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