Pharmaco-proteogenomic characterization of liver cancer organoids for precision oncology

被引：53

作者：

Ji, Shuyi ^{[1
,2
]}

Feng, Li ^{[3
]}

Fu, Zile ^{[2
]}

Wu, Gaohua ^{[2
]}

Wu, Yingcheng ^{[2
]}

Lin, Youpei ^{[2
]}

Lu, Dayun ^{[4
,5
]}

Song, Yuanli ^{[4
,5
]}

Cui, Peng ^{[6
]}

Yang, Zijian ^{[2
]}

Sang, Chen ^{[2
]}

Song, Guohe ^{[2
]}

Cai, Shangli ^{[6
]}

Li, Yuanchuang ^{[7
]}

Lin, Hanqing ^{[7
]}

Zhang, Shu ^{[2
]}

Wang, Xiaoying ^{[2
]}

Qiu, Shuangjian ^{[2
]}

Zhang, Xiaoming ^{[8
]}

Hua, Guoqiang ^{[9
,10
]}

Li, Junqiang ^{[7
]}

Zhou, Jian ^{[2
,11
]}

Dai, Zhi ^{[2
]}

Wang, Xiangdong ^{[12
]}

Ding, Li ^{[13
]}

Wang, Pei ^{[14
]}

Gao, Daming ^{[15
]}

Zhang, Bing ^{[16
]}

Rodriguez, Henry ^{[17
]}

Fan, Jia ^{[2
,9
,10
]}

Clevers, Hans ^{[18
,19
]}

Zhou, Hu ^{[2
,4
,5
,20
]}

Sun, Yidi ^{[3
]}

Gao, Qiang ^{[1
,2
,11
,21
]}

机构：

[1] Fudan Univ, Jinshan Hosp, Ctr Tumor Diag & Therapy, Shanghai 201508, Peoples R China

[2] Fudan Univ, Key Lab Carcinogenesis & Canc Invas, Dept Liver Surg & Transplantat, Liver Canc Inst,Zhongshan Hosp,Minist Educ, Shanghai 200032, Peoples R China

[3] Chinese Acad Sci, Inst Neurosci, CAS Ctr Excellence Brain Sci & Intelligence Techn, Shanghai 200031, Peoples R China

[4] Chinese Acad Sci, Dept Analyt Chem, Shanghai 201203, Peoples R China

[5] Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China

[6] Burning Rock Biotech, Shanghai 201114, Peoples R China

[7] D1 Med Technol, Shanghai 200235, Peoples R China

[8] Chinese Acad Sci, Inst Pasteur Shanghai, Key Lab Mol Virol & Immunol, Shanghai 200031, Peoples R China

[9] Fudan Univ, Shanghai Canc Ctr, Dept Radiat Oncol, Shanghai 200032, Peoples R China

[10] Fudan Univ, Shanghai Canc Ctr, Canc Inst, Shanghai 200032, Peoples R China

[11] Fudan Univ, Inst Biomed Sci, Key Lab Med Epigenet & Metab, Shanghai 200032, Peoples R China

[12] Fudan Univ, Zhongshan Hosp, Dept Pulm & Crit Care Med, Inst Clin Sci,Shanghai Med Coll, Shanghai 200032, Peoples R China

[13] Washington Univ, McDonnell Genome Inst, Siteman Canc Ctr, Dept Med, St Louis, MO 63108 USA

[14] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[15] Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, CAS Ctr Excellence Mol Cell Sci, State Key Lab Cell Biol, Shanghai 200031, Peoples R China

[16] Baylor Coll Med, Lester & Sue Smith Breast Ctr, Dept Mol & Human Genet, One Baylor Plaza, Houston, TX 77030 USA

[17] NCI, Off Canc Clin Prote Res, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA

[18] Hubrecht Inst, Oncode Inst, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands

[19] Univ Med Ctr Utrecht, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands

[20] Univ Ottawa, Shanghai Inst Mat Med, Joint Res Ctr Syst & Personalized Pharmacol, Shanghai 201203, Peoples R China

[21] Fudan Univ, Human Phenome Inst, State Key Lab Genet Engn, Shanghai 200433, Peoples R China

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2023年 / 15卷 / 706期

基金：

中国国家自然科学基金;

关键词：

HEPATOCELLULAR-CARCINOMA; SENSITIVITY; ACTIVATION; PATHWAY; HGF;

D O I：

10.1126/scitranslmed.adg3358

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Organoid models have the potential to recapitulate the biological and pharmacotypic features of parental tumors. Nevertheless, integrative pharmaco-proteogenomics analysis for drug response features and biomarker investigation for precision therapy of patients with liver cancer are still lacking. We established a patient-derived liver cancer organoid biobank (LICOB) that comprehensively represents the histological and molecular characteristics of various liver cancer types as determined by multiomics profiling, including genomic, epigenomic, transcriptomic, and proteomic analysis. Proteogenomic profiling of LICOB identified proliferative and metabolic organoid subtypes linked to patient prognosis. High-throughput drug screening revealed distinct response patterns of each subtype that were associated with specific multiomics signatures. Through integrative analyses of LICOB pharmaco-proteogenomics data, we identified the molecular features associated with drug responses and predicted potential drug combinations for personalized patient treatment. The synergistic inhibition effect of mTOR inhibitor temsirolimus and the multitargeted tyrosine kinase inhibitor lenvatinib was validated in organoids and patient-derived xenografts models. We also provide a user-friendly web portal to help serve the biomedical research community. Our study is a rich resource for investigation of liver cancer biology and pharmacological dependencies and may help enable functional precision medicine.

引用

页数：15

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