Researchers at Johns Hopkins Medicine say they have created a lab-grown three-dimensional “organoid” model, derived from human tissue, that should improve understanding of how early-stage cancer develops at the gastroesophageal junction (GEJ) – the dot , where the alimentary tube of the digestive system meets the stomach.
A report on the results of the organoid model, published November 30 in Science Translational Medicinealso unveils a possible biological target for treating GEJ cancer 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 cancer claims more than a million lives worldwide each year, with rates of GEJ cancer more than doubling in recent decades, from 500,000 to 1 million new cases per year. Acid reflux, smoking, and gastric bacterial Helicobacter pylori infection are known risk factors for esophageal and gastric tumors. However, experts say it has been difficult to show how cancer begins at the junction of the stomach and esophagus, partly due to a lack of biologically relevant GEJ-specific early disease models for research.
“Because we don’t have a unique model that distinguishes GEJ tumors, gastroesophageal cancers are often classified as either esophageal cancer or gastric cancer — not GEJ cancer,” says gastroenterologist Stephen Meltzer, MD, of Harry and Betty Myerberg/Thomas R. Hendrix and American Cancer Society Clinical Research Professor of Medicine at Johns Hopkins University School of Medicine and corresponding author of the study. “Our model not only helps to identify crucial changes that occur during tumor growth at the GEJ, but also sets a strategy for future studies to help understand tumors of other organs.”
Meltzer and a team of experts in cell biology, epigenomics, lipid profiling and big data analysis created the GEJ disease model by taking normal human biopsy tissues from patients who underwent upper endoscopy. Organoids include three-dimensional assemblages of cells derived from stem cells that can replicate the properties of an organ or the function of an organ, e.g. B. the production of certain types of cells.
Using clustered regularly spaced palindromic repeats (CRISPR/Cas9), a gene editing technology, the researchers then knocked out two key tumor suppressor genes (TP53 and CDKN2A) in the organoids. Double knocking out these genes caused the cells to become more cancerous, with faster growth and microscopic features closer to malignancy. These altered organoids also formed tumors in immunocompromised mice.
The team also found 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 upregulated lipid in GEJ organoids. Platelets circulate in the bloodstream and bind or clump together when they detect damaged blood vessels, and they can cause clotting disorders in some people. Researchers used WEB2086, which stopped the growth of implanted organoid GEJ tumors. WEB2086, a compound approved by the Food and Drug Administration and used to treat platelet disease, inhibits platelet-activating factor receptors in mine.
Meltzer says more preclinical studies may be needed before using the compound for human patients, but that organoids can help advance such studies.
“The combination of organoids with this gene editing method [CRISPR/Cas9] is a potentially fruitful strategy to study other human tumors in general,” says Meltzer.
Other researchers who collaborated on this study are Hua Zhao, Yulan Cheng, Andrew Kalra, Ke Ma, Eun Ji Shin, Saowanee Ngamruengphong, Mouen Khashab, Vikesh Singh and Simran Jit from the Department of Gastroenterology and Hepatology, Department of Medicine, at The Johns School of Medicine at Hopkins University; Robert Anders from the Department of Pathology, Johns Hopkins University School of Medicine; Kristine Glunde and Nicolas Wyhs of the Sidney Kimmel Comprehensive Cancer Center in Johns Hopkins; Caitlin Tressler from the Johns Hopkins University School of Medicine Division of Cancer Imaging Research; Benjamin Ziman and Dechen Lin from the University of Southern California (USC); Wei Chen and Xu Li with Xi’an Jiaotong University First Affiliated Hospital; and Yueyuan Zheng at Cedars-Sinai Medical Center.
The authors declare no conflicts of interest in this study.
Supported by grants from the National Institutes of Health, the DeGregorio Family Foundation, the Emerson Collective Cancer Research Fund, and the Herman Ostrow School of Dentistry at the USC Center for Craniofacial Molecular Biology.