Gastric intestinal metaplasia (IM) is a pre-cancerous stage that can increase the risk of developing stomach cancer. A research team from the Centre for Oncology and Immunology (COI) and the University of Hong Kong (HKU) have found that IM involves significant cellular and molecular changes that contribute to this increased cancer risk. Their study, titled "Divergent lineage trajectories and genetic landscapes in human gastric intestinal metaplasia organoids associated with early neoplastic progression", was published in Gut and provides a detailed analysis of these changes, offering new insights into the early stages of gastric cancer progression and potential avenues for early detection and targeted treatment.
Background
Gastric cancer is a leading cause of cancer-related deaths globally, with high prevalence rates in East Asia, particularly in China. A critical precursor to this deadly disease is IM, a condition whereby normal stomach cells undergo a series of changes and transform into cells that are more intestinal-like. This transformation is significant because it substantially increases the risk of developing gastric cancer. Unfortunately, the mechanisms driving the progression from IM to gastric cancer remains poorly understood, primarily due to the limitations of traditional cell line models which fail to capture the full spectrum of cellular and genetic changes that occur in IM. Thus, there is an unmet need for advanced cell models that can accurately replicate the complexities of IM.
To address this issue, COI/HKU researchers leveraged organoid technology to create a biobank of gastric IM organoids. Organoids are three-dimensional, miniaturized versions of organs that can be grown in the lab from patient tumour and normal tissue. These organoids provide a more accurate representation of the cellular and molecular landscape of IM, allowing researchers to study the progression of IM to gastric cancer in greater detail. By closely mimicking the architecture and function of actual human tissues, organoids enable the study of disease mechanisms, drug testing, and personalized medicine approaches. They also capture the heterogeneity of patient tumours, including genetic and epigenetic variations, which are often missed in traditional cell line models. This makes organoids an invaluable tool for understanding disease progression, identifying early markers of neoplastic transformation, and developing targeted therapies.
Research Methods and Results
The COI/HKU research team established a large cohort of human gastric IM organoids, encompassing a total of 70 organoids—28 IM and 42 normal—derived from tissue samples of 47 gastric cancer patients These tissues exhibited varying degrees of IM, encapsulating the full spectrum of cellular states, from normal gastric cells to advanced IM cells. The organoids were subjected to comprehensive multi-omics profiling, including genomic, transcriptomic, and epigenetic analyses. The researchers also performed single-cell RNA sequencing (scRNAseq) to obtain a high-resolution view of the cellular composition and differentiation trajectories within the organoids, allowing them to track changes in gene expression at the single-cell level, thus providing a view of how individual cells evolve as they transition from normal to IM states.
The results revealed that IM organoids contained hybrid cells that exhibited characteristics of both gastric and intestinal cells. The IM cells also showed a high degree of lineage plasticity, meaning they can differentiate into various cell types beyond just gastric or intestinal cells. This plasticity was accompanied by a reactivation of a fetal gene program, which is a hallmark of early cancer development and indicates a reversion to a more primitive, stem-like state. The study also identified specific genetic and epigenetic changes in IM cells, including frequent gains in chromosome 20. These changes are crucial as they provide insights into the genetic landscape that predisposes IM cells to become cancerous. The presence of these genetic alterations, along with the observed cellular plasticity, highlights the neoplastic potential of IM cells, even before they acquire additional mutations commonly seen in cancer. Moreover, the researchers demonstrated that IM cells can grow independently of certain growth factors, such as FGF10, and can survive without adhering to a matrix, a characteristic known as cell-matrix adhesion independence (CMi). This ability to grow without the usual support structures is a significant step towards understanding how cancer cells proliferate and spread to other tissues.
Impact of the Study
This study significantly advances the current understanding of gastric IM and its role in the progression to gastric cancer. By identifying early cellular changes and specific genetic markers, the research provides a valuable resource as well as crucial insights that could lead to earlier detection and targeted treatments. Dr Helen Yan explains, “Using organoid technology, we were able to successfully model gastric intestinal metaplasia, which offers a powerful tool for cancer research. Our study provides a unique look into the early cellular changes that occur as stomach cells transform into pre-cancerous cells. The markers we identified in these pre-cancerous cells could eventually help clinicians pinpoint which patients are at highest risk for developing gastric cancer, allowing for earlier and more targeted interventions. This could be a game-changer in how we understand and eventually prevent gastric cancer in the future.” Overall, this research represents a step forward in the fight against gastric cancer, with the potential to improve patient outcomes through better prevention, diagnosis, and treatment strategies.
About the authors
The research was led by Dr Helen Yan and Prof Suet Yi Leung. Dr Helen Yan is a principal investigator at COI and an Assistant Professor in the Department of Pathology at the Li Ka Shing Faculty of Medicine, HKU. Prof Suet Yi Leung is Co-director of COI, Chairperson of the Department of Pathology at the Li Ka Shing Faculty of Medicine, HKU, Chair Professor of Gastrointestinal Cancer Genetics and Genomics (HKU), and Director of the Centre for PanorOmic Sciences (HKU). The first authors are Dr Sarah Yue, a former PhD student and Dr Yin Tong, a post-doctoral fellow, in Dr Helen Yan and Prof Suet Yi Leung’s lab.