Penile squamous cell carcinoma (PSCC) accounts for over 95% of penile malignancies and causes significant mortality and morbidity in developing countries. Molecular mechanisms and therapies of PSCC are understudied, owing to scarcity of laboratory models. Herein, we describe a genetically engineered mouse model of PSCC, by co-deletion of Smad4 and Apc in the androgen-responsive epithelium of the penis. Mouse PSCC fosters an immunosuppressive microenvironment with myeloid-derived suppressor cells (MDSCs) as a dominant population. Preclinical trials in the model demonstrate synergistic efficacy of immune checkpoint blockade with the MDSC-diminishing drugs cabozantinib or celecoxib. A critical clinical problem of PSCC is chemoresistance to cisplatin, which is induced by Pten deficiency on the backdrop of Smad4/Apc co-deletion. Drug screen studies informed by targeted proteomics identify a few potential therapeutic strategies for PSCC. Our studies have established what we believe to be essential resources for studying PSCC biology and developing therapeutic strategies.
Nature communications. 2020 May 01*** epublish ***
Tianhe Huang, Xi Cheng, Jad Chahoud, Ahmed Sarhan, Pheroze Tamboli, Priya Rao, Ming Guo, Ganiraju Manyam, Li Zhang, Yu Xiang, Leng Han, Xiaoying Shang, Pingna Deng, Yanting Luo, Xuemin Lu, Shan Feng, Magaly Martinez Ferrer, Y Alan Wang, Ronald A DePinho, Curtis A Pettaway, Xin Lu
Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, 46556, USA., Department of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Department of Pathology/Lab Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Department of Bioinformatics & Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Department of Environmental Health, University of Cincinnati, Cincinnati, OH, 45267, USA., Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX, 77030, USA., Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Mass Spectrometry Core Facility, School of Life Sciences, Westlake University, Hangzhou, 310024, Zhejiang, China., Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico, San Juan, PR, 00936, USA., Department of Biological Sciences, Boler-Parseghian Center for Rare and Neglected Diseases, Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN, 46556, USA. .