结直肠癌细胞进入休眠样 DTP 状态以耐受化疗。
Colorectal Cancer Cells Enter a Diapause-like DTP State to Survive Chemotherapy.
机构信息
Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G 1L7, Canada.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5T 3L9, Canada.
出版信息
Cell. 2021 Jan 7;184(1):226-242.e21. doi: 10.1016/j.cell.2020.11.018.
Cancer cells enter a reversible drug-tolerant persister (DTP) state to evade death from chemotherapy and targeted agents. It is increasingly appreciated that DTPs are important drivers of therapy failure and tumor relapse. We combined cellular barcoding and mathematical modeling in patient-derived colorectal cancer models to identify and characterize DTPs in response to chemotherapy. Barcode analysis revealed no loss of clonal complexity of tumors that entered the DTP state and recurred following treatment cessation. Our data fit a mathematical model where all cancer cells, and not a small subpopulation, possess an equipotent capacity to become DTPs. Mechanistically, we determined that DTPs display remarkable transcriptional and functional similarities to diapause, a reversible state of suspended embryonic development triggered by unfavorable environmental conditions. Our study provides insight into how cancer cells use a developmentally conserved mechanism to drive the DTP state, pointing to novel therapeutic opportunities to target DTPs.
癌细胞进入可逆的药物耐受持久状态（DTP）以逃避化疗和靶向药物的杀伤。越来越多的证据表明，DTP 是导致治疗失败和肿瘤复发的重要驱动因素。我们在来源于患者的结直肠癌细胞模型中结合细胞条形码和数学建模的方法来鉴定和描述对化疗产生反应的 DTP。条形码分析表明，进入 DTP 状态并在治疗停止后复发的肿瘤并没有丧失克隆复杂性。我们的数据符合这样一个数学模型，即所有的癌细胞，而不是一小部分癌细胞，都具有同等的能力成为 DTP。从机制上看，我们确定 DTP 表现出与休眠（diapause）显著的转录和功能相似性，休眠是由不利的环境条件引发的胚胎发育暂停的可逆状态。我们的研究深入了解了癌细胞如何利用一种保守的发育机制来驱动 DTP 状态，这为靶向 DTP 提供了新的治疗机会。
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