Lau Lab (KenLauLab)
Data-driven machine learning approaches to obtain a systems biology view of how environmental components and epithelial cells interact as an ecosystem to generate tissue architecture and function
Director: Ken Lau
My laboratory is dedicated to tackling questions encompassing epithelial cell plasticity and the maturation of cell states in the gut. Forward state transitions, in the form of differentiation, are key to embryonic development, where the specification of the intestine progresses from definitive endoderm to fore/hindgut endoderm, culminating in the formation of intestinal tissue. Likewise, intestinal homeostasis is maintained through ongoing stem cell-driven renewal and differentiation. Specialized epithelial cells, in addition to providing a barrier function, play a key role in transmitting signals from the luminal environment to underlying host cells. In our prior research, we unveiled numerous instances of epithelial transitions that significantly influenced the intestinal microenvironment in clinically relevant disease settings. In a study published in Gastroenterology, we unveiled a lineage specification mechanism of immunomodulatory epithelial tuft cells (Banerjee et al., 2020). These cells, inducible by luminal stimuli, can be leveraged to effectively reverse ileal inflammatory disease by replacing a type 1/17 immune response. In damage-repair scenarios often seen in disease contexts, epithelial cells undergo reverse state transitions, reverting to a primitive state to repopulate damaged areas. Here, aberrant cell plasticity can result in dysplastic foci that eventually leads to neoplastic transformation. Our study, published in Cell, deciphered that serrated polyps originate from differentiated cells through embryonic reversion into pyloric metaplasia, while conventional adenomas arise from normal stem cells through aberrant expansion (Chen et al. 2021). These distinct routes to form premalignant polyps control cytotoxic T cell infiltration into the lesion independent of mutation burden. We further revealed in a Cancer Discovery study that luminal response to neoplasia-promoting Clostridioides difficile can induce a serrated gene program in colonocytes when compared to progenitor cells (Drewes et al., 2022). This result reveals the potential role of the microbiome in triggering a metaplastic reparative response in epithelial cells. Given that epithelial metaplasia can potentially be leveraged to shape gut immunity in a variety of damaging conditions such as IBD and premalignancy, this relatively untapped research area holds paramount significance for clinical translational applications. Illustrating the synergy between wet-lab and dry-lab investigations, we published a recent study in Cell that charts evolutionary trajectories using spatial genomic scaffolds (Heiser et al., 2023). We currently have a manuscript in Nature under review after revision on single-cell mutational barcoding.