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

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

Gut

10.1136/gutjnl-2023-330483

http://dx.doi.org/10.1136/gutjnl-2023-330483

Jing Han Hong, Chern Han Yong, Hong Lee Heng, Jason Yongsheng Chan, Mai Chan Lau, Jianfeng Chen, Jing Yi Lee, Abner Herbert Lim, Zhimei Li, Peiyong Guan, Pek Lim Chu, Arnoud Boot, Sheng Rong Ng, Xiaosai Yao, Felicia Yu Ting Wee, Jeffrey Chun Tatt Lim, Wei Liu, Peili Wang, Rong Xiao, Xian Zeng, Yichen Sun, Joanna Koh, Xiu Yi Kwek, Cedric Chuan Young Ng, Poramate Klanrit, Yaojun Zhang, Jiaming Lai, David Wai Meng Tai, Chawalit Pairojkul, Simona Dima, Irinel Popescu, Sen-Yung Hsieh, Ming-Chin Yu, Joe Yeong, Sarinya Kongpetch, Apinya Jusakul, Watcharin Loilome, Patrick Tan, Jing Tan, Bin Tean Teh

24 November 2023

Hong, J. H., Yong, C. H., Heng, H. L., Chan, J. Y., Lau, M. C., Chen, J., Lee, J. Y., Lim, A. H., Li, Z., Guan, P., Chu, P. L., Boot, A., Ng, S. R., Yao, X., Wee, F. Y. T., Lim, J. C. T., Liu, W., Wang, P., Xiao, R., … Teh, B. T. (2023). Integrative multiomics enhancer activity profiling identifies therapeutic vulnerabilities in cholangiocarcinoma of different etiologies. Gut, 73(6), 966–984. https://doi.org/10.1136/gutjnl-2023-330483

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.ResultsWe identified three distinct groups, associated with different etiologies and unique pathways. Drug inhibitors of identified pathways reduced tumour growth inin vitroandin vivomodels. The first group (ESTRO), with mostly fluke-positive CCAs, displayed activation in estrogen signalling and were sensitive to MTOR inhibitors. Another group (OXPHO), with mostlyBAP1andIDH-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.

Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

This research / project is supported by the National Research Medical Council Singapore - Young Individual Research Grant
Grant Reference no. : MOH-000232 and COVIDTUG21-0087

This research / project is supported by the Duke-NUS Medical School - Khoo Postdoctoral Fellowship Award
Grant Reference no. : Duke-NUS-KPFA/2019/0034

This research / project is supported by the Agency for Science, Technology and Research - Singapore Therapeutics Development Review Pre-Pilot
Grant Reference no. : H23G1a0009

This research / project is supported by the SingHealth Academic Medicine (AM) - SingHealth Academic Medicine (AM) Research Grant
Grant Reference no. : AM/SU021/201

This research / project is supported by the National Natural Science Foundation of PR. China - National Natural Science Foundation of PR. China
Grant Reference no. : 81972596, 81772963, 82320108015 and 81773279

This research / project is supported by the Natural Science Foundation of Guangdong Province, China - Natural Science Foundation of Guangdong Province, China
Grant Reference no. : 2021A1515011131

This research / project is supported by the National Key R&D Program of China - National Key R&D Program of China
Grant Reference no. : 2022YFA1304000

This research / project is supported by the Ministry of Health, National Medical Research Council - Singapore Translational Research Investigator Award
Grant Reference no. : MOH000248-00

This research / project is supported by the Ministry of Health, National Medical Research Council - Open Fund-Individual Research Grant
Grant Reference no. : MOH-000144 and COVID19TUG21-0146

This research was supported by the Verdant Foundation

This research was supported by the NCC Cancer Fund

This article has been accepted for publication in Gut, 2023 following peer review, and the Version of Record can be accessed online at http://dx.doi.org/10.1136/gutjnl-2023-330483

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Genome Institute of Singapore