小柯机器人

四川大学Chong Chen，Yu Liu和Qiang Wei共同合作近期取得重要工作进展，他们研究发现化疗期间获得性半鳞状化表明分化可以作为膀胱癌的一种治疗策略。相关论文2022年9月12日在线发表于《癌细胞》杂志上。

研究人员建立了一个具有基因编辑类器官的原位MIBC小鼠模型，以再现患者的整个化疗过程。他们发现，部分鳞状细胞分化（即半鳞状细胞化）与小鼠和人类MIBC的获得性耐药有关。多组学分析表明，组织蛋白酶H（CTSH）与化疗耐药和半鳞状化相关。E64处理对组织蛋白酶的抑制诱导完全的鳞状细胞分化和细胞焦亡，从而特异性地抑制化学耐药MIBC。从机制上讲，E64治疗激活了肿瘤坏死因子通路，这是化学耐药MIBC细胞终末分化和细胞焦亡所必需的。他们的研究表明，半鳞状化是一种与化学耐药相关的谱系可塑性，表明通过靶向CTSH进行分化可以作为化学耐药MIBC的潜在治疗策略。

据介绍，以顺铂为基础的化疗仍然是不可切除和转移性膀胱癌（MIBC）的主要治疗方法，然而，肿瘤经常产生化学抗性。

附：英文原文

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

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

Issue&Volume: 2022/09/12

Abstract: Cisplatin-based chemotherapy remains the primary treatment for unresectable and metastaticmuscle-invasive bladder cancers (MIBCs). However, tumors frequently develop chemoresistance.Here, we established a primary and orthotopic MIBC mouse model with gene-edited organoidsto recapitulate the full course of chemotherapy in patients. We found that partialsquamous differentiation, called semi-squamatization, is associated with acquiredchemoresistance in both mice and human MIBCs. Multi-omics analyses showed that cathepsinH (CTSH) is correlated with chemoresistance and semi-squamatization. Cathepsin inhibitionby E64 treatment induces full squamous differentiation and pyroptosis, and thus specificallyrestrains chemoresistant MIBCs. Mechanistically, E64 treatment activates the tumornecrosis factor pathway, which is required for the terminal differentiation and pyroptosisof chemoresistant MIBC cells. Our study revealed that semi-squamatization is a typeof lineage plasticity associated with chemoresistance, suggesting that differentiationvia targeting of CTSH is a potential therapeutic strategy for the treatment of chemoresistantMIBCs.

DOI: 10.1016/j.ccell.2022.08.010

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00374-9

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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