A hepatocyte differentiation model reveals two subtypes of liver cancer with different oncofetal properties and therapeutic targets

Liu，Ming1,2; Yan，Qian3; Sun，Yi4,5; Nam，Yoonhee6; Hu，Liang4,5; Loong，Jane H.C.7,8; Ouyang，Qi4,5; Zhang，Yu3; Li，Hao Long1,2; Kong，Fan En1,2; Li，Lei3; Li，Yan9,14; Li，Mei Mei1,2; Cheng，Wei1,2; Jiang，Ling Xi10; Fang，Shuo3; Yang，Xiao Dong3; Mo，Jia Qiang11; Gong，Yuan Feng1; Tang，Yun Qiang1; Li，Yan12,13,15,16; Yuan，Yun Fei12,13; Ma，Ning Fang1,2; Lin，Ge4,5; Ma，Stephanie7,8; Wang，Ji Guang6; Guan，Xin Yuan1,2,12,13

2020-03-17

10.1073/pnas.1912146117

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   影响因子和分区

0027-8424

1091-6490

Clinical observation of the association between cancer aggressiveness and embryonic development stage implies the importance of developmental signals in cancer initiation and therapeutic resistance. However, the dynamic gene expression during organogenesis and the master oncofetal drivers are still unclear, which impeded the efficient elimination of poor prognostic tumors, including human hepatocellular carcinoma (HCC). In this study, human embryonic stem cells were induced to differentiate into adult hepatocytes along hepatic lineages to mimic liver development in vitro. Combining transcriptomic data from liver cancer patients with the hepatocyte differentiation model, the active genes derived from different hepatic developmental stages and the tumor tissues were selected. Bioinformatic analysis followed by experimental assays was used to validate the tumor subtype-specific oncofetal signatures and potential therapeutic values. Hierarchical clustering analysis revealed the existence of two subtypes of liver cancer with different oncofetal properties. The gene signatures and their clinical significance were further validated in an independent clinical cohort and The Cancer Genome Atlas database. Upstream activator analysis and functional screening further identified E2F1 and SMAD3 as master transcriptional regulators. Small-molecule inhibitors specifically targeting the oncofetal drivers extensively down-regulated subtype-specific developmental signaling and inhibited tumorigenicity. Liver cancer cells and primary HCC tumors with different oncofetal properties also showed selective vulnerability to their specific inhibitors. Further precise targeting of the tumor initiating steps and driving events according to subtype-specific biomarkers might eliminate tumor progression and provide novel therapeutic strategy.

Cancer subtype Hepatocyte differentiation Liver development Oncofetal properties Oncogenic driver

SCI

英语

NI期刊

其他

Shenzhen Peacock Team Project[KQTD2015033117210153] ; Shenzhen Peacock Team Project[KQTD2018041118502879]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:000520011000073

NATL ACAD SCIENCES

BIOLOGY & BIOCHEMISTRY;CLINICAL MEDICINE;MULTIDISCIPLINARY;PLANT & ANIMAL SCIENCE;ENVIRONMENT/ECOLOGY;SOCIAL SCIENCES, GENERAL;MICROBIOLOGY;ECONOMICS BUSINESS;IMMUNOLOGY;MATERIALS SCIENCE;MATHEMATICS;SPACE SCIENCE;MOLECULAR BIOLOGY & GENETICS;PHARMACOLOGY & TOXICOLOGY;CHEMISTRY;PSYCHIATRY/PSYCHOLOGY;NEUROSCIENCE & BEHAVIOR;PHYSICS;GEOSCIENCES;AGRICULTURAL SCIENCES;ENGINEERING

2-s2.0-85081702329

Scopus

1.Affiliated Cancer Hospital Institute of Guangzhou Medical University,Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation,School of Basic Medical Sciences,Guangzhou Medical University,Guangzhou,510095,China
2.State Key Laboratory of Respiratory Disease,Guangzhou Medical University,Guangzhou,510120,China
3.Department of Clinical Oncology,Center for Cancer Research,State Key Laboratory for Liver Research,University of Hong Kong,852,Hong Kong
4.Institute of Reproductive and Stem Cell Engineering,School of Basic Medical Science,Central South University,Changsha,410000,China
5.Key Laboratory of Stem Cells and Reproductive Engineering,Ministry of Health,National Engineering and Research Center of Human Stem Cell,Central South University,Changsha,410000,China
6.Division of Life Science,Department of Chemical and Biological Engineering,Hong Kong University of Science and Technology,852,Hong Kong
7.School of Biomedical Sciences,Li Ka Shing Faculty of Medicine,University of Hong Kong,852,Hong Kong
8.State Key Laboratory of Liver Research,University of Hong Kong,852,Hong Kong
9.Department of Biology,Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research,Shenzhen Key Laboratory of Cell Microenvironment,Southern University of Science and Technology,Shenzhen,518055,China
10.Shanghai Key Laboratory of Gastric Neoplasms,Ruijin Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai,200000,China
11.Department of Hepatopancreatobiliary Surgery,Second Affiliated Hospital of Guangzhou University of Chinese Medicine,Guangzhou,510000,China
12.State Key Laboratory of Oncology in Southern China,Sun Yat-sen University Cancer Center,Guangzhou,510000,China
13.Collaborative Innovation Center for Cancer Medicine,Sun Yat-sen University Cancer Center,Guangzhou,510000,China
14.Department of Biology,Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research,Shenzhen Key Laboratory of Cell Microenvironment,Southern University of Science and Technology,Shenzhen,518055,China
15.State Key Laboratory of Oncology in Southern China,Sun Yat-sen University Cancer Center,Guangzhou,510000,China
16.Collaborative Innovation Center for Cancer Medicine,Sun Yat-sen University Cancer Center,Guangzhou,510000,China

Liu，Ming,Yan，Qian,Sun，Yi,et al. A hepatocyte differentiation model reveals two subtypes of liver cancer with different oncofetal properties and therapeutic targets[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2020,117(11):6103-6113.

Liu，Ming.,Yan，Qian.,Sun，Yi.,Nam，Yoonhee.,Hu，Liang.,...&Guan，Xin Yuan.(2020).A hepatocyte differentiation model reveals two subtypes of liver cancer with different oncofetal properties and therapeutic targets.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,117(11),6103-6113.

Liu，Ming,et al."A hepatocyte differentiation model reveals two subtypes of liver cancer with different oncofetal properties and therapeutic targets".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 117.11(2020):6103-6113.