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 Lee; Ming 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

doi:10.1016/j.ccell.2016.11.004

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

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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 language	English
Pages (from-to)	879-890
Number of pages	12
Journal	Cancer Cell
Volume	30
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2016.11.004
State	Published - 12 Dec 2016

Keywords

cancer chemoprevention
gene signature
hepatocellular carcinoma
prognostic prediction
transcriptome

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10.1016/j.ccell.2016.11.004

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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

@article{86f1db6050d6475dae06d39b509e6a75,

title = "Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition",

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.",

keywords = "cancer chemoprevention, gene signature, hepatocellular carcinoma, prognostic prediction, transcriptome",

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

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = dec,

day = "12",

doi = "10.1016/j.ccell.2016.11.004",

language = "English",

volume = "30",

pages = "879--890",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "6",

}

Nakagawa, S, Wei, L, Song, WM, Higashi, T, Ghoshal, S, Kim, RS, Bian, CB, Yamada, S, Sun, X, Venkatesh, A, Goossens, N, Bain, G, Lauwers, GY, Koh, AP, El-Abtah, M, Ahmad, NB, Hoshida, H, Erstad, DJ, Gunasekaran, G, Lee, Y, Yu, ML, Chuang, WL, Dai, CY, Kobayashi, M, Kumada, H, Beppu, T, Baba, H, Mahajan, M, Nair, VD, Lanuti, M, Villanueva, A, Sangiovanni, A, Iavarone, M, Colombo, M, Llovet, JM, Subramanian, A, Tager, AM, Friedman, SL, Baumert, TF, Schwarz, ME, Chung, RT, Tanabe, KK, Zhang, B, Fuchs, BC & Hoshida, Y 2016, 'Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition', Cancer Cell, vol. 30, no. 6, pp. 879-890. https://doi.org/10.1016/j.ccell.2016.11.004

TY - JOUR

T1 - Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition

AU - Nakagawa, Shigeki

AU - Wei, Lan

AU - Song, Won Min

AU - Higashi, Takaaki

AU - Ghoshal, Sarani

AU - Kim, Rosa S.

AU - Bian, C. Billie

AU - Yamada, Suguru

AU - Sun, Xiaochen

AU - Venkatesh, Anu

AU - Goossens, Nicolas

AU - Bain, Gretchen

AU - Lauwers, Gregory Y.

AU - Koh, Anna P.

AU - El-Abtah, Mohamed

AU - Ahmad, Noor B.

AU - Hoshida, Hiroki

AU - Erstad, Derek J.

AU - Gunasekaran, Ganesh

AU - Lee, Youngmin

AU - Yu, Ming Lung

AU - Chuang, Wan Long

AU - Dai, Chia Yen

AU - Kobayashi, Masahiro

AU - Kumada, Hiromitsu

AU - Beppu, Toru

AU - Baba, Hideo

AU - Mahajan, Milind

AU - Nair, Venugopalan D.

AU - Lanuti, Michael

AU - Villanueva, Augusto

AU - Sangiovanni, Angelo

AU - Iavarone, Massimo

AU - Colombo, Massimo

AU - Llovet, Josep M.

AU - Subramanian, Aravind

AU - Tager, Andrew M.

AU - Friedman, Scott L.

AU - Baumert, Thomas F.

AU - Schwarz, Myron E.

AU - Chung, Raymond T.

AU - Tanabe, Kenneth K.

AU - Zhang, Bin

AU - Fuchs, Bryan C.

AU - Hoshida, Yujin

PY - 2016/12/12

Y1 - 2016/12/12

N2 - 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.

AB - 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.

KW - cancer chemoprevention

KW - gene signature

KW - hepatocellular carcinoma

KW - prognostic prediction

KW - transcriptome

UR - http://www.scopus.com/inward/record.url?scp=85003904956&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2016.11.004

DO - 10.1016/j.ccell.2016.11.004

M3 - Article

C2 - 27960085

AN - SCOPUS:85003904956

SN - 1535-6108

VL - 30

SP - 879

EP - 890

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

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

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Keywords

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