title: Targeting YAP-Dependent MDSC Infiltration Impairs Tumor Progression.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Guocan
authors.initials: G
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.affiliation: 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.
authors.forename: Prasenjit
authors.initials: P
authors.lastname: Dey
authors.affiliation: 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.
authors.forename: Pingna
authors.initials: P
authors.lastname: Deng
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chia Chin
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Zhuangna
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhao
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Konaparthi
authors.affiliation: 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.
authors.forename: Sujun
authors.initials: S
authors.lastname: Hua
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Elsa M
authors.initials: EM
authors.lastname: Li-Ning-Tapia
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Avnish
authors.initials: A
authors.lastname: Kapoor
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Chang-Jiun
authors.initials: CJ
authors.lastname: Wu
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Neelay Bhaskar
authors.initials: NB
authors.lastname: Patel
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Vandhana
authors.initials: V
authors.lastname: Ramamoorthy
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Trang N
authors.initials: TN
authors.lastname: Tieu
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Tim
authors.initials: T
authors.lastname: Heffernan
authors.affiliation: 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.
authors.forename: Di
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Shang
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Sunada
authors.initials: S
authors.lastname: Khadka
authors.affiliation: 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.
authors.forename: Pingping
authors.initials: P
authors.lastname: Hou
authors.affiliation: 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.
authors.forename: Baoli
authors.initials: B
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Jin
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Wantong
authors.initials: W
authors.lastname: Yao
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Pan
authors.affiliation: Sanofi Oncology, Cambridge, Massachusetts.
authors.forename: Zhihu
authors.initials: Z
authors.lastname: Ding
authors.affiliation: 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.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Shi
authors.affiliation: 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.
authors.forename: Liren
authors.initials: L
authors.lastname: Li
authors.affiliation: Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chang
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Patricia
authors.initials: P
authors.lastname: Troncoso
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
authors.affiliation: Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: McArthur
authors.affiliation: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.affiliation: 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.
authors.forename: Y Alan
authors.initials: YA
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. yalanwang@mdanderson.org rdepinho@mdanderson.org.
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D054365:Chemokine CXCL5 / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D000090683:Hippo Signaling Pathway; D006801:Humans; D008297:Male; D051379:Mice; D022423:Myeloid Cells / Q000276:immunology*; D051059:PTEN Phosphohydrolase / Q000172:deficiency*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051901:Smad4 Protein / Q000172:deficiency*; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D054365:Chemokine CXCL5; C094739:Cxcl5 protein, mouse; D010750:Phosphoproteins; D023063:Receptors, Interleukin-8B; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D017346:Protein Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse