PT - JOURNAL ARTICLE AU - Wang, Guocan AU - Lu, Xin AU - Dey, Prasenjit AU - Deng, Pingna AU - Wu, Chia Chin AU - Jiang, Shan AU - Fang, Zhuangna AU - Zhao, Kun AU - Konaparthi, Ramakrishna AU - Hua, Sujun AU - Zhang, Jianhua AU - Li-Ning-Tapia, Elsa M. AU - Kapoor, Avnish AU - Wu, Chang-Jiun AU - Patel, Neelay Bhaskar AU - Guo, Zhenglin AU - Ramamoorthy, Vandhana AU - Tieu, Trang N. AU - Heffernan, Tim AU - Zhao, Di AU - Shang, Xiaoying AU - Khadka, Sunada AU - Hou, Pingping AU - Hu, Baoli AU - Jin, Eun-Jung AU - Yao, Wantong AU - Pan, Xiaolu AU - Ding, Zhihu AU - Shi, Yanxia AU - Li, Liren AU - Chang, Qing AU - Troncoso, Patricia AU - Logothetis, Christopher J. AU - McArthur, Mark J. AU - Chin, Lynda AU - Wang, Y. Alan AU - DePinho, Ronald A. TI - Targeting YAP-Dependent MDSC Infiltration Impairs Tumor Progression AID - 10.1158/2159-8290.CD-15-0224 DP - 2016 Jan 01 TA - Cancer Discovery PG - 80--95 VI - 6 IP - 1 4099 - http://cancerdiscovery.aacrjournals.org/content/6/1/80.short 4100 - http://cancerdiscovery.aacrjournals.org/content/6/1/80.full SO - Cancer Discov2016 Jan 01; 6 AB - 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. Cancer Discov; 6(1); 80–95. ©2015 AACR.This article is highlighted in the In This Issue feature, p. 1