Clathrin Light Chain A-enriched Small Extracellular Vesicles Remodel Microvascular Niche to Induce Hepatocellular Carcinoma Metastasis

Overview

Journal J Extracell Vesicles

Publisher Wiley

Date 2023 Aug 22

PMID 37606345

Authors

Yi Xu

Yue Yao

Liang Yu

Xiaoxin Zhang

Xiaowen Mao

Sze Keong Tey

Samuel Wan Ki Wong

Cherlie Lot Sum Yeung

Tung Him Ng

Melody Ym Wong

Chi-Ming Che

Terence Kin Wah Lee

Yi Gao

Yunfu Cui

Judy Wai Ping Yam

Affiliations

Soon will be listed here.

Abstract

Small extracellular vesicles (sEVs) play a key role in exchanging cargoes between cells in tumour microenvironment. This study aimed to elucidate the functions and mechanisms of hepatocellular carcinoma (HCC) derived sEV-clathrin light chain A (CLTA) in remodelling microvascular niche. CLTA level in the circulating sEVs of HCC patients was analysed by enzyme-linked immunosorbent assay (ELISA). The functions of sEV-CLTA in affecting HCC cancerous properties were examined by multiple functional assays. Mass spectrometry was used to identify downstream effectors of sEV-CLTA in human umbilical vein endothelial cells (HUVECs). Tube formation, sprouting, trans-endothelial invasion and vascular leakiness assays were performed to determine the functions of sEV-CLTA and its effector, basigin (BSG) in HUVECs. BSG inhibitor, SP-8356, was tested in a mouse model of patient-derived xenografts (PDXs). Circulating sEVs of HCC patients had markedly enhanced CLTA levels than control individuals and were reduced in patients after surgery. HCC derived sEV-CLTA enhanced HCC cancerous properties, disrupted endothelial integrity and induced angiogenesis. Mechanistically, CLTA remodels microvascular niche by stabilizing and upregulating BSG. Last, SP-8356 alone or in combination with sorafenib attenuated PDXs growth. The study reveals the role of HCC derived sEV-CLTA in microvascular niche formation. Inhibition of CLTA and its mediated pathway may illuminate a new therapeutic strategy for HCC patients.

Citing Articles

Exosomal PSM-E inhibits macrophage M2 polarization to suppress prostate cancer metastasis through the RACK1 signaling axis.

Qin X, Niu R, Tan Y, Huang Y, Ren W, Zhou W Biomark Res. 2024; 12(1):138.

PMID: 39538297 PMC: 11562865. DOI: 10.1186/s40364-024-00685-8.

Multi-stage mechanisms of tumor metastasis and therapeutic strategies.

Liu Z, Chen J, Ren Y, Liu S, Ba Y, Zuo A Signal Transduct Target Ther. 2024; 9(1):270.

PMID: 39389953 PMC: 11467208. DOI: 10.1038/s41392-024-01955-5.

The new advance of exosome-based liquid biopsy for cancer diagnosis.

Tang H, Yu D, Zhang J, Wang M, Fu M, Qian Y J Nanobiotechnology. 2024; 22(1):610.

PMID: 39380060 PMC: 11463159. DOI: 10.1186/s12951-024-02863-0.

Pre-metastatic niche: formation, characteristics and therapeutic implication.

Wang Y, Jia J, Wang F, Fang Y, Yang Y, Zhou Q Signal Transduct Target Ther. 2024; 9(1):236.

PMID: 39317708 PMC: 11422510. DOI: 10.1038/s41392-024-01937-7.

Role of extracellular vesicle-associated proteins in the progression, diagnosis, and treatment of hepatocellular carcinoma.

Liu Y, Jiang S, Zhang J, Zheng H, Zhang L, Zhao H Cell Biosci. 2024; 14(1):113.

PMID: 39227992 PMC: 11373138. DOI: 10.1186/s13578-024-01294-6.

References

Biancospino M, Buel G, Nino C, Maspero E, Scotto di Perrotolo R, Raimondi A . Clathrin light chain A drives selective myosin VI recruitment to clathrin-coated pits under membrane tension. Nat Commun. 2019; 10(1):4974. PMC: 6823378. DOI: 10.1038/s41467-019-12855-6. View

Xu Y, Yao Y, Yu L, Zhang X, Mao X, Tey S . Clathrin light chain A-enriched small extracellular vesicles remodel microvascular niche to induce hepatocellular carcinoma metastasis. J Extracell Vesicles. 2023; 12(8):e12359. PMC: 10443339. DOI: 10.1002/jev2.12359. View

Huang Z, Luo R, Yang L, Chen H, Zhang X, Han J . CPT1A-Mediated Fatty Acid Oxidation Promotes Precursor Osteoclast Fusion in Rheumatoid Arthritis. Front Immunol. 2022; 13:838664. PMC: 8902079. DOI: 10.3389/fimmu.2022.838664. View

