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Establishment of Primary Liver Cancer Organoids and Application on Sorafenib Resistance

ABSTRACT: Current in vitro models of primary liver cancer fail to recapitulate the key characteristics of original cancer. We construct the long-term organoids culture from tumor tissue of primary liver cancer (PLC) patients with varieties of subtypes. PLC organoids retain the histopathological features of originating tumor. Organoids transplantation proved that the tumorogenic potential and histological characteristics of PLC organoids are well preserved in vivo. PLC organoids are amenable for preclinical drug screening test and identification of mammalian target of rapamycin (mTOR) inhibitor compound as a potential therapeutic treatment for PLC. Besides, we also establish sorafenib-resistant hepatocellular carcinoma (HCC) organoids to clarify the mechanisms that drive resistance. In conclusion, PLC organoids models provide a platform for drug development for PLC and theoretical basis for HCC resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE182593 | GEO | 2023/02/22

REPOSITORIES: GEO

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Project description:Hepatocellular carcinoma (HCC) is the second prominent cause of cancer-associated death worldwide. Usually, HCC is diagnosed in advanced stages, where sorafenib, a multiple target ty-rosine kinase inhibitor, is used as the first line of treatment. Unfortunately, resistance to sorafenib is usually encountered within six months of the treatment. Therefore, there is a critical need to identify the underlying reasons for drug resistance. In the present study, we investigated the proteomic and metabolomics alterations accompanying to sorafenib resistance in hepatocellular carcinoma Hep3B cells by employing ultra-high-performance liquid chromatography quadrupole time of flight mass spectrometry (UHPLC-QTOF-MS). The Bruker Human Metabolome Database (HMDB) library was used to identify the differentially abundant metabolites through MetaboScape 4.0 software (Bruker). For protein annotation and identification, the Uniprot proteome for Homo sapiens (Human) da-tabase was utilised through MaxQuant. The results revealed that 27 metabolites and 18 proteins were significantly dysregulated due to sorafenib resistance in Hep3B cells compared to the parental phenotype. D-alanine, L-proline, o-tyrosine, succinic acid and phosphatidylcholine (PC, 16:0/16:0) were among the significantly altered metabolites. Ubiquitin carboxyl-terminal hydrolase isozyme L1, mitochondrial superoxide dismutase, UDP-glucose-6-dehydrogenase, sorbitol dehydrogenase and calpain small subunit 1 were among the significantly altered proteins. The findings revealed that resistant Hep3B cells demonstrated significant alterations in amino acid and nucleotide met-abolic pathways, energy production pathways and other pathways related to cancer aggressive-ness, migration, proliferation, and drug-resistance. Joint pathway enrichment analysis unveiled unique pathways, including the antifolate resistance pathway and other important pathways that maintain cancer cells' survival, growth, and proliferation. Collectively, the results identified po-tential biomarkers for sorafenib-resistant HCC and gave insights into their role in chemotherapeutic drug resistance, cancer initiation, progression, and aggressiveness, which may contribute to better prognosis and chemotherapeutic outcomes.

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Establishment of Primary Liver Cancer Organoids and Application on Sorafenib Resistance

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