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29.08.2022 | Original Article

Heterogeneity, inherent and acquired drug resistance in patient-derived organoid models of primary liver cancer

verfasst von: Linfeng Xian, Pei Zhao, Xi Chen, Zhimin Wei, Hongxiang Ji, Jun Zhao, Wenbin Liu, Zishuai Li, Donghong Liu, Xue Han, Youwen Qian, Hui Dong, Xiong Zhou, Junyan Fan, Xiaoqiong Zhu, Jianhua Yin, Xiaojie Tan, Dongming Jiang, Hongping Yu, Guangwen Cao

Erschienen in: Cellular Oncology | Ausgabe 5/2022

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Abstract

Purpose

We aimed to elucidate the applicability of tumor organoids for inherent drug resistance of primary liver cancer (PLC) and mechanisms of acquired drug resistance.

Methods

PLC tissues were used to establish organoids, organoid-derived xenograft (ODX) and patient-derived xenograft (PDX) models. Acquired drug resistance was induced in hepatocellular carcinoma (HCC) organoids. Gene expression profiling was performed by RNA-sequencing.

Results

Fifty-two organoids were established from 153 PLC patients. Compared with establishing PDX models, establishing organoids of HCC showed a trend toward a higher success rate (29.0% vs. 23.7%) and took less time (13.0 ± 4.7 vs. 25.1 ± 5.4 days, p = 2.28 × 10⁻¹³). Larger tumors, vascular invasion, higher serum AFP levels, advanced stages and upregulation of stemness- and proliferation-related genes were significantly associated with the successful establishment of HCC organoids and PDX. Organoids and ODX recapitulated PLC histopathological features, but were enriched in more aggressive cell types. PLC organoids were mostly resistant to lenvatinib in vitro but sensitive to lenvatinib in ODX models. Stemness– and epithelial–mesenchymal transition (EMT)–related gene sets were found to be upregulated, whereas liver development– and liver specific molecule–related gene sets were downregulated in acquired sorafenib-resistant organoids. Targeting the mTOR signaling pathway was effective in treating acquired sorafenib-resistant HCC organoids, possibly via inducing phosphorylated S6 kinase. Genes upregulated in acquired sorafenib-resistant HCC organoids were associated with an unfavorable prognosis.

Conclusions

HCC organoids perform better than PDX for drug screening. Acquired sorafenib resistance in organoids promotes HCC aggressiveness via facilitating stemness, retro-differentiation and EMT. Phosphorylated S6 kinase may be predictive for drug resistance in HCC.

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Titel: Heterogeneity, inherent and acquired drug resistance in patient-derived organoid models of primary liver cancer
verfasst von: Linfeng Xian
Pei Zhao
Xi Chen
Zhimin Wei
Hongxiang Ji
Jun Zhao
Wenbin Liu
Zishuai Li
Donghong Liu
Xue Han
Youwen Qian
Hui Dong
Xiong Zhou
Junyan Fan
Xiaoqiong Zhu
Jianhua Yin
Xiaojie Tan
Dongming Jiang
Hongping Yu
Guangwen Cao
Publikationsdatum: 29.08.2022
Verlag: Springer Netherlands
Erschienen in: Cellular Oncology / Ausgabe 5/2022
Print ISSN: 2211-3428
Elektronische ISSN: 2211-3436
DOI: https://doi.org/10.1007/s13402-022-00707-3

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Heterogeneity, inherent and acquired drug resistance in patient-derived organoid models of primary liver cancer

Abstract

Purpose

Methods

Results

Conclusions

Neu im Fachgebiet Pathologie

Molekularpathologische Untersuchungen im Wandel der Zeit

Vergleichende Pathologie in der onkologischen Forschung

Gastrointestinale Stromatumoren

Personalisierte Medizin in der Onkologie

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusions

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