Research
Gastric carcinogenesis is a multistep process involving genetic and epigenetic dysregulation that transforms normal gastric mucosa into an aberrant phenotype. The most widely accepted Correa’s model for human gastric cancer (GC) development follows a series of histological stages. These stages include various pre-cancerous phases such as chronic gastritis, atrophic gastritis, intestinal metaplasia and dysplasia, ultimately leading to advanced stages known as adenocarcinoma and metastasis. These pre-malignant stages are marked by dramatic changes in cell states, where normal gastric epithelial cells lining the stomach are replaced by cell types not typically found in a healthy stomach, such as intestinal enterocytes and goblet cells. Despite significant interest over the past half-century in the causality of these aberrant cell formations during GC tumorigenesis, the precise timing (when) and mechanisms (how) governing the emergence of GC from pre-cancerous lesions remain a mystery. Our long-term scientific interest lies in understanding the intricate relationship between gastrointestinal tract function and dysfunction. Specifically, we aim to uncover the molecular mechanisms that control adult gastrointestinal stem cell activity, cell lineage differentiation and tumorigenesis.
Modeling Gastric Cancer in Primary 3D Organoids
We are developing novel human gastric cancer models using CRISPR/Cas9 genome editing technologies within 3D organoids to functionally validate novel oncogenic loci. This cutting edge approach allows us to delve deeply into the molecular mechanisms and oncogenic signaling pathways involved in gastric tumorigenesis. These CRISPR/Cas9-engineered tumor organoids recapitulate a broad spectrum of gastric pre-cancer and cancer stages, providing a robust and innovative functional genomics platform. For instance, we have reported the first forward genetic human transformation model of ARID1A (Cancer Discovery 2021), a very interesting tumor suppressor gene that is lost at high frequency across numerous solid tumor types. Our research focuses on understanding the root cause of tumor development and evolution, which will pave the way for identifying potential cancer interception methods and creating new therapeutic strategies.
Adult GI Stem Cell and Cancer Biology
Under physiological conditions, intrinsic signaling pathways control gastrointestinal epithelial stem cell activity, guiding stem cells toward specific cell lineages and maintaining epithelial homeostasis. This delicate balance is often disrupted during cancer development, leading to dynamic changes in cell states. These alterations are crucial in driving tumor development and contribute to the heterogeneous nature of malignancies. As a result, this heterogeneity significantly impacts the therapeutic vulnerabilities of cancer cells to existing therapies, often leading to unfavorable clinical outcomes. We are particularly interested in studying the driving forces behind intestinal metaplasia, a pre-malignant condition where normal gastric epithelial cells are replaced by intestinal-like cells. Understanding these mechanisms is crucial, as intestinal metaplasia patients face an elevated risk of developing gastric cancer. Our objective is to advance the current understanding of cell plasticity and develop new therapeutic strategies that target unique pre-cancer cell states.
Tumor Microenvironment and Tumor-immune Interactions
We are developing advanced human 3D models that can accurately replicate the stromal components of tumor microenvironment ex vivo, with the goal of filling an unmet need in immuno-oncology. By creating new 3D functional genomics platforms, we aim to better understand how tumors interact with their microenvironment and gain deeper insights into these complex processes.