WDR4-driven PML destruction fosters immunosuppressive and pro-metastatic lung tumor microenvironment
Ya-Ting Wang1,2Jocelyn Chen1,2Chou-Wei Chang1Jayu Jen3,4Tzu-Yu Huang1Chun-Ming Chen1Roger Shen5Suh-Yuen Liang1I-Cheng Cheng6Shuenn-Chen Yang5Wu-Wei Lai7Kuang-Hung Cheng8Tao-Shih Hsieh6Ming-Zong Lai9Hung-Chi Cheng3,10Yi-Ching Wang3,4Ruey-Hwa Chen1,2
1. Institute of Biological Chemistry,“Academia Sinica”2. Institute of Biochemical Sciences,College of Life Science,Taiwan University3. Institute of Basic Medical Sciences,College of Medicine,Cheng Kung University4. Department of Pharmacology,College of Medicine,Cheng Kung University5. Institute of Biomedical Sciences,“Academia Sinica”6. Institute of Cellular and Organismic Biology,“Academia Sinica”7. Department of Surgery,Cheng Kung University Hospital8. Graduate Institute of Biomedical Science,Sun Yat-Sen University9. Institute of Molecular Biology,“Academia Sinica”10. Department of Biochemistry and Molecular Biology,College of Medicine,Cheng Kung University
摘要：The tumor microenvironment plays an important role in tumor growth and metastasis.However,the mechanism by which tumor cells regulate the cell and non-cell constituents of surrounding stroma remains incompletely understood.PML is a pleiotropic tumor suppressor but its role in tumor microenvironment regulation is poorly characterized.PML protein is frequently downregulated in many cancer types,including lung cancer.Here,we identify a novel PML ubiquitination/destruction pathway mediated by ubiquitin ligase CRL4WDR4.Clinically,this PML destruction pathway is hyperactivated in lung cancer and correlates with poor prognosis.The WDR4/PML axis induces a set of cell surface or secreted factors,including CD73,uPAR,and SAA2,which elicit paracrine effects to stimulate migration,invasion,and metastasis in multiple lung cancer models.Furthermore,in both xenograft and genetically engineered mouse models,the WDR4/PML axis elevates intratumoral Tregs and M2-like macrophages and reduces CD8+ T cells to promote lung tumor growth and these immunosuppressive effects are all reversed by CD73 blockade.Our study identifies WDR4 as a novel oncoprotein which negatively regulates PML via ubiquitination to promote lung cancer progression by fostering an immunosuppressive and pro-metastatic tumor microenvironment and suggests a potential of immune-modulatory approaches for treating lung cancer with aberrant PML degradation.