Lactate receptor GPR81 drives breast cancer growth and invasiveness through regulation of ECM properties and Notch ligand DLL4.

Autor: Lundø K; Faculty of Health, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Dmytriyeva O; Faculty of Health, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Spøhr L; Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark., Goncalves-Alves E; Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark., Yao J; The Bioinformatics Centre, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.; Biotech Research and Innovation Centre, Faculty of Health, University of Copenhagen, Copenhagen, Denmark., Blasco LP; Biotech Research and Innovation Centre, Faculty of Health, University of Copenhagen, Copenhagen, Denmark., Trauelsen M; Faculty of Health, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark., Ponniah M; Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark., Severin M; Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark., Sandelin A; The Bioinformatics Centre, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.; Biotech Research and Innovation Centre, Faculty of Health, University of Copenhagen, Copenhagen, Denmark., Kveiborg M; Biotech Research and Innovation Centre, Faculty of Health, University of Copenhagen, Copenhagen, Denmark., Schwartz TW; Faculty of Health, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark. tws@sund.ku.dk., Pedersen SF; Section for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark. sfpedersen@bio.ku.dk.
Jazyk: angličtina
Zdroj: BMC cancer [BMC Cancer] 2023 Nov 22; Vol. 23 (1), pp. 1136. Date of Electronic Publication: 2023 Nov 22.
DOI: 10.1186/s12885-023-11631-6
Abstrakt: Background: The lactate receptor GPR81 contributes to cancer development through unclear mechanisms. Here, we investigate the roles of GPR81 in three-dimensional (3D) and in vivo growth of breast cancer cells and study the molecular mechanisms involved.
Methods: GPR81 was stably knocked down (KD) in MCF-7 human breast cancer cells which were subjected to RNA-seq analysis, 3D growth, in situ- and immunofluorescence analyses, and cell viability- and motility assays, combined with KD of key GPR81-regulated genes. Key findings were additionally studied in other breast cancer cell lines and in mammary epithelial cells.
Results: GPR81 was upregulated in multiple human cancer types and further upregulated by extracellular lactate and 3D growth in breast cancer spheroids. GPR81 KD increased spheroid necrosis, reduced invasion and in vivo tumor growth, and altered expression of genes related to GO/KEGG terms extracellular matrix, cell adhesion, and Notch signaling. Single cell in situ analysis of MCF-7 cells revealed that several GPR81-regulated genes were upregulated in the same cell clusters. Notch signaling, particularly the Notch ligand Delta-like-4 (DLL4), was strikingly downregulated upon GPR81 KD, and DLL4 KD elicited spheroid necrosis and inhibited invasion in a manner similar to GPR81 KD.
Conclusions: GPR81 supports breast cancer aggressiveness, and in MCF-7 cells, this occurs at least in part via DLL4. Our findings reveal a new GPR81-driven mechanism in breast cancer and substantiate GPR81 as a promising treatment target.
(© 2023. The Author(s).)
Databáze: MEDLINE
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