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Sci Signal. 2017 Oct 3;10(499). pii: eaal2987. doi: 10.1126/scisignal.aal2987.

Genome-wide functional analysis reveals central signaling regulators of lymphatic endothelial cell migration and remodeling.

Author information

1
Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
2
Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Parkville, Victoria 3010, Australia.
3
Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
4
Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia.
5
Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
6
Bioinformatics Core, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
7
Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria 3000, Australia.
8
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora, Victoria 3086, Australia.
9
Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia.
10
Centre for Dynamic Imaging, Systems Biology and Personalised Medicine Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
11
Division of Genomics of Development and Disease, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
12
School of Mathematics and Statistics, University of Melbourne, Parkville, Victoria 3010, Australia.
13
Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
14
Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
15
Development and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
16
Tumour Angiogenesis and Microenvironment Program, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia. steven.stacker@petermac.org.

Abstract

Lymphatic vessels constitute a specialized vasculature that is involved in development, cancer, obesity, and immune regulation. The migration of lymphatic endothelial cells (LECs) is critical for vessel growth (lymphangiogenesis) and vessel remodeling, processes that modify the lymphatic network in response to developmental or pathological demands. Using the publicly accessible results of our genome-wide siRNA screen, we characterized the migratome of primary human LECs and identified individual genes and signaling pathways that regulate LEC migration. We compared our data set with mRNA differential expression data from endothelial and stromal cells derived from two in vivo models of lymphatic vessel remodeling, viral infection and contact hypersensitivity-induced inflammation, which identified genes selectively involved in regulating LEC migration and remodeling. We also characterized the top candidates in the LEC migratome in primary blood vascular endothelial cells to identify genes with functions common to lymphatic and blood vascular endothelium. On the basis of these analyses, we showed that LGALS1, which encodes the glycan-binding protein Galectin-1, promoted lymphatic vascular growth in vitro and in vivo and contributed to maintenance of the lymphatic endothelial phenotype. Our results provide insight into the signaling networks that control lymphangiogenesis and lymphatic remodeling and potentially identify therapeutic targets and biomarkers in disease specific to lymphatic or blood vessels.

PMID:
28974649
DOI:
10.1126/scisignal.aal2987
[Indexed for MEDLINE]

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