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
[...] Read more.
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.
Full article
