The goal of the laboratory is to unravel the biological mechanisms leading to primary liver and biliary tract cancers and thus, understand the molecular pathogenesis. Our ambition is to translate solutions to the clinic for improved patient outcome.
We focus mainly on omics-driven solutions to unravel perturbed mechanisms required for the tumor to develop, to grow and to metastasize. Primary liver cancers (PLC) often evade diagnosis until late-stage in the disease where the tumor is locally advanced or metastatic. We utilize genome-wide approaches in patient characterization and stratification, diagnostic and prognostic biomarkers to facilitate precision therapy.
Lewinska M et al. EBioMedicine, 2021. The altered serum lipidome and its diagnostic potential for Non-Alcoholic Fatty Liver (NAFL)-associated hepatocellular carcinoma.
Non-alcoholic fatty liver disease (NAFLD) is a group of metabolic disorders that can progress to hepatocellular carcinoma (HCC) often without a background of cirrhosis. NAFLD is known to affect 24% of the global population. Liver cancers, developing in the background of NAFLD is on the rise. In this study, we show:
- The first comprehensive serum lipidomics investigating a broad-range of lipid classes in NAFLD and NAFLD-HCC
- Evidence of lipidomics in detection of NAFLD-HCC. We have developed a NAFLD-HCC Diagnostic Score (NHDS) as a putative screening tool for HCC development in a metabolic liver background
- How fatty acid (FA) uptake is increased in NAFLD-HCC tumors, which result in FA depletion in the blood circulation of NAFLD-HCC patients
2. Integrative molecular characterization of gallbladder cancer (GBC) reveals microenvironment-associated subtypes
Nepal, Zhu & O’Rourke et al. Journal of Hepatology, 2020. Integrative molecular characterization of gallbladder cancer (GBC) reveals microenvironment-associated subtypes
Gallbladder cancer is highly fatal, and its causes are poorly understood.
- We found evidence of aflatoxin exposure in GBC based on an aflatoxin-related genetic signature. Aflatoxins are a family of toxins produced by certain fungi that grow on agricultural crops such as corn and peanuts. Out of 92 patients with GBC, 39 (42%) had the aflatoxin-related signature, and these mutations tended to be clonal present in more than 50% of the cancer cells, suggesting that aflatoxin exposure resulted in early molecular changes.
- Immune cells surrounding the tumors (tumor microenvironment) were associated with survival
3. BTC: Serum IL-6 as a prognostic biomarker and therapeutic target.
Hogdall et al. Clinical Cancer Research, 2020. Serum IL-6 as a prognostic biomarker and IL-6R as a therapeutic target in biliary tract cancers
Biliary tract cancer (BTC) patients typically survive less than one year on standard-of-care chemotherapy. Adapting prognostic biomarkers to guide BTC patient management remains challenging. In this study, we measured serum IL-6, YKL-40, and CA19-9 before and during chemotherapy in 452 advanced BTC patients.
- While all markers provided variable prognostic information prior to treatment, longitudinal analysis of IL-6 was superior in predicting death during treatment.
- Blocking IL-6 (IL-6 receptor) signalling with tocilizumab significantly increased response to gemcitabine in a mouse model of human BTC.
- Thus, the IL-6 axis may be prognostically informative and therapeutically attractive in this rare patient demographic.
5. Theranostic response signature defining NOTCH-driven cholangiocarcinoma.
O’Rourke et al. Hepatology, 2019. Identification of a pan-gamma-secretase inhibitor response signature for notch-driven cholangiocarcinoma.
6. Novel integrative genomic strategy to stratify intrahepatic cholangiocarcinoma patients.
Nepal et al. Hepatology, 2017. Genomic perturbations reveal distinct regulatory networks in intrahepatic cholangiocarcinoma.
Technology in our laboratory spans broadly genomic and epigenomic characterization, functional high-throughput screens to elucidate disease-relevant genes and drug resistant mechanisms as well as disease-modelling in primary cultures and mice over diagnostic or metabolic rearrangement in the early onset of liver disease.
