Muscle-invasive bladder cancer (MIBC) is the most common and malignant tumor of the urinary system. Cisplatin based chemotherapy is the first-line treatment for nonsurgical and metastatic MIBC. However, due to the generation of chemotherapy resistance, a large number of patients will fail chemotherapy, leading to tumor recurrence and progression.
In collaboration with Prof. Qiang Wei of the Department of Urology, the research team of Prof. Chong Chen and Prof. Yu Liu of the State Key Laboratory of Biotherapy and Cancer Center(SKLBCC) published in Cancer Cell a research article entitled “Acquired Semi-squamatization During Chemotherapy Suggests Differentiation as a Therapeutic Strategy for Bladder Cancer”. The article was published on September 12, 2022. Dr. Manli Wang, Dr. Xuelan Chen, Dr. Ping Tan, and doctoral candidate Yiyun Wang from SKLBCC and the Department of Urology are the co first authors of the article. Chong Chen, Yu Liu, and Qiang Wei of the West China Hospital are the corresponding authors. Yuquan Wei, a CAS academician, provided guidance for the work.
“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.” (Summary)
This research work is innovative in the following four aspects. First, a new type of bladder cancer model based on gene editing normal organoids was constructed to reproduce the whole process of bladder cancer chemotherapy. Second. Researchers found a new lineage plasticity - "semi squamous differentiation" in chemoresistance in bladder cancer patients. Third, a new therapeutic target CTSH for drug-resistant bladder cancer was identified. Fourth, the molecular and cellular mechanism of CTSH in the treatment of bladder cancer patients with drug-resistance was clarified, and the differentiation treatment strategy of solid tumors was proposed.
Chong Chen and his team has long studied the molecular mechanism of tumor occurrence, metastasis and drug resistance. Relevant work has been published in Nature, Nature Cancer, Cancer Discovery, Cancer Cell, STTT, etc. The research work was funded by the National Natural Science Foundation of China, the key special project of the Ministry of Science and Technology, West China Hospital of Sichuan University.
https://doi.org/10.1016/j.ccell.2022.08.010
