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

Shigeki Nakagawa 1, 2 Lan Wei 3 Won Min Song 1, 4 Takaaki Higashi 1, 2 Sarani Ghoshal 3 Rosa Kim 1 C. Billie Bian 1 Suguru Yamada 3 Xiaochen Sun 1 Anu Venkatesh 1 Nicolas Goossens 1, 5 Gretchen Bain 6 Gregory Lauwers 7 Anna Koh 1 Mohamed El-Abtah 1 Noor Ahmad 1 Hiroki Hoshida 1 Derek Erstad 3 Ganesh Gunasekaran 8 Youngmin Lee 1 Ming-Lung Yu 9, 10, 11 Wan-Long Chuang 9, 10 Chia-Yen Dai 9, 10 Masahiro Kobayashi 12 Hiromitsu Kumada 12 Toru Beppu 2 Hideo Baba 2 Milind Mahajan 4 Venugopalan Nair 13 Michael Lanuti 14 Augusto Villanueva 1 Angelo Sangiovanni 15 Massimo Iavarone 15 Massimo Colombo 15 Josep Llovet 16, 1 Aravind Subramanian 17 Andrew Tager 18 Scott Friedman 1 Thomas Baumert 19, 20, 21, * Myron Schwarz 8 Raymond Chung 21 Kenneth Tanabe 3 Bin Zhang 4 Bryan Fuchs 3 Yujin Hoshida 1, *
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.
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Shigeki Nakagawa, Lan Wei, Won Min Song, Takaaki Higashi, Sarani Ghoshal, et al.. Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition. Cancer Cell, Elsevier, 2016, 30 (6), pp.879-890. ⟨10.1016/j.ccell.2016.11.004⟩. ⟨inserm-02312659⟩

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