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  • Integrative multiomics enhancer activity profiling identifies therapeutic vulnerabilities in cholangiocarcinoma of different etiologies

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Hepatology
Original research
Integrative multiomics enhancer activity profiling identifies therapeutic vulnerabilities in cholangiocarcinoma of different etiologies
  1. Jing Han Hong1,
  2. Chern Han Yong2,3,
  3. Hong Lee Heng2,
  4. Jason Yongsheng Chan4,5,6,
  5. Mai Chan Lau7,8,
  6. Jianfeng Chen9,
  7. Jing Yi Lee2,5,
  8. Abner Herbert Lim2,5,
  9. Zhimei Li2,5,
  10. Peiyong Guan10,
  11. Pek Lim Chu1,
  12. Arnoud Boot1,11,
  13. Sheng Rong Ng12,
  14. Xiaosai Yao12,
  15. Felicia Yu Ting Wee13,
  16. Jeffrey Chun Tatt Lim13,
  17. Wei Liu2,
  18. Peili Wang9,
  19. Rong Xiao9,
  20. Xian Zeng9,
  21. Yichen Sun9,
  22. Joanna Koh12,
  23. Xiu Yi Kwek2,
  24. Cedric Chuan Young Ng2,5,
  25. Poramate Klanrit14,15,
  26. Yaojun Zhang9,16,
  27. Jiaming Lai17,
  28. David Wai Meng Tai4,6,
  29. Chawalit Pairojkul18,
  30. Simona Dima19,
  31. Irinel Popescu19,
  32. Sen-Yung Hsieh20,
  33. Ming-Chin Yu21,
  34. Joe Yeong13,22,23,
  35. Sarinya Kongpetch24,25,
  36. Apinya Jusakul24,26,
  37. Watcharin Loilome14,15,24,
  38. Patrick Tan1,10,27,
  39. Jing Tan2,28,
  40. Bin Tean Teh1,2,10,12
  1. 1 Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, Singapore
  2. 2 Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore
  3. 3 Department of Computer Science, National University of Singapore, Singapore
  4. 4 Division of Medical Oncology, National Cancer Centre Singapore, Singapore
  5. 5 Cancer Discovery Hub, National Cancer Centre Singapore, Singapore
  6. 6 Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore
  7. 7 Singapore Immunology Network, Agency for Science Technology and Research (A*STAR), Singapore
  8. 8 Bioinformatics Institute (BII), Agency for Science Technology and Research (A*STAR), Singapore
  9. 9 State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
  10. 10 Genome Institute of Singapore, Agency for Science Technology and Research (A*STAR), Singapore
  11. 11 Centre for Computational Biology, Duke-NUS Medical School, Singapore
  12. 12 Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore
  13. 13 Institute of Molecular and Cell Biology, Integrative Biology for Theranostics Lab, Agency for Science Technology and Research (A*STAR), Singapore
  14. 14 Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen, Thailand
  15. 15 Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
  16. 16 Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong
  17. 17 Department of Pancreaticobiliary Surgery, Sun Yat-sen University, Guangzhou, China
  18. 18 Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
  19. 19 Center of Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, Bucuresti, Romania
  20. 20 Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
  21. 21 Department of General Surgery, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan
  22. 22 Department of Anatomical Pathology, Singapore General Hospital, Singapore
  23. 23 Pathology Academic Clinical Program, Duke-NUS Medical School, Singapore
  24. 24 Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, Thailand
  25. 25 Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
  26. 26 Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
  27. 27 Cancer Science Institute of Singapore, National University of Singapore, Singapore
  28. 28 State Key Laboratory of Oncology, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
  1. Correspondence to Professor Bin Tean Teh, Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore; teh.bin.tean{at}singhealth.com.sg

Abstract

Objectives Cholangiocarcinoma (CCA) is a heterogeneous malignancy with high mortality and dismal prognosis, and an urgent clinical need for new therapies. Knowledge of the CCA epigenome is largely limited to aberrant DNA methylation. Dysregulation of enhancer activities has been identified to affect carcinogenesis and leveraged for new therapies but is uninvestigated in CCA. Our aim is to identify potential therapeutic targets in different subtypes of CCA through enhancer profiling.

