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 F. Baumert (19, 20, 21) , Myron Schwarz (8) , Raymond Chung (21) , Kenneth Tanabe (3) , Bin Zhang (4) , Bryan Fuchs (3) , Yujin Hoshida (1)

1 Department of Medicine [New York]
2 Department of Gastroenterological Surgery [Kumamoto, Japan]
3 Division of Surgical Oncology [Boston, MA, USA]
4 Department of Genetics and Genomic Sciences
5 Division of Gastroenterology and Hepatology [Geneva, Switzerland]
6 PharmAkea Therapeutics [San Diego, CA, USA]
7 Department of Pathology [Boston, MA, USA]
8 Recanati/Miller Transplantation Institute [New York, NY, USA]
9 Hepatobiliary Division - Department of Internal Medicine and Hepatitis Center [Kaohsiung, Taiwan]
10 Center for Infectious Disease and Cancer Research [Kaohsiung, Taiwan]
11 Institute of Biomedical Sciences [Kaohsiung, Taiwan]
12 Department of Hepatology [Tokyo, Japan]
13 Department of Neurology [New York, NY, USA]
14 Division of Thoracic Surgery [Boston, MA, USA]
15 1st Division of Gastroenterology - M. & A. Migliavacca Center for Liver Disease [Milan, Italy]
16 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
17 Cancer Program [Cambridge, MA, USA]
18 Pulmonary and Critical Care Unit [Boston, MA, USA]
19 IVH - Institut de Recherche sur les Maladies Virales et Hépatiques
20 Pôle hépato-digestif [Strasbourg]
21 Liver Center - Department of Medicine - Gastrointestinal Division [Boston, MA, USA]

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.

Mots clés: prognostic prediction; hepatocellular carcinoma; gene signature; cancer chemoprevention; transcriptome

Domaines: Médecine humaine et pathologie; Hépatologie et Gastroentérologie

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, 2016, 30 (6), pp.879-890. ⟨10.1016/j.ccell.2016.11.004⟩. ⟨inserm-02312659⟩