December 2, 2022 -- Researchers at Johns Hopkins Medicine have created a laboratory-grown 3D organoid model that is derived from human tissue to advance the understanding of how early stages of cancer develop at the gastroesophageal junction -- the point where the digestive system's food tube meets the stomach.
Although gastroesophageal cancers claim more than a million lives every year worldwide, including over 16,000 deaths in the U.S. in 2022, it has been difficult for experts to show how cancer begins at the junction of the stomach and the esophagus, in part due to a lack of biologically relevant GEJ-specific early disease models for research. Because there is no model that distinguishes GEJ tumors, gastroesophageal cancers are often classified as either esophageal cancer or gastric cancer, not GEJ cancer, according to the Johns Hopkins researchers.
In their study, published November 30 in the journal Science Translational Medicine, the research team -- which included experts in cell biology, epigenomics, lipid profiling, and big data analysis -- describe how they created the GEJ disease model by taking normal human biopsy tissue from patients receiving upper endoscopies.
Using CRISPR-Cas9 gene editing, the researchers then knocked out two key tumor suppressor genes (TP53 and CDKN2A) in the organoids. Dual knockout of these genes caused cells to become more cancerous, with more rapid growth and microscopic features closer to malignancy. These altered organoids also formed tumors in immunodeficient mice.
The team further found abnormalities in a class of lipids that store energy but also exert a variety of other functions, and they identified platelet activating factor as a key upregulated lipid in GEJ organoids. They used WEB2086 -- a compound approved by the U.S. Food and Drug Administration and used to treat platelet diseases -- which stopped the growth of implanted GEJ organoid tumors.
"Our model not only helps identify crucial changes happening during tumor growth at the GEJ, but also establishes a strategy for future studies to help understand tumors of other organs," corresponding author Dr. Stephen Meltzer, American Cancer Society clinical research professor and the Harry and Betty Myerberg/Thomas R. Hendrix professor of gastroenterology, said in a statement.
More preclinical studies may be needed before the compound can be used for human patients, but organoids may help advance these studies, Meltzer added.