Lactate receptor GPR81 drives breast cancer growth and invasiveness through regulation of ECM properties and Notch ligand DLL4
Abstract 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...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-11-01
|
| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12885-023-11631-6 |
| _version_ | 1797452301672120320 |
|---|---|
| author | Kathrine Lundø Oksana Dmytriyeva Louise Spøhr Eliana Goncalves-Alves Jiayi Yao Laia P. Blasco Mette Trauelsen Muthulakshmi Ponniah Marc Severin Albin Sandelin Marie Kveiborg Thue W. Schwartz Stine F. Pedersen |
| author_facet | Kathrine Lundø Oksana Dmytriyeva Louise Spøhr Eliana Goncalves-Alves Jiayi Yao Laia P. Blasco Mette Trauelsen Muthulakshmi Ponniah Marc Severin Albin Sandelin Marie Kveiborg Thue W. Schwartz Stine F. Pedersen |
| author_sort | Kathrine Lundø |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-03-09T15:06:41Z |
| format | Article |
| id | doaj.art-4dce1bc40e524fe2bbe93834d25ecd0f |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-03-09T15:06:41Z |
| publishDate | 2023-11-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-4dce1bc40e524fe2bbe93834d25ecd0f2023-11-26T13:36:45ZengBMCBMC Cancer1471-24072023-11-0123112010.1186/s12885-023-11631-6Lactate receptor GPR81 drives breast cancer growth and invasiveness through regulation of ECM properties and Notch ligand DLL4Kathrine Lundø0Oksana Dmytriyeva1Louise Spøhr2Eliana Goncalves-Alves3Jiayi Yao4Laia P. Blasco5Mette Trauelsen6Muthulakshmi Ponniah7Marc Severin8Albin Sandelin9Marie Kveiborg10Thue W. Schwartz11Stine F. Pedersen12Faculty of Health, Novo Nordisk Foundation Center for Basic Metabolic Research, University of CopenhagenFaculty of Health, Novo Nordisk Foundation Center for Basic Metabolic Research, University of CopenhagenSection for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of CopenhagenSection for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of CopenhagenThe Bioinformatics Centre, Department of Biology, Faculty of Science, University of CopenhagenBiotech Research and Innovation Centre, Faculty of Health, University of CopenhagenFaculty of Health, Novo Nordisk Foundation Center for Basic Metabolic Research, University of CopenhagenSection for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of CopenhagenSection for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of CopenhagenThe Bioinformatics Centre, Department of Biology, Faculty of Science, University of CopenhagenBiotech Research and Innovation Centre, Faculty of Health, University of CopenhagenFaculty of Health, Novo Nordisk Foundation Center for Basic Metabolic Research, University of CopenhagenSection for Cell Biology and Physiology, Department of Biology, Faculty of Science, University of CopenhagenAbstract 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.https://doi.org/10.1186/s12885-023-11631-6HCAR1Tumor microenvironmentSpheroidEPHA7PCDH7Notch |
| spellingShingle | Kathrine Lundø Oksana Dmytriyeva Louise Spøhr Eliana Goncalves-Alves Jiayi Yao Laia P. Blasco Mette Trauelsen Muthulakshmi Ponniah Marc Severin Albin Sandelin Marie Kveiborg Thue W. Schwartz Stine F. Pedersen Lactate receptor GPR81 drives breast cancer growth and invasiveness through regulation of ECM properties and Notch ligand DLL4 BMC Cancer HCAR1 Tumor microenvironment Spheroid EPHA7 PCDH7 Notch |
| title | Lactate receptor GPR81 drives breast cancer growth and invasiveness through regulation of ECM properties and Notch ligand DLL4 |
| title_full | Lactate receptor GPR81 drives breast cancer growth and invasiveness through regulation of ECM properties and Notch ligand DLL4 |
| title_fullStr | Lactate receptor GPR81 drives breast cancer growth and invasiveness through regulation of ECM properties and Notch ligand DLL4 |
| title_full_unstemmed | Lactate receptor GPR81 drives breast cancer growth and invasiveness through regulation of ECM properties and Notch ligand DLL4 |
| title_short | Lactate receptor GPR81 drives breast cancer growth and invasiveness through regulation of ECM properties and Notch ligand DLL4 |
| title_sort | lactate receptor gpr81 drives breast cancer growth and invasiveness through regulation of ecm properties and notch ligand dll4 |
| topic | HCAR1 Tumor microenvironment Spheroid EPHA7 PCDH7 Notch |
| url | https://doi.org/10.1186/s12885-023-11631-6 |
| work_keys_str_mv | AT kathrinelundø lactatereceptorgpr81drivesbreastcancergrowthandinvasivenessthroughregulationofecmpropertiesandnotchliganddll4 AT oksanadmytriyeva lactatereceptorgpr81drivesbreastcancergrowthandinvasivenessthroughregulationofecmpropertiesandnotchliganddll4 AT louisespøhr lactatereceptorgpr81drivesbreastcancergrowthandinvasivenessthroughregulationofecmpropertiesandnotchliganddll4 AT elianagoncalvesalves lactatereceptorgpr81drivesbreastcancergrowthandinvasivenessthroughregulationofecmpropertiesandnotchliganddll4 AT jiayiyao lactatereceptorgpr81drivesbreastcancergrowthandinvasivenessthroughregulationofecmpropertiesandnotchliganddll4 AT laiapblasco lactatereceptorgpr81drivesbreastcancergrowthandinvasivenessthroughregulationofecmpropertiesandnotchliganddll4 AT mettetrauelsen lactatereceptorgpr81drivesbreastcancergrowthandinvasivenessthroughregulationofecmpropertiesandnotchliganddll4 AT muthulakshmiponniah lactatereceptorgpr81drivesbreastcancergrowthandinvasivenessthroughregulationofecmpropertiesandnotchliganddll4 AT marcseverin lactatereceptorgpr81drivesbreastcancergrowthandinvasivenessthroughregulationofecmpropertiesandnotchliganddll4 AT albinsandelin lactatereceptorgpr81drivesbreastcancergrowthandinvasivenessthroughregulationofecmpropertiesandnotchliganddll4 AT mariekveiborg lactatereceptorgpr81drivesbreastcancergrowthandinvasivenessthroughregulationofecmpropertiesandnotchliganddll4 AT thuewschwartz lactatereceptorgpr81drivesbreastcancergrowthandinvasivenessthroughregulationofecmpropertiesandnotchliganddll4 AT stinefpedersen lactatereceptorgpr81drivesbreastcancergrowthandinvasivenessthroughregulationofecmpropertiesandnotchliganddll4 |