Abstract：
Cisplatin-based chemotherapy remains the primary treatment for unresectable and metastatic muscle-invasive bladder cancers (MIBCs). However, tumors frequently develop chemoresistance. Here, we established a primary and orthotopic MIBC mouse model with gene-edited organoids to recapitulate the full course of chemotherapy in patients. We found that partial squamous differentiation, called semi-squamatization, is associated with acquired chemoresistance in both mice and human MIBCs. Multi-omics analyses showed that cathepsin H (CTSH) is correlated with chemoresistance and semi-squamatization. Cathepsin inhibition by E64 treatment induces full squamous differentiation and pyroptosis, and thus specifically restrains chemoresistant MIBCs. Mechanistically, E64 treatment activates the tumor necrosis factor pathway, which is required for the terminal differentiation and pyroptosis of chemoresistant MIBC cells. Our study revealed that semi-squamatization is a type of lineage plasticity associated with chemoresistance, suggesting that differentiation via targeting of CTSH is a potential therapeutic strategy for the treatment of chemoresistant MIBCs.
摘要：
基于顺铂的化疗仍然是不可切除和转移性肌肉浸润性膀胱癌（MIBCs）的主要治疗方法。然而,肿瘤经常发展化疗耐药。这里,我们用基因编辑的类器官建立了原发性和原位MIBC小鼠模型,以概括患者化疗的整个过程.我们发现部分鳞状分化，称为半空间化，与小鼠和人类MIBCs的获得性化学抗性有关。多组学分析表明，组织蛋白酶H（CTSH）与化学抗性和半污损化相关。E64治疗抑制组织蛋白酶诱导完全鳞状细胞分化和焦亡，并因此特别抑制化学抗性MIBCs。机械上,E64治疗激活肿瘤坏死因子途径，这对于化学抗性MIBC细胞的终末分化和焦亡是必需的。我们的研究表明，半菌化是一种与化学抗性相关的谱系可塑性，提示通过靶向CTSH进行分化是治疗化疗耐药MIBCs的潜在治疗策略。
