Microglial lysophosphatidic acid promotes glioblastoma proliferation and migration via LPA₁ receptor

Abstract

Glioblastomas (GBMs) are highly aggressive primary brain tumors characterized by cellular heterogeneity, insensitivity to chemotherapy and poor patient survival. Lysophosphatidic acid (LPA) is a lysophospholipid that acts as a bioactive signaling molecule and plays important roles in diverse biological events during development and disease, including several cancer types. Microglial cells, the resident macrophages of the central nervous system, express high levels of Autotaxin (ATX,Enpp2), an enzyme that synthetizes LPA. Our study aimed to investigate the role of LPA on tumor growth and invasion in the context of microglia-GBM interaction. First, through bioinformatics studies, patient data analysis demonstrated that more aggressive GBM expressed higher levels of ENPP2, which was also associated with worse patient prognosis with proneural GBM. Using GBM-microglia co-culture system we then demonstrated that GBM secreted factors were able to increase LPA 1 and ATX in microglia, which could be further enhanced by hypoxia. On the other hand, interaction with microglial cells also increased ATX expression in GBM. Furthermore, microglialinduced GBM proliferation and migration could be inhibited by pharmacological inhibition of LPA 1 , suggesting that microglial-derived LPA could support tumor growth and invasion. Finally, increased LPA 1 expression was observed in GBM comparing with other gliomas and could be also associated with worse patient survival. These results show for the first time a microglia-GBM interaction through the LPA pathway with relevant implications for tumor progression. A better understanding of this interaction can lead to the development of new therapeutic strategies setting LPA as a potential target for GBM treatment.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and glial cells: Insights and perspectives

“…Whether this response collaborates in the development or delay of the disease is still a matter of discussion and is highly dependent on the insult, stage of the disease and brain region. Emerging evidence from our group and others supports the concept that reactive glial cells, astrocytes and microglia have a duality in their phenotype, neurotoxic or neuroprotective properties, depending on the age, infectious stimuli, and physiological/pathological condition ( Moraes et al., 2015 ; Diniz et al., 2017 ; Diniz et al., 2019 ; Matias et al., 2019 ; do Amaral et al., 2020 ). The underlying mechanisms of their activation, cellular interplays and the impact of regional astrocytic and microglial heterogeneity are still a matter of discussion.…”

Lysophosphatidic Acid Receptor Antagonists and Cancer: The Current Trends, Clinical Implications, and Trials

“…Studies show that LPAR1 enhances metastasis and tumor motility [ 18 ]. Aberrant LPAR1 expressions were observed in many cancer cell lines and primary tumors, including ovarian cancer [ 24 ], breast cancer [ 25 ], liver cancer [ 26 ], gastric cancer [ 27 ], pancreatic cancer [ 28 , 29 ], lung cancer [ 30 , 31 ], glioblastoma (GBM) [ 32 , 33 , 34 ], and osteosarcoma [ 35 ]. Ovarian cancer is the most investigated cancer in studying the malignancy of LPA signaling.…”

“…For lung A549 cancer cells, the LPAR1/Gi/MAP kinase/NF-κB pathway is involved in LPA-induced oncogenesis, and using the LPAR1/3 antagonist Ki16425 to block LPAR1-mediated signaling would significantly reduce tumor volume [ 31 ]. In GBM, LPAR1 expression is also significantly higher than other gliomas [ 32 ]. Of interest, the LPA pathway of microglia-and-GBM interaction is a target to improve survival because microglia-derived LPA and ATX upon hypoxia stress may promote GBM proliferation and migration [ 32 ].…”

“…In GBM, LPAR1 expression is also significantly higher than other gliomas [ 32 ]. Of interest, the LPA pathway of microglia-and-GBM interaction is a target to improve survival because microglia-derived LPA and ATX upon hypoxia stress may promote GBM proliferation and migration [ 32 ]. A recent report indicates LPAR1/PKCα/progesterone receptor pathway is involved in GBM migration [ 40 ].…”

Macrophages/Microglia in the Glioblastoma Tumor Microenvironment

“…Autotaxin (also termed ATX or Enpp2) is an enzyme that synthetizes Lysophosphatidic acid (LPA) which is a lysophospholipid that acts as a bioactive signaling molecule. Microglial cells express high levels of Autotaxin, suggesting a microglia-GBM interaction through the LPA pathway with relevant implications for tumor progression [ 53 ].…”