Scientists grow new organoid model for studying human gastroesophageal cancer

Inactivation of the tumor suppressor genes tumor protein p53 (TP53) and cell cycle protein-dependent kinase inhibitor 2A (CDKN2A) usually occurs early in the tumorigenesis of the gastroesophageal junction (GEJ) site. However, the pro-carcinogenic outcome of TP53 and CDKN2A inactivation at the GEJ site has not been elucidated due to the lack of a GEJ-specific disease model for current researchers.

In a recent study published in the international journal Science Translational Medicine, entitled "Generation and multiomic profiling of a TP53/CDKN2A double-knockout gastroesophageal junction organoid model," scientists from the University of Southern California and other institutes have developed a laboratory-grown, 3D organoid model using human tissue that may be used to gain insight into the early stages of cancer development and its processes at GEJ.

In this study, researchers have proposed a possible biomarker for the treatment of GEJ cancer and have demonstrated that the drug slows or blocks the growth of tumors in the mouse organism. According to the American Cancer Society, gastroesophageal cancer causes more than 1 million deaths worldwide each year, and its incidence has more than tripled in the past 10 years, from 500,000 to 1 million cases per year, with acid reflux, smoking, and H. pylori infection all identified as risk factors for esophageal and gastric cancers.

Researchers believed that it has been difficult for studies to elucidate exactly how cancer begins to appear at the junction of the stomach and esophagus, in part because of the lack of biologically relevant GEJ-specific early disease models for research.

"Because we lack a specific model that distinguishes GEJ tumors, gastroesophageal cancers are frequently classified as esophageal or gastric cancers rather than GEJ cancers," said Stephen Meltzer, M.D. "The model we developed in this study will not only help identify key changes that occur during tumor growth at the GEJ locus, but will also establish a strategy to help further research to better understand how tumors occur in other organs."

The researchers developed the novel GEJ disease model using normal biopsy tissue from the bodies of patients who underwent upper endoscopy. The organoid consists of 3D collections of cells derived from stem cells that replicate the characteristics of an organ or the functions of that organ, such as making specific types of cells. Using CRISPR/Cas9 technology, the researchers knocked out two key tumor suppressor genes called TP53 and CDKN2A in the organoid. Double knockdown of these genes resulted in cells that were more oncogenic and could grow rapidly and more closely resemble malignant tumors under the microscope, and these altered organoids were able to form tumors in the immunodeficient mouse organism.

Upon further study, the researchers identified a class of lipid molecules that may have some abnormalities, which store energy and perform a variety of other functions. The researchers also identified platelet-activating factor as a key upregulated lipid in GEJ organoids. Platelets circulate in the bloodstream and bind together or form clots when they recognize a damaged blood vessel, and can also cause clotting disorders in certain populations. The researchers used an FDA-approved drug called WEB2086, which blocks the growth of implanted tumors in GEJ organoids, a compound previously used to treat platelet disorders that inhibits the function of the body's platelet-activating factor receptor.

More preclinical research will be required before this compound can be utilized in patients, but this class of organoids may significantly improve the existing process of such investigations.

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