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Research Articles

Targeting YAP-Dependent MDSC Infiltration Impairs Tumor Progression

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 and Ronald A. DePinho
Guocan Wang
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Xin Lu
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Prasenjit Dey
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Pingna Deng
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Chia Chin Wu
3Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Shan Jiang
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Zhuangna Fang
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
4Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.
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Kun Zhao
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Ramakrishna Konaparthi
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Sujun Hua
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Jianhua Zhang
3Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Elsa M. Li-Ning-Tapia
5Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Avnish Kapoor
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Chang-Jiun Wu
3Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Neelay Bhaskar Patel
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Zhenglin Guo
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Vandhana Ramamoorthy
3Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Trang N. Tieu
3Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Tim Heffernan
3Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Di Zhao
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Xiaoying Shang
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Sunada Khadka
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Pingping Hou
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Baoli Hu
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Eun-Jung Jin
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6Department of Biological Science, College of Natural Sciences, Wonkwang University, Cheonbuk, Iksan, South Korea.
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Wantong Yao
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Xiaolu Pan
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Zhihu Ding
7Sanofi Oncology, Cambridge, Massachusetts.
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Yanxia Shi
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
4Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.
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Liren Li
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
4Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.
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Qing Chang
3Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Patricia Troncoso
8Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Christopher J. Logothetis
5Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Mark J. McArthur
9Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Lynda Chin
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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Y. Alan Wang
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • For correspondence: yalanwang@mdanderson.org rdepinho@mdanderson.org
Ronald A. DePinho
1Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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  • For correspondence: yalanwang@mdanderson.org rdepinho@mdanderson.org
DOI: 10.1158/2159-8290.CD-15-0224 Published January 2016
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Abstract

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

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Received February 23, 2015.
  • Revision received October 5, 2015.
  • Accepted October 16, 2015.
  • ©2015 American Association for Cancer Research.
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Cancer Discovery: 6 (1)
January 2016
Volume 6, Issue 1
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Targeting YAP-Dependent MDSC Infiltration Impairs Tumor Progression
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 and Ronald A. DePinho
Cancer Discov January 1 2016 (6) (1) 80-95; DOI: 10.1158/2159-8290.CD-15-0224

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Targeting YAP-Dependent MDSC Infiltration Impairs Tumor Progression
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 and Ronald A. DePinho
Cancer Discov January 1 2016 (6) (1) 80-95; DOI: 10.1158/2159-8290.CD-15-0224
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