Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition

Shigeki Nakagawa, Lan Wei, Won Min Song, Takaaki Higashi, Sarani Ghoshal, Rosa S. Kim, C. Billie Bian, Suguru Yamada, Xiaochen Sun, Anu Venkatesh, Nicolas Goossens, Gretchen Bain, Gregory Y. Lauwers, Anna P. Koh, Mohamed El-Abtah, Noor B. Ahmad, Hiroki Hoshida, Derek J. Erstad, Ganesh Gunasekaran, Youngmin LeeMing Lung Yu, Wan Long Chuang, Chia Yen Dai, Masahiro Kobayashi, Hiromitsu Kumada, Toru Beppu, Hideo Baba, Milind Mahajan, Venugopalan D. Nair, Michael Lanuti, Augusto Villanueva, Angelo Sangiovanni, Massimo Iavarone, Massimo Colombo, Josep M. Llovet, Aravind Subramanian, Andrew M. Tager, Scott L. Friedman, Thomas F. Baumert, Myron E. Schwarz, Raymond T. Chung, Kenneth K. Tanabe, Bin Zhang, Bryan C. Fuchs, Yujin Hoshida

Research output: Contribution to journalArticle

70 Scopus citations

Abstract

Cirrhosis is a milieu that develops hepatocellular carcinoma (HCC), the second most lethal cancer worldwide. HCC prediction and prevention in cirrhosis are key unmet medical needs. Here we have established an HCC risk gene signature applicable to all major HCC etiologies: hepatitis B/C, alcohol, and non-alcoholic steatohepatitis. A transcriptome meta-analysis of >500 human cirrhotics revealed global regulatory gene modules driving HCC risk and the lysophosphatidic acid pathway as a central chemoprevention target. Pharmacological inhibition of the pathway in vivo reduced tumors and reversed the gene signature, which was verified in organotypic ex vivo culture of patient-derived fibrotic liver tissues. These results demonstrate the utility of clinical organ transcriptome to enable a strategy, namely, reverse-engineering precision cancer prevention.

Original languageEnglish (US)
Pages (from-to)879-890
Number of pages12
JournalCancer Cell
Volume30
Issue number6
DOIs
StatePublished - Dec 12 2016

Keywords

  • cancer chemoprevention
  • gene signature
  • hepatocellular carcinoma
  • prognostic prediction
  • transcriptome

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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  • Cite this

    Nakagawa, S., Wei, L., Song, W. M., Higashi, T., Ghoshal, S., Kim, R. S., Bian, C. B., Yamada, S., Sun, X., Venkatesh, A., Goossens, N., Bain, G., Lauwers, G. Y., Koh, A. P., El-Abtah, M., Ahmad, N. B., Hoshida, H., Erstad, D. J., Gunasekaran, G., ... Hoshida, Y. (2016). Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition. Cancer Cell, 30(6), 879-890. https://doi.org/10.1016/j.ccell.2016.11.004