当前位置:科学网首页 > 小柯机器人 >详情
前列腺癌的谱系可塑性取决于JAK/STAT炎症信号
作者:小柯机器人 发布时间:2022/8/21 23:03:17

美国纪念斯隆-凯特琳癌症中心Charles L. Sawyers等研究人员合作发现,前列腺癌的谱系可塑性取决于JAK/STAT炎症信号。2022年8月18日,《科学》杂志在线发表了这项成果。

利用小鼠类器官和基因工程小鼠模型,研究人员揭示了前列腺癌中细胞系可塑性的原因及其与雄激素抗性的关系。研究人员发现,可塑性开始于一个由混合管腔-基底表型定义的上皮细胞群,它取决于JAK和FGFR活性的提高。来自去势抵抗患者的类器官培养物含有混合谱系细胞,在JAK和FGFR抑制剂治疗后,通过上调管腔基因表达,再现了在小鼠中观察到的依赖性。

单细胞分析证实,在转移性疾病患者的一个亚群中存在着JAK/STAT和FGFR信号升高的混合谱系细胞,这对临床试验中的患者分层有意义。

据悉,癌症的耐药性往往与肿瘤细胞状态或谱系的变化有关,但驱动这种可塑性的分子机制仍不清楚。

附:英文原文

Title: Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling

Author: Joseph M. Chan, Samir Zaidi, Jillian R. Love, Jimmy L. Zhao, Manu Setty, Kristine M. Wadosky, Anuradha Gopalan, Zi-Ning Choo, Sitara Persad, Jungmin Choi, Justin LaClair, Kayla E. Lawrence, Ojasvi Chaudhary, Tianhao Xu, Ignas Masilionis, Irina Linkov, Shangqian Wang, Cindy Lee, Afsar Barlas, Michael J. Morris, Linas Mazutis, Ronan Chaligne, Yu Chen, David W. Goodrich, Wouter R. Karthaus, Dana Pe’er, Charles L. Sawyers

Issue&Volume: 2022-08-18

Abstract: Drug resistance in cancer is often linked to changes in tumor cell state or lineage, but the molecular mechanisms driving this plasticity remain unclear. Using murine organoid and genetically engineered mouse models, we investigated the causes of lineage plasticity in prostate cancer and its relationship to antiandrogen resistance. We found that plasticity initiates in an epithelial population defined by mixed luminal-basal phenotype and that it depends on elevated JAK and FGFR activity. Organoid cultures from patients with castration-resistant disease harboring mixed-lineage cells reproduce the dependency observed in mice, by upregulating luminal gene expression upon JAK and FGFR inhibitor treatment. Single-cell analysis confirms the presence of mixed lineage cells with elevated JAK/STAT and FGFR signaling in a subset of patients with metastatic disease, with implications for stratifying patients for clinical trials.

DOI: abn0478

Source: https://www.science.org/doi/10.1126/science.abn0478

 

期刊信息
Science:《科学》,创刊于1880年。隶属于美国科学促进会,最新IF:41.037