Unraveling the mysteries of gastroesophageal junction development

The transition from the esophagus to the stomach is a delicate area from a medical point of view, which is often associated with pathological disorders leading to cancer. An international research team has now gained new insights into this region. These pave the way for new prevention and treatment options.

The area where the stomach and esophagus meet, the so-called gastro-esophageal junction, is an area of ​​the human body that has not adapted to the modern lifestyle. Stress, alcohol, nicotine and severe obesity often induce pathological changes to the mucosal membrane in this area, which often causes esophageal cancer.

An international research team has now gained new insights into the development of cells, their interactions with each other and their regulation at the junction of the esophagus and stomach. With the help of specially developed tiny organelles, called organoids, and techniques that enable tracking and profiling of individual cells, they were able to follow the development of the gastro-oesophageal junction in detail from embryo to adult. Using animal experiments.

New insights into the development of the gastrointestinal tract

Their results reveal complex communication at the cellular level and the specific pathways these cells use to communicate. They provide new insights into the development of the gastro-oesophageal junction and thus have significant implications for the understanding, prevention and treatment of gastrointestinal diseases. At the same time, they present new starting points for clinical research and the development of new therapies.

Cindrilla Sumthuri was responsible for the study, which is now published in the journal Nature Communications. Until recently, the infectious and cancer biologist was a research group leader in the Department of Microbiology at the Julius-Maximilians-Universität Würzburg (JMU); He is now Associate Professor at Aarhus University (Denmark). Other participants came from the Charité – Universitätsmedizin and the Max Planck Institute for Infectious Biology in Berlin.

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„This collaboration underscores the importance of diverse expertise to advance our understanding of the biology of the gastrointestinal tract,” says Sumthuri.

She has many years of experience in research with organoids. Among other things, he used the miniorgans he created to study how cells in the cervix degenerate and become cancerous—another area where different types of mucosal cells collide.

A place where different epithelia meet

The squamous epithelia of the esophagus and the columnar epithelia of the stomach meet at the gastroesophageal junction.”

Dr. Naveen Kumar Nirchal, one of the first authors of the study

This area is called a „hotspot for the development of metaplasia” – the replacement of one type of cell by another.

Barrett's esophagus, a precursor to esophageal cancer, often develops there, and its incidence has increased dramatically in Western countries over the past four decades. „Barrett's esophagus is characterized by the replacement of the resident squamous epithelium of the esophagus by other cell types not normally found in this tissue,” says the scientist.

However, it is not yet clear why this region is so susceptible to this process. To better understand this transition, it is first necessary to have a detailed understanding of the normal developmental process – from embryo to mature adult. „This is the only way to determine the tissue changes that drive disease progression,” explains Dr. Rajendra Kumar Gurumurthy, another researcher on the study.

An unprecedented view of the region's development

This has now been achieved: by using a novel approach that combines organoid and mouse models with advanced single-cell transcriptome analyzes in time and space, the research team shed light on the complex developmental process of the gastroesophageal junction. „We were able to provide unprecedented insight into the development of this region from embryonic stage to adulthood in mice and identify the complex composition of cells involved and how they develop,” explains Pon Kanish Prakash, another scientist involved in the study.

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This work shows the sophisticated communication between different cell types and the signaling pathways involved in the gastroesophageal junction. „This understanding opens up new avenues for research into gastrointestinal diseases,” says Cintrilla Sumthuri.

Above all, the precision of single-cell analysis in their study opens new doors to understanding how pathological processes develop and developing innovative treatments, the team writes in its study. This work will therefore be a „cornerstone for understanding the development of such diseases” and will significantly influence the approach to early detection and treatment of diseases in this important part of the digestive system.

Source:

Journal Note:

Kumar, N. and many others. (2024) Decoding spatiotemporal transcriptional dynamics and epithelial fibroblast crosstalk during gastroesophageal junction development by single-cell analysis. Natural communication. doi.org/10.1038/s41467-024-47173-z.

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