Dataset Information

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.

SUBMITTER: Steele NG

PROVIDER: S-EPMC6279812 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

An Organoid-Based Preclinical Model of Human Gastric Cancer.

Steele Nina G NG Chakrabarti Jayati J Wang Jiang J Biesiada Jacek J Holokai Loryn L Chang Julie J Nowacki Lauren M LM Hawkins Jennifer J Mahe Maxime M Sundaram Nambirajan N Shroyer Noah N Medvedovic Mario M Helmrath Michael M Ahmad Syed S Zavros Yana Y

Cellular and molecular gastroenterology and hepatology 20180920 1

<h4>Background & aims</h4>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.<h4>Methods</h4>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- ...[more]

PMID: 30522949

Similar Datasets

Project description:"Biomarker-driven targeted therapy," the practice of tailoring patients' treatment to the expression/activity levels of disease-specific genes/proteins, remains challenging. For example, while the anti-ERBB2 monoclonal antibody, trastuzumab, was first developed using well-characterized, diverse in vitro breast cancer models (and is now a standard adjuvant therapy for ERBB2-positive breast cancer patients), trastuzumab approval for ERBB2-positive gastric cancer was largely based on preclinical studies of a single cell line, NCI-N87. Ensuing clinical trials revealed only modest patient efficacy, and many ERBB2-positive gastric cancer (GC) patients failed to respond at all (i.e., were inherently recalcitrant), or succumbed to acquired resistance.To assess mechanisms underlying GC insensitivity to ERBB2 therapies, we established a diverse panel of GC cells, differing in ERBB2 expression levels, for comprehensive in vitro and in vivo characterization. For higher throughput assays of ERBB2 DNA and protein levels, we compared the concordance of various laboratory quantification methods, including those of in vitro and in vivo genetic anomalies (FISH and SISH) and xenograft protein expression (Western blot vs. IHC), of both cell and xenograft (tissue-sectioned) microarrays.The biomarker assessment methods strongly agreed, as did correlation between RNA and protein expression. However, although ERBB2 genomic anomalies showed good in vitro vs. in vivo correlation, we observed striking differences in protein expression between cultured cells and mouse xenografts (even within the same GC cell type). Via our unique pathway analysis, we delineated a signaling network, in addition to specific pathways/biological processes, emanating from the ERBB2 signaling cascade, as a potential useful target of clinical treatment. Integrated analysis of public data from gastric tumors revealed frequent (10 - 20 %) amplification of the genes NFKBIE, PTK2, and PIK3CA, each of which resides in an ERBB2-derived subpathway network.Our comprehensive bioinformatics analyses of highly heterogeneous cancer cells, combined with tumor "omics" profiles, can optimally characterize the expression patterns and activity of specific tumor biomarkers. Subsequent in vitro and in vivo validation, of specific disease biomarkers (using multiple methodologies), can improve prediction of patient stratification according to drug response or nonresponse.

Dataset Information

An Organoid-Based Preclinical Model of Human Gastric Cancer.

Publications

An Organoid-Based Preclinical Model of Human Gastric Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets