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