Single-Exosome Profiling Identifies ITGB3+ and ITGAM+ Exosome Subpopulations as Promising Early Diagnostic Biomarkers and Therapeutic Targets for Colorectal Cancer

Wei Guo; Yanling Cai; Xianming Liu; Yuge Ji; Cuiyu Zhang; Liyan Wang; Wenting Liao; Yuefei Liu; Nan Cui; Jinsheng Xiang; Zesong Li; Di Wu; Jingxin Li

doi:10.34133/research.0041

Single-Exosome Profiling Identifies ITGB3+ and ITGAM+ Exosome Subpopulations as Promising Early Diagnostic Biomarkers and Therapeutic Targets for Colorectal Cancer

Research (Wash D C). 2023:6:0041. doi: 10.34133/research.0041. Epub 2023 Jan 30.

Authors

Wei Guo¹, Yanling Cai^{1

2

3}, Xianming Liu⁴, Yuge Ji¹, Cuiyu Zhang¹, Liyan Wang⁵, Wenting Liao⁶, Yuefei Liu⁶, Nan Cui⁶, Jinsheng Xiang⁶, Zesong Li^{2

3}, Di Wu^{6

7}, Jingxin Li¹

Affiliations

¹ Department of Physiology, School of Basic Medical Sciences, Department of Colorectal Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
² Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, 518035, China.
³ Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, 518035, China.
⁴ Department of Gastrointestinal Surgery, Shenzhen People's Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of Southern University of Science and Technology, Shenzhen, Guangdong, 518020, China.
⁵ Center for Experimental Nuclear Medicine and Electron Microscope, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, 250012, China.
⁶ Shenzhen SecreTech Co., Ltd., Shenzhen, China.
⁷ Vesicode AB, Nobelsvag 16, Solna, Sweden.

Abstract

Tumor metastasis is a hallmark of colorectal cancer (CRC), in which exosome plays a crucial role with its function in intercellular communication. Plasma exosomes were collected from healthy control (HC) donors, localized primary CRC and liver-metastatic CRC patients. We performed proximity barcoding assay (PBA) for single-exosome analysis, which enabled us to identify the alteration in exosome subpopulations associated with CRC progression. By in vitro and in vivo experiments, the biological impact of these subpopulations on cancer proliferation, migration, invasion, and metastasis was investigated. The potential application of exosomes as diagnostic biomarkers was evaluated in 2 independent validation cohorts by PBA. Twelve distinct exosome subpopulations were determined. We found 2 distinctly abundant subpopulations: one ITGB3-positive and the other ITGAM-positive. The ITGB3-positive cluster is rich in liver-metastatic CRC, compared to both HC group and primary CRC group. On the contrary, ITGAM-positive exosomes show a large-scale increase in plasma of HC group, compared to both primary CRC and metastatic CRC groups. Notably, both discovery cohort and validation cohort verified ITGB3+ exosomes as potential diagnostic biomarker. ITGB3+ exosomes promote proliferation, migration, and invasion capability of CRC. In contrast, ITGAM+ exosomes suppress CRC development. Moreover, we also provide evidence that one of the sources of ITGAM+ exosomes is macrophage. ITGB3+ exosomes and ITGAM+ exosomes are proven 2 potential diagnostic, prognostic, and therapeutic biomarkers for management of CRC.