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

Cisplatin-based chemotherapy remains the primary treatment for unresectable and metastatic muscle -inva-sive 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 che-moresistant 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 dif-ferentiation via targeting of CTSH is a potential therapeutic strategy for the treatment of chemoresist-ant MIBCs.

Automated summary

This study established a mouse model using gene-edited organoids to mimic the chemotherapy process in patients. The findings revealed that semi-squamatization is associated with acquired chemoresistance in MIBCs. Cathepsin H was correlated with chemoresistance and semi-squamatization. Treatment with E64, a cathepsin inhibitor, induced full squamous differentiation and pyroptosis, specifically targeting chemoresistant MIBCs.