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Exploring liver cancer biology through functional genetic screens

Abstract

As the fourth leading cause of cancer-related death in the world, liver cancer poses a major threat to human health. Although a growing number of therapies have been approved for the treatment of hepatocellular carcinoma in the past few years, most of them only provide a limited survival benefit. Therefore, an urgent need exists to identify novel targetable vulnerabilities and powerful drug combinations for the treatment of liver cancer. The advent of functional genetic screening has contributed to the advancement of liver cancer biology, uncovering many novel genes involved in tumorigenesis and cancer progression in a high-throughput manner. In addition, this unbiased screening platform also provides an efficient tool for the exploration of the mechanisms involved in therapy resistance as well as identifying potential targets for therapy. In this Review, we describe how functional screens can help to deepen our understanding of liver cancer and guide the development of new therapeutic strategies.

Key points

  • Functional screens enable the unbiased and high-throughput interrogation of diverse processes in liver cancer.

  • Through in vivo and in vitro screens, many novel oncogenes and tumour suppressor genes have been elucidated, deepening our understanding of the tumorigenesis and progression of liver cancer.

  • Functional screens have been utilized to explore the mechanisms driving drug resistance and to identify promising drug combination strategies.

  • Findings from functional screens provide new insight into the potential therapeutic targets of liver cancer, with important translational implications.

  • Further opportunities exist to explore the aspects of tumour heterogeneity, metastasis and recurrence, and tumour–immune interactions by utilizing functional screens.

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Fig. 1: The experimental strategy and types of screening methods in functional genetic screens.
Fig. 2: Application of transposon systems in genetic screening.
Fig. 3: Schematic representation of in vitro or in vivo library screens in liver cancer.
Fig. 4: Future outlook of functional screens in the field of liver cancer research.

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Acknowledgements

The research of the authors was funded by grants from the European Research Council (ERC 787925 to R.B.), the National Key Sci-Tech Special Projects of Infectious Diseases of China (2018ZX10732202-002-003), the National Natural Science Foundation of China (81920108025, 8167110450, 81874229 and 8207100977), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20181703) and Shanghai Cancer Institute (ZZ2002YJ and ZZ2004YJ).

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Correspondence to Cun Wang, René Bernards or Wenxin Qin.

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Nature Reviews Gastroenterology & Hepatology thanks Carmen Chak-Lui Wong, Darjus Tschaharganeh and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Wang, C., Cao, Y., Yang, C. et al. Exploring liver cancer biology through functional genetic screens. Nat Rev Gastroenterol Hepatol 18, 690–704 (2021). https://doi.org/10.1038/s41575-021-00465-x

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