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

Cancer Cell. 2022 Sep 12;40(9):1044-1059.e8. doi: 10.1016/j.ccell.2022.08.010.

Manli Wang ¹, Xuelan Chen ², Ping Tan ¹, Yiyun Wang ², Xiangyu Pan ², Tianhai Lin ¹, Yong Jiang ³, Bo Wang ², Huan Xu ³, Yuying Wang ², Yucen Yang ², Jian Wang ², Lei Zhao ², Jiapeng Zhang ¹, Ailing Zhong ², Yiman Peng ², Jiajia Du ², Qi Zhang ², Jianan Zheng ², Jingyao Chen ², Siqi Dai ², Feifei Na ⁴, Zhenghao Lu ⁵, Jiaming Liu ¹, Xiaonan Zheng ¹, Lu Yang ¹, Peng Zhang ¹, Ping Han ¹, Qiyong Gong ⁶, Qian Zhong ⁷, Kai Xiao ⁸, Hanshuo Yang ², Hongxin Deng ², Yinglan Zhao ², Hubing Shi ², Jianghong Man ⁹, Maling Gou ², Chengjian Zhao ², Lunzhi Dai ², Zhihong Xue ², Lu Chen ², Yuan Wang ², Musheng Zeng ⁷, Canhua Huang ², Qiang Wei ¹⁰, Yuquan Wei ², Yu Liu ¹¹, Chong Chen ¹²

Affiliations

1 Department of Urology, Institute of Urology, State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu, Sichuan 610041, China.
2 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
3 Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
4 Department of Thoracic Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
5 Chengdu OrganoidMed Medical Laboratory, West China Health Valley, Chengdu, Sichuan 610041, China.
6 Huaxi MR Research Center (HMRRC), Department of Radiology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, Sichuan 610041, China.
7 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510000, China.
8 Laboratory of Non-Human Primate Disease Model Research, State Key Laboratory of Biotherapy, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
9 State Key Laboratory of Proteomics, National Center of Biomedical Analysis, Beijing 100850, China.
10 Department of Urology, Institute of Urology, State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: weiqiang@scu.edu.cn.
11 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: yuliuscu@scu.edu.cn.
12 Department of Urology, Institute of Urology, State Key Laboratory of Biotherapy and Cancer Center, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: chongchen@scu.edu.cn.

PMID: 36099882 DOI: 10.1016/j.ccell.2022.08.010

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.

Keywords

E64; MIBC; TNF pathway; acquired chemoresistance; cathepsin H; differentiation therapy; lineage plasticity; pyroptosis; semi-squamatization.

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