TY - JOUR

T1 - Lactate receptor GPR81 drives breast cancer growth and invasiveness through regulation of ECM properties and Notch ligand DLL4

AU - Lundø, Kathrine

AU - Dmytriyeva, Oksana

AU - Spøhr, Louise

AU - Goncalves-Alves, Eliana

AU - Yao, Jiayi

AU - Blasco, Laia P.

AU - Trauelsen, Mette

AU - Ponniah, Muthulakshmi

AU - Severin, Marc

AU - Sandelin, Albin

AU - Kveiborg, Marie

AU - Schwartz, Thue W.

AU - Pedersen, Stine F.

N1 - Publisher Copyright: © 2023, The Author(s).

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

KW - EPHA7

KW - Extracellular matrix

KW - HCAR1

KW - Metabolite GPCR

KW - Notch

KW - PCDH7

KW - Spheroid

KW - Tumor microenvironment

U2 - 10.1186/s12885-023-11631-6

DO - 10.1186/s12885-023-11631-6

M3 - Journal article

C2 - 37993804

AN - SCOPUS:85177665545

VL - 23

JO - B M C Cancer

JF - B M C Cancer

SN - 1471-2407

IS - 1

M1 - 1136

ER -