Metastatic penile squamous cell carcinoma (PSCC) has only a 50% response rate to first-line combination chemotherapies and there are currently no targeted-therapy approaches. Therefore, we have an urgent need in advanced-PSCC treatment to find novel therapies. Approximately half of all PSCC cases are positive for high-risk human papillomavirus (HR-HPV). Our objective was to generate HPV-positive (HPV+) and HPV-negative (HPV−) patient-derived xenograft (PDX) models and to determine the biological differences between HPV+ and HPV− disease. We generated four HPV+ and three HPV− PSCC PDX animal models by directly implanting resected patient tumor tissue into immunocompromised mice. PDX tumor tissue was found to be similar to patient tumor tissue (donor tissue) by histology and short tandem repeat fingerprinting. DNA mutations were mostly preserved in PDX tissues and similar APOBEC (apolipoprotein B mRNA editing catalytic polypeptide) mutational fractions in donor tissue and PDX tissues were noted. A higher APOBEC mutational fraction was found in HPV+ versus HPV− PDX tissues (p= 0.044), and significant transcriptomic and proteomic expression differences based on HPV status included p16 (CDKN2A), RRM2, and CDC25C. These models will allow for the direct testing of targeted therapies in PSCC and determine their response in correlation to HPV status.
转移性阴茎鳞状细胞癌（PSCC）对一线联合化疗的应答率仅为50%，且目前尚无靶向治疗方法。因此，在晚期PSCC治疗中，我们迫切需要寻找新的疗法。约半数PSCC病例呈高危型人乳头瘤病毒（HR-HPV）阳性。本研究旨在建立HPV阳性（HPV+）与HPV阴性（HPV−）患者来源异种移植（PDX）模型，并明确HPV+与HPV−疾病的生物学差异。通过将手术切除的患者肿瘤组织直接植入免疫缺陷小鼠体内，我们成功构建了4例HPV+和3例HPV− PSCC PDX动物模型。组织学与短串联重复序列指纹分析显示PDX肿瘤组织与患者源肿瘤组织（供体组织）高度相似。DNA突变在PDX组织中基本保留，且供体组织与PDX组织具有相似的载脂蛋白B mRNA编辑催化多肽（APOBEC）突变比例。HPV+ PDX组织的APOBEC突变比例显著高于HPV−组织（p=0.044），基于HPV状态的转录组与蛋白质组表达差异主要体现在p16（CDKN2A）、RRM2和CDC25C等分子。这些模型将直接用于PSCC靶向治疗的测试，并评估其疗效与HPV状态的相关性。
肿瘤(癌症)患者之家