Journal
CANCER DISCOVERY
Volume 10, Issue 3, Pages 371-381Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-19-0400
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Funding
- Cancer Research Institute Irvington Postdoctoral Fellowship
- Harold C. and Mary L. Daily Endowment Fellowship
- Caroline Ross Endowed Fellowship
- Emerson Collective Award
- NIH [R01 CA231349, P01 CA117969, R01 CA084628]
- Clayton & Modesta William Cancer Research Fund
- Burkhart III Distinguished University Chair in Cancer Research Endowment
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Glioblastoma (GBM) is a lethal brain tumor containing a subpopulation of glioma stem cells (GSC). Pan-cancer analyses have revealed that stemness of cancer cells correlates positively with immunosuppressive pathways in many solid tumors, including GBM, prompting us to conduct a gain-of-function screen of epigenetic regulators that may influence GSC self-renewal and tumor immunity. The circadian regulator CLOCK emerged as a top hit in enhancing stem-cell self-renewal, which was amplified in about 5% of human GBM cases. CLOCK and its heterodimeric partner BMAL1 enhanced GSC self-renewal and triggered protumor immunity via transcriptional upregulation of OLFML3, a novel chemokine recruiting immune-suppressive microglia into the tumor microenvironment. In GBM models, CLOCK or OLFML3 depletion reduced intratumoral microglia density and extended overall survival. We conclude that the CLOCK-BMAL1 complex contributes to key GBM hallmarks of GSC maintenance and immunosuppression and, together with its downstream target OLFML3, represents new therapeutic targets for this disease. SIGNIFICANCE: Circadian regulator CLOCK drives GSC self-renewal and metabolism and promotes microglia infiltration through direct regulation of a novel microglia-attracting chemokine, OLFML3. CLOCK and/or OLFML3 may represent novel therapeutic targets for GBM.
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