Inflammatory niche controlled by IL6 promotes liver cancers. As cancer therapies advance, the duration and diversity of treatments are increasing per patient, extending the impact of systemic inflammation and requiring inflammation-directed therapies to impede treatment resistance and mitigate toxicities. In 410 Danish biliary tract cancer (BTC) patients, we have recently shown that serum levels of the cytokine, interleukin-6 (IL6), prior to and particularly during chemotherapy are associated with poor prognosis (read more about serum IL6 as a prognostic biomarker). Therefore, chronic IL6 signaling may result in de novo tumor behavior and therapeutic sensitivities, characterization of which can be exploited to develop new predictive biomarkers and drug combinations to target cancer-promoting inflammation and increase survival of cancer patients.
Understanding the molecular pathogenesis of hepatobiliary cancers. Despite tantalizing clues as to the importance of genetics in hepatobiliary carcinogenesis, little is known about the genetic underpinnings of these malignancies. In this program, our primary goal is to characterize the molecular alterations important in intrahepatic and extrahepatic bile duct cancers, leveraging a multi-omics approach to emphasize patient subset for precision therapy.
Characterizing the deregulated epigenomic control in metastasis and guiding treatment. Epigenetic alterations ‘epimutations’ comprise alternative genomic perturbation mechanisms, the dynamic nature of which may present rapid tumor diversification during disease progression. We know primary liver cancers are highly polarized at the epigenomic level both in the primary and metastatic stages of the disease. This suggests a fundamental difference in their molecular pathogenesis, which may be exploited therapeutically (epi-therapy).
Understanding the early metabolic rearrangements in the liver. The endemic increase in obesity promotes Non-Alcoholic Fatty Liver Disease (NAFLD) and Steatohepatitis (NASH), which affect up to 40% of the European population. The liver is a key organ in controlling metabolic homeostasis, and rearrangements in these processes are known to cause HCC. However, the exact alterations causing metabolic disease to progress to HCC remain elusive. Manipulation of central genes controlling the metabolic imbalance will allow us to understand the biology and consequence in HCC progression. This knowledge is crucial to improve diagnosis, patient stratification and design novel treatment options.
Utilizing non-coding RNAs in biomarker discovery and drug resistance. To elucidate the role of ncRNAs in diagnosis, prognosis and in controlling treatment resistant mechanisms.
The altered serum lipidome and its diagnostic potential for Non-Alcoholic Fatty Liver (NAFL)-associated hepatocellular carcinoma. Lewinska M, Santos-Laso A, Arretxe E, Alonso C, Zhuravleva E, Jimenez-Agüero R, Eizaguirre E, Pareja MJ, Romero-Gómez M, Jimenez MA, Suppli MP, Knop FK, Oversoe SK, Villadsen GE, Decaens T, Carrilho FJ, de Oliveira CP, Sangro B, Macias RIR, Banales JM, Andersen JB. EBioMedicine. 2021 Oct 28;73:103661. doi: 10.1016/j.ebiom.2021.103661. Online ahead of print. PMID: 34740106 Fr
Integrative molecular characterisation of gallbladder cancer reveals micro-environment-associated subtypes. Nepal C, Zhu B, O'Rourke CJ, Bhatt DK, Lee D, Song L, Wang D, Van Dyke AL, Choo-Wosoba H, Liu Z, Hildesheim A, Goldstein AM, Dean M, LaFuente-Barquero J, Lawrence S, Mutreja K, Olanich ME, Lorenzo Bermejo J; CGR Exome Studies Group, Ferreccio C, Roa JC, Rashid A, Hsing AW, Gao YT, Chanock SJ, Araya JC, Andersen JB, Koshiol J. J Hepatol. 2021 May;74(5):1132-1144. doi: 10.1016/j.jhep.2020.11.033. Epub 2020 Dec 1. PMID: 33276026
