Molecular Subgroups of Intrahepatic Cholangiocarcinoma Discovered by Single-Cell RNA Sequencing–Assisted Multiomics Analysis

Author:

Bao Xuanwen1ORCID,Li Qiong1ORCID,Chen Jinzhang2ORCID,Chen Diyu3ORCID,Ye Chanqi1ORCID,Dai Xiaomeng1ORCID,Wang Yanfang4ORCID,Li Xin5ORCID,Rong Xiaoxiang2ORCID,Cheng Fei6ORCID,Jiang Ming7ORCID,Zhu Zheng8ORCID,Ding Yongfeng1ORCID,Sun Rui910ORCID,Liu Chuan11ORCID,Huang Lingling12ORCID,Jin Yuzhi1ORCID,Li Bin1ORCID,Lu Juan13ORCID,Wu Wei1ORCID,Guo Yixuan1ORCID,Fu Wenguang14ORCID,Langley Sarah Raye15ORCID,Tano Vincent15ORCID,Fang Weijia1ORCID,Guo Tiannan910ORCID,Sheng Jianpeng16ORCID,Zhao Peng1ORCID,Ruan Jian1ORCID

Affiliation:

1. 1Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University and Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, Zhejiang Province, People's Republic of China.

2. 2Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, People's Republic of China.

3. 3Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.

4. 4Ludwig-Maximilians-Universität München (LMU), Munich, Germany.

5. 5Department Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.

6. 6Pathology Department, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China.

7. 7The Children's Hospital, Zhejiang University School of Medicine and National Clinical Research Center for Child Health, Hangzhou, Zhejiang Province, People's Republic of China.

8. 8Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

9. 9Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province, China.

10. 10Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, Hangzhou, Zhejiang Province, China.

11. 11China Medical University, Shenyang, Liaoning Province, People's Republic of China.

12. 12Westlake Omics (Hangzhou) Biotechnology Co., Ltd., Hangzhou, Zhejiang Province, China.

13. 13State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Hangzhou, Zhejiang University.

14. 14Department of Hepatobiliary Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, People's Republic of China.

15. 15Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Republic of Singapore.

16. 16Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, People's Republic of China.

Abstract

Abstract Intrahepatic cholangiocarcinoma (ICC) is a relatively rare but highly aggressive tumor type that responds poorly to chemotherapy and immunotherapy. Comprehensive molecular characterization of ICC is essential for the development of novel therapeutics. Here, we constructed two independent cohorts from two clinic centers. A comprehensive multiomics analysis of ICC via proteomic, whole-exome sequencing (WES), and single-cell RNA sequencing (scRNA-seq) was performed. Novel ICC tumor subtypes were derived in the training cohort (n = 110) using proteomic signatures and their associated activated pathways, which were further validated in a validation cohort (n = 41). Three molecular subtypes, chromatin remodeling, metabolism, and chronic inflammation, with distinct prognoses in ICC were identified. The chronic inflammation subtype was associated with a poor prognosis. Our random forest algorithm revealed that mutation of lysine methyltransferase 2D (KMT2D) frequently occurred in the metabolism subtype and was associated with lower inflammatory activity. scRNA-seq further identified an APOE+C1QB+ macrophage subtype, which showed the capacity to reshape the chronic inflammation subtype and contribute to a poor prognosis in ICC. Altogether, with single-cell transcriptome-assisted multiomics analysis, we identified novel molecular subtypes of ICC and validated APOE+C1QB+ tumor-associated macrophages as potential immunotherapy targets against ICC.

Funder

National Natural Science Foundation of China

National Key R&D Program of China

Young Investigator Research Program

Natural Science Foundation of Zhejiang Province

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Immunology

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