Kurpinska A, Suraj J, Bonar E, Zakrzewska A, Stojak M, Sternak M . Proteomic characterization of early lung response to breast cancer metastasis in mice. Exp Mol Pathol. 2019; 107:129-140. DOI: 10.1016/j.yexmp.2019.02.001. View

Gai C, Carpanetto A, Deregibus M, Camussi G . Extracellular vesicle-mediated modulation of angiogenesis. Histol Histopathol. 2015; 31(4):379-91. DOI: 10.14670/HH-11-708. View

Kalra H, Drummen G, Mathivanan S . Focus on Extracellular Vesicles: Introducing the Next Small Big Thing. Int J Mol Sci. 2016; 17(2):170. PMC: 4783904. DOI: 10.3390/ijms17020170. View

Yin Z, Cai H, Wang Z, Jiang Y . Pseudolaric Acid B Inhibits Proliferation, Invasion, and Angiogenesis in Esophageal Squamous Cell Carcinoma Through Regulating CD147. Drug Des Devel Ther. 2020; 14:4561-4573. PMC: 7605399. DOI: 10.2147/DDDT.S269915. View

Gimona M, Pachler K, Laner-Plamberger S, Schallmoser K, Rohde E . Manufacturing of Human Extracellular Vesicle-Based Therapeutics for Clinical Use. Int J Mol Sci. 2017; 18(6). PMC: 5486013. DOI: 10.3390/ijms18061190. View

Lampe M, Vassilopoulos S, Merrifield C . Clathrin coated pits, plaques and adhesion. J Struct Biol. 2016; 196(1):48-56. DOI: 10.1016/j.jsb.2016.07.009. View

10.

Chen Y, Zhang H, Gou X, Horikawa Y, Xing J, Chen Z . Upregulation of HAb18G/CD147 in activated human umbilical vein endothelial cells enhances the angiogenesis. Cancer Lett. 2009; 278(1):113-21. DOI: 10.1016/j.canlet.2009.01.004. View

11.

Luo Z, Zhang X, Zeng W, Su J, Yang K, Lu L . TRAF6 regulates melanoma invasion and metastasis through ubiquitination of Basigin. Oncotarget. 2016; 7(6):7179-92. PMC: 4872777. DOI: 10.18632/oncotarget.6886. View

12.

Mao X, Tey S, Yeung C, Kwong E, Fung Y, Chung C . Nidogen 1-Enriched Extracellular Vesicles Facilitate Extrahepatic Metastasis of Liver Cancer by Activating Pulmonary Fibroblasts to Secrete Tumor Necrosis Factor Receptor 1. Adv Sci (Weinh). 2020; 7(21):2002157. PMC: 7640351. DOI: 10.1002/advs.202002157. View

13.

Xu Y, Leng K, Yao Y, Kang P, Liao G, Han Y . A Circular RNA, Cholangiocarcinoma-Associated Circular RNA 1, Contributes to Cholangiocarcinoma Progression, Induces Angiogenesis, and Disrupts Vascular Endothelial Barriers. Hepatology. 2020; 73(4):1419-1435. DOI: 10.1002/hep.31493. View

14.

Khayati F, Perez-Cano L, Maouche K, Sadoux A, Boutalbi Z, Podgorniak M . EMMPRIN/CD147 is a novel coreceptor of VEGFR-2 mediating its activation by VEGF. Oncotarget. 2015; 6(12):9766-80. PMC: 4496396. DOI: 10.18632/oncotarget.2870. View

15.

Ostman A, Corvigno S . Microvascular Mural Cells in Cancer. Trends Cancer. 2018; 4(12):838-848. DOI: 10.1016/j.trecan.2018.10.004. View

16.

Birgani M, Carloni V . Tumor Microenvironment, a Paradigm in Hepatocellular Carcinoma Progression and Therapy. Int J Mol Sci. 2017; 18(2). PMC: 5343939. DOI: 10.3390/ijms18020405. View

17.

Sleeman J . The lymph node pre-metastatic niche. J Mol Med (Berl). 2015; 93(11):1173-84. DOI: 10.1007/s00109-015-1351-6. View

18.

Siegel R, Miller K, Fuchs H, Jemal A . Cancer Statistics, 2021. CA Cancer J Clin. 2021; 71(1):7-33. DOI: 10.3322/caac.21654. View

19.

van Niel G, DAngelo G, Raposo G . Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018; 19(4):213-228. DOI: 10.1038/nrm.2017.125. View

20.

Redlingshofer L, McLeod F, Chen Y, Camus M, Burden J, Palomer E . Clathrin light chain diversity regulates membrane deformation in vitro and synaptic vesicle formation in vivo. Proc Natl Acad Sci U S A. 2020; 117(38):23527-23538. PMC: 7519287. DOI: 10.1073/pnas.2003662117. View