Serum IL6 as a Prognostic Biomarker and IL6R as a Therapeutic Target in Biliary Tract Cancers. Høgdall D, O'Rourke CJ, Dehlendorff C, Larsen OF, Jensen LH, Johansen AZ, Dang H, Factor VM, Grunnet M, Mau-Sørensen M, Oliveira DVNP, Linnemann D, Boisen MK, Wang XW, Johansen JS, Andersen JB. Clin Cancer Res. 2020 Nov 1;26(21):5655-5667. doi: 10.1158/1078-0432.CCR-19-2700. Epub 2020 Sep 15. PMID: 32933994
Identification of a pan-gamma-secretase inhibitor response signature for notch-driven cholangiocarcinoma. O'Rourke CJ, Matter MS, Nepal C, Caetano-Oliveira R, Ton PT, Factor VM, Andersen JB. Hepatology. 2019 Jun 18. PMID:31211856
Epigenome Remodeling in Cholangiocarcinoma. O'Rourke CJ, Lafuente-Barquero J, Andersen JB. Trends in Cancer. 2019 Jun;5(6):335-350. Review. PMID:31208696
Genomic perturbations reveal distinct regulatory networks in intrahepatic cholangiocarcinoma. Nepal C, O'Rourke CJ, Oliveira DVNP, Taranta A, Shema S, Gautam P, Calderaro J, Barbour A, Raggi C, Wennerberg K, Wang XW, Lautem A, Roberts LR, Andersen JB. Hepatology. 2018 Sep;68(3):949-963. PMID:29278425
Desmoplastic Tumor Microenvironment and Immunotherapy in Cholangiocarcinoma. Høgdall D, Lewinska M, Andersen JB. Trends in Cancer. 2018 Mar;4(3):239-255. Review. PMID:29506673
MIR21 Drives Resistance to Heat Shock Protein 90 Inhibition in Cholangiocarcinoma. Lampis A, Carotenuto P, Vlachogiannis G, Cascione L, Hedayat S, Burke R, Clarke P, Bosma E, Simbolo M, Scarpa A, Yu S, Cole R, Smyth E, Mateos JF, Begum R, Hezelova B, Eltahir Z, Wotherspoon A, Fotiadis N, Bali MA, Nepal C, Khan K, Stubbs M, Hahne JC, Gasparini P, Guzzardo V, Croce CM, Eccles S, Fassan M, Cunningham D, Andersen JB, Workman P, Valeri N, Braconi C. Gastroenterology. 2018 Mar;154(4):1066-1079. PMID:29113809
Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma. Chaisaingmongkol J, Budhu A, Dang H, Rabibhadana S, Pupacdi B, Kwon SM, Forgues M, Pomyen Y, Bhudhisawasdi V, Lertprasertsuke N, Chotirosniramit A, Pairojkul C, Auewarakul CU, Sricharunrat T, Phornphutkul K, Sangrajrang S, Cam M, He P, Hewitt SM, Ylaya K, Wu X, Andersen JB, Thorgeirsson SS, Waterfall JJ, Zhu YJ, Walling J, Stevenson HS, Edelman D, Meltzer PS, Loffredo CA, Hama N, Shibata T, Wiltrout RH, Harris CC, Mahidol C, Ruchirawat M, Wang XW; TIGER-LC Consortium. Cancer Cell. 2017 Jul 10;32(1):57-70. PMID:28648284
Association of Aflatoxin and Gallbladder Cancer. Koshiol J, Gao YT, Dean M, Egner P, Nepal C, Jones K, Wang B, Rashid A, Luo W, Van Dyke AL, Ferreccio C, Malasky M, Shen MC, Zhu B, Andersen JB, Hildesheim A, Hsing AW, Groopman J. Gastroenterology. 2017 Aug;153(2):488-494. PMID:28428144
An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer. Vallejo A, Perurena N, Guruceaga E, Mazur PK, Martinez-Canarias S, Zandueta C, Valencia K, Arricibita A, Gwinn D, Sayles LC, Chuang CH, Guembe L, Bailey P, Chang DK, Biankin A, Ponz-Sarvise M, Andersen JB, Khatri P, Bozec A, Sweet-Cordero EA, Sage J, Lecanda F, Vicent S. Nature Communications. 2017 Feb 21;8:14294. PMID:28220783
News from Andersen group
iMED PhD student Lea Duwe to give an oral presentation titled “MicroRNA-27a-3p modulates FoxO1 to induce tumor-like phenotypes in the bile ducts” in the session “Liver Tumors Experimental and Pathophysiology” at The International Liver Congress 2021 (EASL).
