Journal
CANCER DISCOVERY
Volume 6, Issue 1, Pages 80-95Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-15-0224
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Funding
- Prostate Cancer Research Program (PCRP) [W81XWH-13-1-0202, W81XWH-14-1-0429]
- Idea Development Award-New Investigator Option from the Department of Defense [W81XWH-14-1-0576]
- Clayton & Modesta Williams Cancer Research Fund
- Jane Coffin Childs Memorial Fund Postdoctoral Fellowship
- Korean Governments (MISP) [2011-0030130]
- [U01CA141508]
- NATIONAL CANCER INSTITUTE [R37CA084628, P30CA016672, U01CA141508, K99CA194289] Funding Source: NIH RePORTER
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The signaling mechanisms between prostate cancer cells and infiltrating immune cells may illuminate novel therapeutic approaches. Here, utilizing a prostate adenocarcinoma model driven by loss of Pten and Smad4, we identify polymorphonuclear myeloid-derived suppressor cells (MDSC) as the major infiltrating immune cell type, and depletion of MDSCs blocks progression. Employing a novel dual reporter prostate cancer model, epithelial and stromal transcriptomic profiling identified CXCL5 as a cancer-secreted chemokine to attract CXCR2-expressing MDSCs, and, correspondingly, pharmacologic inhibition of CXCR2 impeded tumor progression. Integrated analyses identified hyperactivated Hippo-YAP signaling in driving CXCL5 upregulation in cancer cells through the YAP-TEAD complex and promoting MDSC recruitment. Clinicopathologic studies reveal upregulation and activation of YAP1 in a subset of human prostate tumors, and the YAP1 signature is enriched in primary prostate tumor samples with stronger expression of MDSC-relevant genes. Together, YAP-driven MDSC recruitment via heterotypic CXCL5-CXCR2 signaling reveals an effective therapeutic strategy for advanced prostate cancer. SIGNIFICANCE: We demonstrate a critical role of MDSCs in prostate tumor progression and discover a cancer cell nonautonomous function of the Hippo-YAP pathway in regulation of CXCL5, a ligand for CXCR2-expressing MDSCs. Pharmacologic elimination of MDSCs or blocking the heterotypic CXCL5-CXCR2 signaling circuit elicits robust antitumor responses and prolongs survival. (C) 2015 AACR.
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