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Integrative multiomics enhancer activity profiling identifies therapeutic vulnerabilities in cholangiocarcinoma of
Jing Han Hong1, Chern Han Yong2,3, Hong Lee Heng2
1Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, Singapore.
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.
Insights
Researchers identified three distinct cholangiocarcinoma (CCA) subtypes by profiling enhancers. Each subtype showed unique pathway activations and sensitivities to specific targeted therapies, offering new treatment strategies for this deadly cancer.
Area of Science:
- Oncology
- Epigenetics
- Genomics
Background:
- Cholangiocarcinoma (CCA) is a deadly cancer with limited treatment options.
- Current understanding of CCA epigenetics mainly focuses on DNA methylation, neglecting enhancer activity.
- Enhancer dysregulation is implicated in cancer, but its role in CCA remains unexplored.
Purpose of the Study:
- To identify potential therapeutic targets in different CCA subtypes by analyzing enhancer activity.
- To characterize the epigenetic landscape of CCA through enhancer profiling.
Main Methods:
- Integrative multiomics enhancer activity profiling was performed on diverse CCA models.
- NanoString, multiplex immunohistochemistry, and single-cell spatial transcriptomics were employed.
- In vitro and in vivo models were used to test drug inhibitors targeting identified pathways.
Main Results:
- Three distinct CCA groups (ESTRO, OXPHO, IMMUN) were identified, each linked to specific etiologies and pathways.
- The ESTRO group (fluke-positive) responded to mTOR inhibitors, while the OXPHO group (BAP1/IDH-mutant) responded to oxidative phosphorylation inhibitors.
- The IMMUN group showed activated immune-related pathways, with intratumoral differences in aristolochic acid mutation load correlating with immune cell populations.
Conclusions:
- This study reveals mechanisms of enhancer dysregulation in CCA subtypes.
- It deepens the understanding of CCA tumorigenesis, highlighting distinct subtype-specific vulnerabilities.
- Findings offer potential therapeutic strategies and clinical benefits for cholangiocarcinoma treatment.
