Establishment of Patient-derived Organoids and a Characterization Based Drug Discovery Platform for Treatment of Gastric Cancer

Overview

Journal Cancer Cell Int

Publisher Biomed Central

Date 2024 Aug 14

PMID 39143546

Authors

Guo Chen

Ruidong Han

Li Wang

Wen Ma

Wenli Zhang

Zifan Lu

Lei Wang

Affiliations

Soon will be listed here.

Abstract

Background: Gastric cancer (GC) encompasses many different histological and molecular subtypes. It is a major driver of cancer mortality because of poor survival and limited treatment options. Personalised medicine in the form of patient-derived organoids (PDOs) represents a promising approach for improving therapeutic outcomes. The goal of this study was to overcome the limitations of current models by ameliorating organoid cultivation.

Methods: Organoids derived from cancer tissue were evaluated by haematoxylin and eosin staining, immunohistochemistry, mRNA, and whole-exome sequencing. Three representative chemotherapy drugs, 5-fluorouracil, docetaxel, and oxaliplatin, were compared for their efficacy against different subtypes of gastric organoids by ATP assay and apoptosis staining. In addition, drug sensitivity screening results from two publicly available databases, the Genomics of Drug Sensitivity in Cancer and Cancer Cell Line Encyclopaedia, were pooled and applied to organoid lines. Once key targeting genes were confirmed, chemotherapy was used in combination with poly (ADP ribose) polymerase (PARP)-targeted therapy.

Results: We successfully constructed GC PDOs surgically resected from GC patient tissue. PDOs closely reflected the histopathological and genomic features of the corresponding primary tumours. Whole-exosome sequencing and mRNA analysis revealed that changes to the original tumour genome were maintained during long-term culture. The drugs caused divergent responses in intestinal, poorly differentiated intestinal, and diffuse gastric cancer organoids, which were confirmed in organoid lines. Poorly differentiated intestinal GC patients benefited from a combination of 5-fluorouracil and veliparib.

Conclusion: The present study demonstrates that combining chemotherapy with PARP targeting may improve the treatment of chemotherapy-resistant tumours.

References

Steele N, Chakrabarti J, Wang J, Biesiada J, Holokai L, Chang J . An Organoid-Based Preclinical Model of Human Gastric Cancer. Cell Mol Gastroenterol Hepatol. 2018; 7(1):161-184. PMC: 6279812. DOI: 10.1016/j.jcmgh.2018.09.008. View

Harley V, Lefebvre V . Twenty Sox, twenty years. Int J Biochem Cell Biol. 2009; 42(3):376-7. DOI: 10.1016/j.biocel.2009.12.004. View

Clevers H . Modeling Development and Disease with Organoids. Cell. 2016; 165(7):1586-1597. DOI: 10.1016/j.cell.2016.05.082. View

LAUREN P . THE TWO HISTOLOGICAL MAIN TYPES OF GASTRIC CARCINOMA: DIFFUSE AND SO-CALLED INTESTINAL-TYPE CARCINOMA. AN ATTEMPT AT A HISTO-CLINICAL CLASSIFICATION. Acta Pathol Microbiol Scand. 1965; 64:31-49. DOI: 10.1111/apm.1965.64.1.31. View

Yao Y, Xu X, Yang L, Zhu J, Wan J, Shen L . Patient-Derived Organoids Predict Chemoradiation Responses of Locally Advanced Rectal Cancer. Cell Stem Cell. 2019; 26(1):17-26.e6. DOI: 10.1016/j.stem.2019.10.010. View

Weeber F, Ooft S, Dijkstra K, Voest E . Tumor Organoids as a Pre-clinical Cancer Model for Drug Discovery. Cell Chem Biol. 2017; 24(9):1092-1100. DOI: 10.1016/j.chembiol.2017.06.012. View

Pasch C, Favreau P, Yueh A, Babiarz C, Gillette A, Sharick J . Patient-Derived Cancer Organoid Cultures to Predict Sensitivity to Chemotherapy and Radiation. Clin Cancer Res. 2019; 25(17):5376-5387. PMC: 6726566. DOI: 10.1158/1078-0432.CCR-18-3590. View

. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014; 513(7517):202-9. PMC: 4170219. DOI: 10.1038/nature13480. View

Wagner A, Syn N, Moehler M, Grothe W, Yong W, Tai B . Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev. 2017; 8:CD004064. PMC: 6483552. DOI: 10.1002/14651858.CD004064.pub4. View

10.

Kopper O, de Witte C, Lohmussaar K, Espejo Valle-Inclan J, Hami N, Kester L . An organoid platform for ovarian cancer captures intra- and interpatient heterogeneity. Nat Med. 2019; 25(5):838-849. DOI: 10.1038/s41591-019-0422-6. View

11.

Yang R, Yu Y . Patient-derived organoids in translational oncology and drug screening. Cancer Lett. 2023; 562:216180. DOI: 10.1016/j.canlet.2023.216180. View

12.

Sahlberg S, Spiegelberg D, Glimelius B, Stenerlow B, Nestor M . Evaluation of cancer stem cell markers CD133, CD44, CD24: association with AKT isoforms and radiation resistance in colon cancer cells. PLoS One. 2014; 9(4):e94621. PMC: 3997403. DOI: 10.1371/journal.pone.0094621. View

13.

Zhao Z, Chen X, Dowbaj A, Sljukic A, Bratlie K, Lin L . Organoids. Nat Rev Methods Primers. 2023; 2. PMC: 10270325. DOI: 10.1038/s43586-022-00174-y. View

14.

Takahashi T, Saikawa Y, Kitagawa Y . Gastric cancer: current status of diagnosis and treatment. Cancers (Basel). 2013; 5(1):48-63. PMC: 3730304. DOI: 10.3390/cancers5010048. View

15.

Reis R . 2nd Consensus conference on definitions on biomaterials science. J Tissue Eng Regen Med. 2020; 14(4):561-562. DOI: 10.1002/term.3016. View

16.

Talhaoui I, Lebedeva N, Zarkovic G, Saint-Pierre C, Kutuzov M, Sukhanova M . Poly(ADP-ribose) polymerases covalently modify strand break termini in DNA fragments in vitro. Nucleic Acids Res. 2016; 44(19):9279-9295. PMC: 5100588. DOI: 10.1093/nar/gkw675. View

17.

Al Shihabi A, Davarifar A, Nguyen H, Tavanaie N, Nelson S, Yanagawa J . Personalized chordoma organoids for drug discovery studies. Sci Adv. 2022; 8(7):eabl3674. PMC: 8849332. DOI: 10.1126/sciadv.abl3674. View

18.

Hunt R, Camilleri M, Crowe S, El-Omar E, Fox J, Kuipers E . The stomach in health and disease. Gut. 2015; 64(10):1650-68. PMC: 4835810. DOI: 10.1136/gutjnl-2014-307595. View

19.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

20.

Wang J, Qin D, Tao Z, Wang B, Xie Y, Wang Y . Identification of cuproptosis-related subtypes, construction of a prognosis model, and tumor microenvironment landscape in gastric cancer. Front Immunol. 2022; 13:1056932. PMC: 9719959. DOI: 10.3389/fimmu.2022.1056932. View