An Organoid-Based Preclinical Model of Human Gastric Cancer.

Abstract

BACKGROUND & AIMS:

Our goal was to develop an initial study for the proof of concept whereby gastric cancer organoids are used as an approach to predict the tumor response in individual patients.

METHODS:

Organoids were derived from resected gastric cancer tumors (huTGOs) or normal stomach tissue collected from sleeve gastrectomies (huFGOs). Organoid cultures were treated with standard-of-care chemotherapeutic drugs corresponding to patient treatment: epirubicin, oxaliplatin, and 5-fluorouracil. Organoid response to chemotherapeutic treatment was correlated with the tumor response in each patient from whom the huTGOs were derived. HuTGOs were orthotopically transplanted into the gastric mucosa of NOD scid gamma mice.

RESULTS:

Whereas huFGOs exhibited a half maximal inhibitory concentration that was similar among organoid lines, divergent responses and varying half maximal inhibitory concentration values among the huTGO lines were observed in response to chemotherapeutic drugs. HuTGOs that were sensitive to treatment were derived from a patient with a near complete tumor response to chemotherapy. However, organoids resistant to treatment were derived from patients who exhibited no response to chemotherapy. Orthotropic transplantation of organoids resulted in the engraftment and development of human adenocarcinoma. RNA sequencing revealed that huTGOs closely resembled the patient's native tumor tissue and not commonly used gastric cancer cell lines and cell lines derived from the organoid cultures.

CONCLUSIONS:

The treatment of patient-derived organoids alongside patients from whom cultures were derived will ultimately test their usefulness to predict individual therapy response and patient outcome.

• Authors: Nina G Steele, Jayati Chakrabarti, Jiang Wang, Jacek Biesiada, Loryn Holokai, Julie Chang, Lauren M Nowacki, Jennifer Hawkins, Maxime Mahe, Nambirajan Sundaram, Noah Shroyer, Mario Medvedovic, Michael Helmrath, Syed Ahmad, Yana Zavros
• Journal: Cellular and molecular gastroenterology and hepatology (Cell Mol Gastroenterol Hepatol) Vol. 7 Issue 1 Pg. 161-184 ( 2019) ISSN: 2352-345X [Electronic] United States
• PMID: 30522949 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Oxaliplatin
• Epirubicin
• ERBB2 protein, human
• Receptor, ErbB-2
• Fluorouracil

Topics

• Adenocarcinoma (drug therapy, pathology)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Proliferation (drug effects)
• Epirubicin (pharmacology, therapeutic use)
• Epithelium (drug effects, pathology)
• Fluorouracil (pharmacology, therapeutic use)
• Gene Ontology
• Humans
• Inhibitory Concentration 50
• Mice
• Organoids (drug effects, pathology)
• Oxaliplatin (pharmacology, therapeutic use)
• Phenotype
• Receptor, ErbB-2 (metabolism)
• Reproducibility of Results
• Sequence Analysis, RNA
• Stomach Neoplasms (drug therapy, pathology)
• Xenograft Model Antitumor Assays