 3D organoid culture system opens up many opportunities to investigate the complex features of biological processes ranging from tissue development to disease progression. Using epithelial stem cells from both normal and patient tissue, we generate 3D organoids and study the pathology of human disease. In addition, we are interested in establishing new co-culture methods to recapitulate the dynamic cellular interactions between stem cells and their niche.  

We are grateful to our funders as listed below for supporting our research team.