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Cancer Discov. 2016 Jan;6(1):80-95. doi: 10.1158/2159-8290.CD-15-0224. Epub 2015 Dec 23.

Targeting YAP-Dependent MDSC Infiltration Impairs Tumor Progression.

Author information

1
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
3
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
4
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China.
5
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Biological Science, College of Natural Sciences, Wonkwang University, Cheonbuk, Iksan, South Korea.
8
Sanofi Oncology, Cambridge, Massachusetts.
9
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
10
Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
11
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. yalanwang@mdanderson.org rdepinho@mdanderson.org.
12
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. yalanwang@mdanderson.org rdepinho@mdanderson.org.

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.

PMID:
26701088
PMCID:
PMC4707102
DOI:
10.1158/2159-8290.CD-15-0224
[Indexed for MEDLINE]
Free PMC Article

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