Jesper B Andersen to give an educational seminar on oncogenomics in cholangiocarcinoma at the Copenhagen University Hospital, Department of Oncology.
Jesper B Andersen to present at the National Cancer Institute (NCI), Center for Cancer Research Liver cancer Program (LCP), NIH.
Yuewan Luo receives 3-year postdoc fellowship from the Lundbeck Foundation.
Jesper B Andersen to host the joint working group 2 (histopathology) and 3 (genomics) meeting under the Euro-CholangioNET COST Action.
Colm J O’Rourke to present “Whole-transcriptome profiling of biopsies from unresectable intrahepatic cholangiocarcinoma (iCCA) reveals a prognostic signature with treatment implications” at the Cholangiocarcinoma Foundation Annual meeting.
This UK-Danish study is a collaboration between the Andersen group and Prof. Chiara Braconi, Glasgow University, UK.
Jesper B Andersen to present at the COST Action EURO-CHOLANGIO-NET Training School in novel experimental models for cholangiocarcinoma: from ex-vivo patients derived organoids to in vivo animal models
Colm J O’Rourke to present a virtual tour of the project “Whole-transcriptome profiling of biopsies from unresectable intrahepatic cholangiocarcinoma (iCCA) reveals a prognostic signature with treatment implications”.
At the Liver Cancer Summit 2021. This UK-Danish study is a collaboration between the Andersen group and Prof. Chiara Braconi, Glasgow University. 09.02.2021
Jesper B Andersen to chair the session “Role of the microenvironment in cholangiocarcinoma” at the Liver Cancer Summit 2021. 09.02.2021
In the media
16.12.2020 by Diagnostisk Tidsskrift
20.10.2020 by Diagnostisk Tidsskrift
15.09.2020 by BRIC
09.05.2020 by Science News
10.12.2019 by Science News
07.06.2019 by CORDIS
11.01.2018 by Danish Cancer Society
Prizes, Honors and Awards
Monika Lewinska: International Liver cancer Association (ILCA) Junior Investigator Award for Basic and Translational Research, 2020
1. The Cancer Genome Atlas is a landmark cancer genomics program molecularly characterizing 33 cancer types funded by the National Institutes of Health (NIH), USA. The Andersen group has participated in these networks.
- TCGA CHOL Network
- TCGA Pan-Cancer TGF-beta Superfamily Network
- Tumor Molecular Pathology (TMP) Analysis Network (ongoing)
2. The European Network for the Study of Cholangiocarcinoma is a network constituting research group located in 13 European countries with focus on the pathophysiology of the biliary tree and development of cholangiocarcinoma. Dr. Andersen co-founded the network and is currently in the steering committee
3. EUROPEAN CHOLANGIOCARCINOMA NETWORK is a network focused on cholangiocarcinoma in Europe. This Cost Action CA18122 is funded by the European Commission. Dr. Andersen is representative of Denmark in the Cost management and chair of the Molecular profiling working group.
4. International Cholangiocarcinoma Research Network is part of the Cholangiocarcinoma Foundation in Salt Lake City, USA. The goal of ICRN is to accelerate the clinical translation of scientific discoveries to impact the lives of patients with cholangiocarcinoma.
5. The global Cholangiocarcinoma Alliance is uniting the global voice in the fight against cholangiocarcinoma. The Alliance is funded by AMMF, the UK Cholangiocarcinoma charity. Dr. Andersen is member of the steering committee.
AP Møller Fonden: Technology grant
|No logo available||Arvid Nilssons Fond: project|
The Lundbeck Foundation: Individual PhD fellowship
|Roche Denmark A/S: Project|
Beckett Fonden: Project
Herlev Hospitals forskningsfond & Capital Region: MD, PhD salary
Aase og Ejnar Danielsens fond: project
|No logo available||
Fabrikant Ejner Willumsens mindelegat: Project