Multi-omics data integration reveals novel drug targets in hepatocellular carcinoma

Christos Dimitrakopoulos; Sravanth Kumar Hindupur; Marco Colombi; Dritan Liko; Charlotte K Y Ng; Salvatore Piscuoglio; Jonas Behr; Ariane L Moore; Jochen Singer; Hans-Joachim Ruscheweyh; Matthias S Matter; Dirk Mossmann; Luigi M Terracciano; Michael N Hall; Niko Beerenwinkel

doi:10.1186/s12864-021-07876-9

Multi-omics data integration reveals novel drug targets in hepatocellular carcinoma

BMC Genomics. 2021 Aug 4;22(1):592. doi: 10.1186/s12864-021-07876-9.

Authors

Christos Dimitrakopoulos^#^{1

2

3}, Sravanth Kumar Hindupur^#^{4

5}, Marco Colombi⁴, Dritan Liko⁴, Charlotte K Y Ng^{6

7}, Salvatore Piscuoglio^{6

8

9}, Jonas Behr^{1

2}, Ariane L Moore^{1

2}, Jochen Singer^{1

2}, Hans-Joachim Ruscheweyh^{1

2}, Matthias S Matter⁶, Dirk Mossmann⁴, Luigi M Terracciano⁶, Michael N Hall¹⁰, Niko Beerenwinkel^{11

12}

Affiliations

¹ Department of Biosystems Science and Engineering, ETH Zürich, 4058, Basel, Switzerland.
² Swiss Institute of Bioinformatics, Basel, Switzerland.
³ Present address: Roche, PTD Biologics Europe, 4070, Basel, Switzerland.
⁴ Biozentrum, University of Basel, 4056, Basel, Switzerland.
⁵ Present address: Novartis Institutes for BioMedical Research, Disease Area Oncology, 4002, Basel, Switzerland.
⁶ Institute of Pathology, University Hospital Basel, 4031, Basel, Switzerland.
⁷ Department of BioMedical Research, University of Bern, 3008, Bern, Switzerland.
⁸ Department of Biomedicine, Visceral Surgery Research Laboratory, Clarunis, Basel, Switzerland.
⁹ Clarunis Universitäres Bauchzentrum Basel, Basel, Switzerland.
¹⁰ Biozentrum, University of Basel, 4056, Basel, Switzerland. m.hall@unibas.ch.
¹¹ Department of Biosystems Science and Engineering, ETH Zürich, 4058, Basel, Switzerland. beerenwinkel@bsse.ethz.ch.
¹² Swiss Institute of Bioinformatics, Basel, Switzerland. beerenwinkel@bsse.ethz.ch.

^# Contributed equally.

Abstract

Background: Genetic aberrations in hepatocellular carcinoma (HCC) are well known, but the functional consequences of such aberrations remain poorly understood.

Results: Here, we explored the effect of defined genetic changes on the transcriptome, proteome and phosphoproteome in twelve tumors from an mTOR-driven hepatocellular carcinoma mouse model. Using Network-based Integration of multi-omiCS data (NetICS), we detected 74 'mediators' that relay via molecular interactions the effects of genetic and miRNA expression changes. The detected mediators account for the effects of oncogenic mTOR signaling on the transcriptome, proteome and phosphoproteome. We confirmed the dysregulation of the mediators YAP1, GRB2, SIRT1, HDAC4 and LIS1 in human HCC.

Conclusions: This study suggests that targeting pathways such as YAP1 or GRB2 signaling and pathways regulating global histone acetylation could be beneficial in treating HCC with hyperactive mTOR signaling.

Keywords: HCC; NetICS; Omics; mTOR signaling.

MeSH terms

Carcinoma, Hepatocellular* / drug therapy
Carcinoma, Hepatocellular* / genetics
Humans
Liver Neoplasms* / drug therapy
Liver Neoplasms* / genetics
MicroRNAs*
Pharmaceutical Preparations*
Transcriptome

Substances

MicroRNAs
Pharmaceutical Preparations

Abstract

MeSH terms

Substances

Grants and funding