Johns Hopkins Medicine researchers claim to have created a three-dimensional, lab-grown ‘organoid’ model derived from human tissue and designed to advance understanding of how early stages of cancer develop at the gastroesophageal junction (GEJ) – the point where the food pipe of the digestive system meets the stomach.
A report on the results of the organoid model, published November 30 in Science Translational Medicinealso reveals a possible biological target for treating GEJ cancers with a drug that researchers have previously shown can slow or stop the growth of such tumors in mice.
According to the American Cancer Society, gastroesophageal cancers claim more than one million lives worldwide each year, with GEJ cancer rates more than doubling in recent decades, from 500,000 to 1 million new cases per year. Acid reflux, smoking, and Helicobacter pylori bacterial infection of the stomach are well-established risk factors for tumors of the esophagus and stomach. But experts say it has been difficult to show how cancer starts at the junction of the stomach and esophagus, in part due to a lack of biologically relevant GEJ-specific early disease models for research. .
Because we don’t have a single pattern that distinguishes GEJ tumors, gastroesophageal cancers are often classified as esophageal cancer or gastric cancer – not GEJ cancer. Our model not only helps identify crucial changes that occur during tumor growth at the GEJ, but also sets a strategy for future studies to help understand tumors in other organs.
Stephen Meltzer, MD, gastroenterologist, Harry and Betty Myerberg/Thomas R. Hendrix Professor of Clinical Research Medicine and American Cancer Society at Johns Hopkins University School of Medicine and study corresponding author
Meltzer and a team of experts in cell biology, epigenomics, lipid profiling and big data analysis created the GEJ disease model by collecting normal human biopsy tissue from patients receiving upper endoscopies. Organoids include three-dimensional collections of cells derived from stem cells that can replicate characteristics of an organ or what an organ does, such as making specific types of cells.
Using clustered regularly spaced palindromic repeats (CRISPR/Cas9) gene editing technology, the researchers then knocked out two key tumor suppressor genes (TP53 and CDKN2A) in the organoids. The double inactivation of these genes made the cells more cancerous, with faster growth and microscopic characteristics closer to malignancy. These altered organoids also formed tumors in immunocompromised mice.
The team further discovered abnormalities in a class of molecules (lipids) that store energy but also perform a variety of other functions, and identified platelet activating factor as a key up-regulated lipid in GEJ organoids. . Platelets circulate in the bloodstream and bind or coagulate when they recognize damaged blood vessels, and they can cause bleeding disorders in some people. The researchers used WEB2086, which stopped the growth of implanted GEJ organoid tumors. WEB2086, a compound approved by the Food and Drug Administration and used to treat platelet disease, inhibits platelet activating factor receptors in me.
Meltzer says more preclinical studies may be needed before using the compound for human patients, but the organoids can help move those studies forward.
“Combining organoids with this gene editing method [CRISPR/Cas9] is a potentially fruitful strategy for studying other human tumors in general,” says Meltzer.
Zhao, H. et al. (2022) Generation and Multiomic Profiling of a TP53/CDKN2A Double Knockout Gastroesophageal Junction Organoid Model. Science Translational Medicine. doi.org/10.1126/scitranslmed.abq6146.
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