American Association for Cancer Research
21598290cd150224-sup-145648_2_supp_3169211_nvkx06.pdf (41.14 kB)

Supplementary Table S5 from Targeting YAP-Dependent MDSC Infiltration Impairs Tumor Progression

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journal contribution
posted on 2023-04-03, 21:00 authored by Guocan Wang, Xin Lu, Prasenjit Dey, Pingna Deng, Chia Chin Wu, Shan Jiang, Zhuangna Fang, Kun Zhao, Ramakrishna Konaparthi, Sujun Hua, Jianhua Zhang, Elsa M. Li-Ning-Tapia, Avnish Kapoor, Chang-Jiun Wu, Neelay Bhaskar Patel, Zhenglin Guo, Vandhana Ramamoorthy, Trang N. Tieu, Tim Heffernan, Di Zhao, Xiaoying Shang, Sunada Khadka, Pingping Hou, Baoli Hu, Eun-Jung Jin, Wantong Yao, Xiaolu Pan, Zhihu Ding, Yanxia Shi, Liren Li, Qing Chang, Patricia Troncoso, Christopher J. Logothetis, Mark J. McArthur, Lynda Chin, Y. Alan Wang, Ronald A. DePinho

Overlapped genes between Genes upregulated in Ptenpc-/-Smad4pc-/- tumors as compared to Ptenpc-/- tumors ({greater than or equal to}2 fold) and genes upregulated in GFP+ tumors cells from Ptenpc-/-Smad4pc-/- mice as compared to Tomato+ cells ({greater than or equal to}4 fold).



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

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