LPA signaling is regulated through the primary cilium: a novel target in glioblastoma

• Published in: Oncogene 2018-03, Vol.37 (11), p.1457-1471
• Main Authors: Loskutov, Yuriy V., Griffin, Caryn L., Marinak, Kristina M., Bobko, Andrey, Margaryan, Naira V., Geldenhuys, Werner J., Sarkaria, Jann N., Pugacheva, Elena N.
• Format: Article
• Language: English
• Subjects: 631/67/1922; 631/80/86/2365; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Astrocytes; Astrocytes - drug effects; Astrocytes - metabolism; Astrocytes - ultrastructure; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain tumors; Cancer; Care and treatment; Cell Biology; Cell growth; Cell membranes; Cell proliferation; Cell Proliferation - drug effects; Cells (Biology); Cellular signal transduction; Cilia; Cilia - drug effects; Cilia - pathology; Cilia - physiology; Gene expression; Genetic aspects; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastomas; Gliomas; Growth rate; Human Genetics; Humans; Internal Medicine; Kinases; Lysophosphatidic acid; Lysophospholipids - antagonists & inhibitors; Lysophospholipids - metabolism; Lysophospholipids - pharmacology; Male; Medical schools; Medicine; Medicine & Public Health; Mice; Mice, Inbred NOD; Mice, Transgenic; Molecular Targeted Therapy; Nanoparticles; Oncology; Phenotypes; Polyethylene glycol; Polylactide-co-glycolide; Receptors, Lysophosphatidic Acid - antagonists & inhibitors; Receptors, Lysophosphatidic Acid - genetics; Receptors, Lysophosphatidic Acid - metabolism; Signal Transduction - drug effects; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-017-0049-3

The primary cilium is a ubiquitous organelle presented on most human cells. It is a crucial signaling hub for multiple pathways including growth factor and G-protein coupled receptors. Loss of primary cilia, observed in various cancers, has been shown to affect cell proliferation. Primary cilia formation is drastically decreased in glioblastoma (GBM), however, the role of cilia in normal astrocyte or glioblastoma proliferation has not been explored. Here, we report that loss of primary cilia in human astrocytes stimulates growth rate in a lysophosphatidic acid (LPA)-dependent manner. We show that lysophosphatidic acid receptor 1 (LPAR1) is accumulated in primary cilia. LPAR1 signaling through Gα12/Gαq was previously reported to be responsible for cancer cell proliferation. We found that in ciliated cells, Gα12 and Gαq are excluded from the cilium, creating a barrier against unlimited proliferation, one of the hallmarks of cancer. Upon loss of primary cilia, LPAR1 redistributes to the plasma membrane with a concomitant increase in LPAR1 association with Gα12 and Gαq. Inhibition of LPA signaling with the small molecule compound Ki16425 in deciliated highly proliferative astrocytes or glioblastoma patient-derived cells/xenografts drastically suppresses their growth both in vitro and in vivo. Moreover, Ki16425 brain delivery via PEG-PLGA nanoparticles inhibited tumor progression in an intracranial glioblastoma PDX model. Overall, our findings establish a novel mechanism by which primary cilium restricts proliferation and indicate that loss of primary cilia is sufficient to increase mitogenic signaling, and is important for the maintenance of a highly proliferative phenotype. Clinical application of LPA inhibitors may prove beneficial to restrict glioblastoma growth and ensure local control of disease.