Acquired semi-squamalization during chemotherapy suggests a differentiation therapy for bladder cancer

Cisplatin-based chemotherapy is the most common treatment for unresectable bladder cancers and also increasingly used as neoadjuvant treatments before or after surgery and radiotherapy. Unfortunately, though many patients respond to the treatment, most of them develop resistance quickly with unclear mechanisms and few further treatment options. Here, we report that semi-squamazation is acquired during chemo treatment in both mice and human. Multi-omics analyses show that cathepsin H (CTSH), a direct target of p63, is associated with chemoresistance and semi-squamation. Treatment with the cathepsin inhibitor E64 specifically restrains chemoresistant but not chemosensitive cancer. Mechanistically, cathepsin inhibition induces fully squamous differentiation of bladder cancer cells, which requires TNF receptor 1alpha and is associated with pyroptosis. Our study suggests that semi-squamazation would be a diagnosistic marker for chemoresistance and differentiation therapy by targeting CTSH might be a potential treatment for chemoresistant bladder cancer. Overall design: Bulk RNAseq, ATAC-seq and sc-RNAseq in chemotherapy- sensitive and resistant mouse bladder cancer; sc-RNAseq in mouse chemo resistant tumors treated with vehicle or E64; Bulk RNAseq in chemotherapy-resistant mouse bladder cancer treated by E64 or vehicle; Bulk RNAseq and sc-RNAseq in chemotherapy-sensitive and resistant human bladder cancer.