Tao Julia, Murray Jason, Tu Hsin-Fang, Fan Darrell, Tsai Ya-Chea, Hu Ming-Hung, Wu Annie A, Xing Deyin, Hung Chien-Fu, Wu T-C
Department of Pathology, Johns Hopkins University School of Medicine, 1550 Orleans Street, CRB II 307, Baltimore, MD, 21287, USA.
Department of Surgery, Yale School of Medicine, Yale University, New Haven, CT, USA.
Cell Biosci. 2025 Jun 18;15(1):84. doi: 10.1186/s13578-025-01427-5.
Human papillomavirus associated head and neck cancer (HPV + HNC) is rising globally, emphasizing the need for improved therapeutic and screening strategies. To test novel therapies and study HPV-related disease progression, it is vital to develop relevant preclinical models. However, many fail to address critical concerns, including generating a representative immune microenvironment and adequately modeling HPV-driven malignant transformation. Recent multi-omics studies reveal the significance of HPV integration location in HPV-related carcinogenesis and highlight the necessity of targeted treatment methods. Thus, we have developed a murine model of HPV16 + HNC modifying the published CRISPR-based Somatic Oncogene kNock-In for Cancer Modeling (CRISPR-SONIC) system for precise integration of HPV oncogenes. We showed that CRISPR-SONIC knock-in of Kras, HPV16 E6 and E7, and a luciferase reporter at the murine β-actin 3'-UTR locus could induce spontaneous buccal tumors with sarcomatous morphology under transient or selective immunosuppression. Both preventative and therapeutic pNGVL4a-CRT/E7(detox) DNA vaccination could induce HPV16 E7-specific immune response and reduce tumor growth. Furthermore, CRISPR-SONIC knock-in of HPV16 E6 and E7 with co-delivery of HNC-relevant oncogenes AKT and c-Myc produced tumors in NSG mice capturing the characteristic carcinomic morphology of HPV + HNC. Overall, our model offers a robust platform for evaluating new therapies and exploring HPV-related carcinogenesis.
人乳头瘤病毒相关头颈癌（HPV + HNC）在全球范围内呈上升趋势，这凸显了改进治疗和筛查策略的必要性。为了测试新型疗法并研究HPV相关疾病的进展，开发相关的临床前模型至关重要。然而，许多模型未能解决关键问题，包括生成具有代表性的免疫微环境以及充分模拟HPV驱动的恶性转化。最近的多组学研究揭示了HPV整合位点在HPV相关致癌作用中的重要性，并强调了靶向治疗方法的必要性。因此，我们开发了一种HPV16 + HNC小鼠模型，对已发表的基于CRISPR的体细胞癌基因敲入癌症建模（CRISPR-SONIC）系统进行了改进，以实现HPV癌基因的精确整合。我们发现，在小鼠β-肌动蛋白3'-UTR位点进行Kras、HPV16 E6和E7以及荧光素酶报告基因的CRISPR-SONIC敲入，可在短暂或选择性免疫抑制下诱导出具有肉瘤形态的自发性颊部肿瘤。预防性和治疗性pNGVL4a-CRT/E7（解毒）DNA疫苗接种均可诱导HPV16 E7特异性免疫反应并减少肿瘤生长。此外，在NSG小鼠中，CRISPR-SONIC敲入HPV16 E6和E7并共递送与HNC相关的癌基因AKT和c-Myc，产生了具有HPV + HNC特征性癌形态的肿瘤。总体而言，我们的模型为评估新疗法和探索HPV相关致癌作用提供了一个强大的平台。
