Abstract

Abstract Glioblastoma is one of the most common brain cancers with a median survival of 13 months. Therapeutic approaches for this type of cancer are very limited, creating an urgent need to develop new strategies for the treatment. Recently several groups reported that glioblastoma have a drastic decrease in primary cilia, suggesting that loss of cilia might be important for glioblastoma biology. The primary cilium is a ubiquitous microtubule based organelle presented on most of human cells. It plays significant role in embryonic development and tissue homeostasis, serving as a hub for multiple signaling cascades including RTK, Sonic Hedgehog, Wnt and Hippo. Here we report that loss of primary cilia in immortalized astrocytes stimulate cell proliferation and drastically change ERK1/2 activation in response to serum. These changes depend on lysophosphotidic acid (LPA), a water-soluble lipid metabolite, implicated in chemotactic and proliferative signaling. The receptor to LPA type 1 tends to accumulate in the primary cilia, indicating its potential role in inhibition/restriction of LPA-dependent mitogenic signaling via dynamic changes in primary cilium. Loss of primary cilia can lead to LPA receptors 1 redistribution to the plasma membrane and switch cellular response for the LPA, allowing it to act as mitogen. Inhibition of LPA receptors with a small molecule inhibitor, Ki16425, is significantly decreasing the growth of glioblastoma PDXs. Overall, our findings clearly indicate that loss of primary cilia is sufficient to severely change mitogen-driven signal transduction and point towards the new therapeutic target for glioblastoma. Citation Format: Yuriy Loskutov. Loss of primary cilia promotes LPA-driven proliferation in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 332. doi:10.1158/1538-7445.AM2017-332

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