Bladder cancer (BC) is the fourth most common cancer in men, with a poor patient prognosis for advanced disease. The poor survival of patients with muscle-invasive bladder cancer (MIBC) and metastatic status emphasizes the urgent need to develop new therapies. Lacking in the field of BC is the availability of relevant advanced BC mouse models, especially metastatic ones, that accurately recapitulate the complexities of human pathology to test and study new therapeutic strategies. Addressing this need, we developed a traceable mouse model of BC that expresses tumor-associated antigens within the context of advanced muscle-invasive BC. This novel system was achieved through the deletion of thetp53andptengenes, alongside the incorporation of the fusion construct of Firefly luciferase (Luc) and the SIYRYYGL (SIY) T-cell antigen. We validate that the presence of the transgene did not impact on the development of the tumors while allowing us to measure tumor progression by bioluminescence. We show that the transgene did not influence the composition of the immune tumor microenvironment. More importantly, we report that this model was unresponsive to anti-PD-1 treatment, as in the majority of patients with BC. We also develop a new model based on the orthotopic injection of BC clonal cell lines derived from our first model. We demonstrate that this new model invades the muscle layer and has a metastasis development rate of 83%. The advantage of this model is that we can visualize tumor growth and metastasis development in vivo. These mouse models’ characteristics, displaying many similarities with the human pathology, provide a valuable tool for tracking tumor progression, metastasis spread in vivo, and treatment resistance, as well as exploring fundamental and translational aspects of BC biology. This work contributes to the improvement in the landscape of mouse models of advanced BC for testing new therapeutic strategies.
膀胱癌是男性第四大常见癌症，晚期患者预后较差。肌层浸润性膀胱癌及转移性膀胱癌患者的低生存率凸显了开发新疗法的迫切需求。当前膀胱癌研究领域缺乏能够准确模拟人类疾病复杂性、用于测试和研究新治疗策略的相关晚期膀胱癌小鼠模型，尤其是转移模型。为满足这一需求，我们开发了一种可追踪的膀胱癌小鼠模型，该模型在晚期肌层浸润性膀胱癌背景下表达肿瘤相关抗原。这一新型系统通过敲除tp53和pten基因，并整合萤火虫荧光素酶与SIYRYYGL T细胞抗原的融合构建体而实现。我们验证了转基因的存在不影响肿瘤发展，同时可通过生物发光技术监测肿瘤进展。研究表明转基因未改变肿瘤免疫微环境的组成。更重要的是，该模型与大多数膀胱癌患者类似，对抗PD-1治疗无响应。基于首代模型衍生的膀胱癌克隆细胞系，我们还通过原位注射技术建立了新模型。该新模型可侵袭肌层，转移发生率达83%，其优势在于能够实现肿瘤生长和转移过程的体内可视化。这些小鼠模型的特征与人类病理学高度相似，为追踪肿瘤进展、体内转移扩散及治疗耐药性提供了重要工具，同时有助于探索膀胱癌生物学的基础与转化研究方向。本研究成果为优化晚期膀胱癌小鼠模型体系、测试新治疗策略作出了贡献。
Development of Traceable Mouse Models of Advanced and Metastatic Bladder Cancer
肿瘤(癌症)患者之家