Design Integrative multiomics enhancer activity profiling of diverse CCA was performed. A panel of diverse CCA cell lines, patient-derived and cell line-derived xenografts were used to study identified enriched pathways and vulnerabilities. NanoString, multiplex immunohistochemistry staining and single-cell spatial transcriptomics were used to explore the immunogenicity of diverse CCA.

Results We identified three distinct groups, associated with different etiologies and unique pathways. Drug inhibitors of identified pathways reduced tumour growth in in vitro and in vivo models. The first group (ESTRO), with mostly fluke-positive CCAs, displayed activation in estrogen signalling and were sensitive to MTOR inhibitors. Another group (OXPHO), with mostly BAP1 and IDH-mutant CCAs, displayed activated oxidative phosphorylation pathways, and were sensitive to oxidative phosphorylation inhibitors. Immune-related pathways were activated in the final group (IMMUN), made up of an immunogenic CCA subtype and CCA with aristolochic acid (AA) mutational signatures. Intratumour differences in AA mutation load were correlated to intratumour variation of different immune cell populations.

Conclusion Our study elucidates the mechanisms underlying enhancer dysregulation and deepens understanding of different tumourigenesis processes in distinct CCA subtypes, with potential significant therapeutics and clinical benefits.

  • CHOLANGIOCARCINOMA
  • CANCER
  • MOLECULAR ONCOLOGY

Data availability statement

Data are available in a public, open access repository. Sequencing datasets can be found at the European Genome-phenome Archive (EGA, Accession number: EGAS00001007309). Data used in this manuscript also includes previously published studies from public repositories: EGA (EGA00001000950) and Gene Expression Omnibus (GEO, GSE89749 and GSE89803). Codes used are available on GitHub (https://github.com/chernycherny/CCA_enhancers_2023).

https://doi.org/10.1136/gutjnl-2023-330483

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    Data availability statement

    Data are available in a public, open access repository. Sequencing datasets can be found at the European Genome-phenome Archive (EGA, Accession number: EGAS00001007309). Data used in this manuscript also includes previously published studies from public repositories: EGA (EGA00001000950) and Gene Expression Omnibus (GEO, GSE89749 and GSE89803). Codes used are available on GitHub (https://github.com/chernycherny/CCA_enhancers_2023).

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    Footnotes

    • JHH and CHY are joint first authors.

    • JT and BTT are joint senior authors.

    • Contributors JHH and CHY contributed equally to this manuscript. Conceptualisation: JHH, CHY and BTT; Writing of original draft: JHH and CHY; Writing (review and editing): JHH, CHY, BTT, JT, JYC, SK, AJ, JY, FYTW, JCTL and PG; Supervision: BTT; Experiments: JHH, CHY, HLH, JC, JYL, ZL, PLC, SRN, PW, XR, XZ, YS, WL, JK, FYTW, JCTL and XYK; Analysis: JHH, CHY, HLH, JYC, MCL, AB, AHL, PG, XY, FYTW, JCTL and JY; Resources and intellectual discussion: HLH, CCYN, PK, YZ, JL, WMDT, CP, SD, IP, S-YH, M-CY, JY, SK, AJ, WL, PT, JT and BTT; Approval of final version of manuscript: all authors. Guarantor: BTT.

    • Funding JHH was supported by the National Research Medical Council Singapore Young Individual Research Grant (MOH-000232 and COVIDTUG21-0087), the Khoo Postdoctoral Fellowship Award (Duke-NUS-KPFA/2019/0034) and the Singapore Therapeutics Development Review Pre-Pilot (H23G1a0009). CHY was supported by the SingHealth Academic Medicine (AM) Research Grant (AM/SU021/201). JT was supported by the National Natural Science Foundation of PR. China (81972596, 81772963, 82320108015 and 81773279), the Natural Science Foundation of Guangdong Province, China (2021A1515011131) and the National Key R&D Program of China (2022YFA1304000). BTT was supported by the National Medical Research Council Singapore Translational Research Investigator Award (MOH000248-00), the National Medical Research Council Open Fund-Individual Research Grant (MOH-000144 and COVID19TUG21-0146), the Verdant Foundation and the NCC Cancer Fund.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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