Acquired semi-squamatization during chemotherapy suggests differentiation as a therapeutic strategy for bladder cancer

• DOI: 10.1016/j.ccell.2022.08.010
• Publication Date: 2022-09-12T14:58:40Z
• Authors: Manli Wang; Xuelan Chen; Ping Tan; Yiyun Wang; Xiangyu Pan; Tianhai Lin; Yong Jiang; Bo Wang; Huan Xu; Yuying Wang; Yucen Yang; Jian Wang; Lei Zhao; Jiapeng Zhang; Ailing Zhong; Yiman Peng; Jiajia Du; Qi Zhang; Jianan Zheng; Jingyao Chen; Siqi Dai; Feifei Na; Zhenghao Lu; Jiaming Liu; Xiaonan Zheng; Lu Yang; Peng Zhang; Ping Han; Qiyong Gong; Qian Zhong; Kai Xiao; Hanshuo Yang; Hongxin Deng; Yinglan Zhao; Hubing Shi; Jianghong Man; Maling Gou; Chengjian Zhao; Lunzhi Dai; Zhihong Xue; Lu Chen; Yuan Wang; Musheng Zeng; Canhua Huang; Qiang Wei; Yuquan Wei; Yu Liu; Chong Chen
• Keywords: Mice; 0303 health sciences; 03 medical and health sciences; Urinary Bladder Neoplasms; Carcinoma, Squamous Cell; Animals; Humans; Cell Differentiation; Cisplatin; 3. Good health

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.