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Lysophosphatidic Acid Receptor Signaling in the Human Breast Cancer Tumor Microenvironment Elicits Receptor-Dependent Effects on Tumor Progression
Lysophosphatidic acid receptors (LPARs) are six G-protein-coupled receptors that mediate LPA signaling to promote tumorigenesis and therapy resistance in many cancer subtypes, including breast cancer. Individual-receptor-targeted monotherapies are under investigation, but receptor agonism or antagon...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10298074/ https://www.ncbi.nlm.nih.gov/pubmed/37372960 http://dx.doi.org/10.3390/ijms24129812 |
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author | Benesch, Matthew G. K. Wu, Rongrong Tang, Xiaoyun Brindley, David N. Ishikawa, Takashi Takabe, Kazuaki |
author_facet | Benesch, Matthew G. K. Wu, Rongrong Tang, Xiaoyun Brindley, David N. Ishikawa, Takashi Takabe, Kazuaki |
author_sort | Benesch, Matthew G. K. |
collection | PubMed |
description | Lysophosphatidic acid receptors (LPARs) are six G-protein-coupled receptors that mediate LPA signaling to promote tumorigenesis and therapy resistance in many cancer subtypes, including breast cancer. Individual-receptor-targeted monotherapies are under investigation, but receptor agonism or antagonism effects within the tumor microenvironment following treatment are minimally understood. In this study, we used three large, independent breast cancer patient cohorts (TCGA, METABRIC, and GSE96058) and single-cell RNA-sequencing data to show that increased tumor LPAR1, LPAR4, and LPAR6 expression correlated with a less aggressive phenotype, while high LPAR2 expression was particularly associated with increased tumor grade and mutational burden and decreased survival. Through gene set enrichment analysis, it was determined that cell cycling pathways were enriched in tumors with low LPAR1, LPAR4, and LPAR6 expression and high LPAR2 expression. LPAR levels were lower in tumors over normal breast tissue for LPAR1, LPAR3, LPAR4, and LPAR6, while the opposite was observed for LPAR2 and LPAR5. LPAR1 and LPAR4 were highest in cancer-associated fibroblasts, while LPAR6 was highest in endothelial cells, and LPAR2 was highest in cancer epithelial cells. Tumors high in LPAR5 and LPAR6 had the highest cytolytic activity scores, indicating decreased immune system evasion. Overall, our findings suggest that potential compensatory signaling via competing receptors must be considered in LPAR inhibitor therapy. |
format | Online Article Text |
id | pubmed-10298074 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-102980742023-06-28 Lysophosphatidic Acid Receptor Signaling in the Human Breast Cancer Tumor Microenvironment Elicits Receptor-Dependent Effects on Tumor Progression Benesch, Matthew G. K. Wu, Rongrong Tang, Xiaoyun Brindley, David N. Ishikawa, Takashi Takabe, Kazuaki Int J Mol Sci Article Lysophosphatidic acid receptors (LPARs) are six G-protein-coupled receptors that mediate LPA signaling to promote tumorigenesis and therapy resistance in many cancer subtypes, including breast cancer. Individual-receptor-targeted monotherapies are under investigation, but receptor agonism or antagonism effects within the tumor microenvironment following treatment are minimally understood. In this study, we used three large, independent breast cancer patient cohorts (TCGA, METABRIC, and GSE96058) and single-cell RNA-sequencing data to show that increased tumor LPAR1, LPAR4, and LPAR6 expression correlated with a less aggressive phenotype, while high LPAR2 expression was particularly associated with increased tumor grade and mutational burden and decreased survival. Through gene set enrichment analysis, it was determined that cell cycling pathways were enriched in tumors with low LPAR1, LPAR4, and LPAR6 expression and high LPAR2 expression. LPAR levels were lower in tumors over normal breast tissue for LPAR1, LPAR3, LPAR4, and LPAR6, while the opposite was observed for LPAR2 and LPAR5. LPAR1 and LPAR4 were highest in cancer-associated fibroblasts, while LPAR6 was highest in endothelial cells, and LPAR2 was highest in cancer epithelial cells. Tumors high in LPAR5 and LPAR6 had the highest cytolytic activity scores, indicating decreased immune system evasion. Overall, our findings suggest that potential compensatory signaling via competing receptors must be considered in LPAR inhibitor therapy. MDPI 2023-06-06 /pmc/articles/PMC10298074/ /pubmed/37372960 http://dx.doi.org/10.3390/ijms24129812 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Benesch, Matthew G. K. Wu, Rongrong Tang, Xiaoyun Brindley, David N. Ishikawa, Takashi Takabe, Kazuaki Lysophosphatidic Acid Receptor Signaling in the Human Breast Cancer Tumor Microenvironment Elicits Receptor-Dependent Effects on Tumor Progression |
title | Lysophosphatidic Acid Receptor Signaling in the Human Breast Cancer Tumor Microenvironment Elicits Receptor-Dependent Effects on Tumor Progression |
title_full | Lysophosphatidic Acid Receptor Signaling in the Human Breast Cancer Tumor Microenvironment Elicits Receptor-Dependent Effects on Tumor Progression |
title_fullStr | Lysophosphatidic Acid Receptor Signaling in the Human Breast Cancer Tumor Microenvironment Elicits Receptor-Dependent Effects on Tumor Progression |
title_full_unstemmed | Lysophosphatidic Acid Receptor Signaling in the Human Breast Cancer Tumor Microenvironment Elicits Receptor-Dependent Effects on Tumor Progression |
title_short | Lysophosphatidic Acid Receptor Signaling in the Human Breast Cancer Tumor Microenvironment Elicits Receptor-Dependent Effects on Tumor Progression |
title_sort | lysophosphatidic acid receptor signaling in the human breast cancer tumor microenvironment elicits receptor-dependent effects on tumor progression |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10298074/ https://www.ncbi.nlm.nih.gov/pubmed/37372960 http://dx.doi.org/10.3390/ijms24129812 |
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