breakthrough!Professor Chen Chong's team found a new mechanism for tumor resistance

Although more and more new tumor treatment plans such as targeted therapy and immunotherapy have entered the clinic in recent years, chemotherapy is still the main means of clinical tumor therapy. However, most tumors are resistant to chemotherapy early or late, thereby recurrence and progress. The molecular mechanism of tumor chemotherapy tolerance is further analyzed. Muscle-invasive Bladder Cancer (MIBC) is the most common and malignant urinary system tumor. Chemotherapy is mainly surgical and metastatic MIBC. Because chemotherapy resistance A large part of the patients will fail chemotherapy, leading to the recurrence and progress of tumor.

Professor Chen Chong and Professor Liu Yu team of the National Key Laboratory of West China Hospital of West China Hospital and Professor Liu Yu jointly published a research papers in Cancer Cell on September 12, 2022 ACQUIRED SEMI-SQUAMAMAMAMAMAMAMAMTINGERINGERAPYRAPESTS DHERAINTICIATINTINTINTIN Bladder Cancer found that semi -scale differentiation is a new feature of bladder cancer chemotherapy, and then proposes a targeting tissue protease CTSH to promote divergent treatment strategies for the ending of drug -resistant tumor cells. The National Key Laboratory of the West China Hospital of Sichuan University and Dr. Wang Manli, Dr. Chen Xuelan, Dr. Tan Ping, Dr. Wang Yitong, the joint first author of the article, Professor Chen Chong, Professor Liu Yu, Wei Qiang, Professor of Huaxi Hospital of Sichuan University, The professor is a communication author. The work was guided by Academician Wei Yuquan. Professor Huang Canhua of Sichuan University participated in the research.

MIBC's animal models are lacking. In this study, Professor Chen Chong's team built the original MIBC mouse models that were lacking in P53 and PTEN, and MYC expressed. This model can accurately characterize the clinical pathological characteristics of MIBC patients. Using this model, the team tested its response to the MIBC clinical chemotherapy scheme (cisplatin+Geishebin), and found that the model can accurately present the entire process of reaction to the recurrence resistance that is similar to clinical reactions.

In order to analyze the molecular mechanism of MIBC chemotherapy resistance, the team used single -cell group analysis to build a molecular path for MIBC to obtain sexual resistance. Through the experiments such as Barcoding Tracer, it is confirmed that the plasticity of tumor cell spectrum is the main way for MIBC to obtain drug resistance. Combining multiple groups and pathological analysis in combination with transcription groups and protein groups, it is found that gradual scale differentiation is a significant feature of MIBC's sexual resistance. Clinically, the MIBC of chemotherapy tolerance also shows the characteristics of scale differentiation, and the scales differentiation score is closely related to the poor prognosis of the patient. Furthermore, the team discovered the tissue protease CTSH with multiple groups of analysis. CTSH gradually increases with chemotherapy in mice and patient MIBC. Tap CTSH can inhibit the growth of the body internal and external internal body in the body. CTSH inhibitors E64 can also effectively inhibit the growth of mice and patients with PDX, which is sensitive to chemotherapy.

Through the analysis of pathological analysis, differentiation of material staining and single -cell group, transcription group, protein group analysis, etc., found that after knockout CTSH or E64 was treated, a certain degree of scale differentiation of the scale differentiation occurred. Division. In the mechanism, after CTSH suppression, the tumor necrosis factor (TNF) was adjusted, and then the tumor cells were divided through TNF receptor (TNFR1) and downstream Caspase-8, and the cells were burnt.

The work starts from the establishment of a new type of precision bladder cancer mouse model, revealing the new characteristics of MIBC's semi -scaled spectrum differentiation of sex chemotherapy and drug -resistant semi -scale differentiation, and proposes a new strategy of targeting CTSH to promote its end -scale dividing treatment. Although differentiated therapy has been treated with leukemia, especially the development of full -anthrodia+arsenic in Chinese scientists, the treatment of acute early early leukemia is successfully applied, but most of the attempts in physical tumors are not very successful. This study is expected to provide new ideas for differentiation of physical tumors.

The main innovation points of this research work include: first, a new type of bladder cancer model that is based on gene editing normal organs based on the normal organs of gene editing, and the entire process of bladder cancer chemotherapy is reproduced; the other is to find bladder cancer cancer. A new spectrum system of chemotherapy tolerance- "semi -scaled differentiation"; third, the new therapeutic target CTSH of drug -resistant bladder cancer is identified; the fourth is to clarify molecular cells targeting ctsh to treat drug -resistant bladder cancer The mechanism proposes the differential treatment strategy of physical tumors.

Professor Chen Chong's team has long studied the molecular mechanism of tumors, metastasis, and drug resistance. By constructing the "precise tumor animal model" with clear positions, original, and driven genes, the molecular mechanism of the development of tumors is explored, and then based on mechanisms and high -throughput screening to identify the treatment targets and drugs. In the early stage, the mechanism of hematological tumors, small cell lung cancer metastasis, bladder cancer chemotherapy and other mechanisms were found. Related work was published in Nature, Nature Cancer, Cancer Discovery, Cancer Cell, STTT, etc.

The research work was supported by the National Natural Science Foundation of China, the key special projects of the Ministry of Science and Technology, and the Huaxi Hospital of Sichuan University.

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