文章目录

干扰素信号在肾癌转移进化过程中促进对染色体不稳定性的耐受性

原文发布日期：2023-06-26

英文摘要：

摘要翻译：

原文链接：

文章：

干扰素信号在肾癌转移进化过程中促进对染色体不稳定性的耐受性

Interferon signaling promotes tolerance to chromosomal instability during metastatic evolution in renal cancer

原文发布日期：2023-06-26

英文摘要：

Molecular routes to metastatic dissemination are critical determinants of aggressive cancers. Through in vivo CRISPR–Cas9 genome editing, we generated somatic mosaic genetically engineered models that faithfully recapitulate metastatic renal tumors. Disruption of 9p21 locus is an evolutionary driver to systemic disease through the rapid acquisition of complex karyotypes in cancer cells. Cross-species analysis revealed that recurrent patterns of copy number variations, including 21q loss and dysregulation of the interferon pathway, are major drivers of metastatic potential. In vitro and in vivo genomic engineering, leveraging loss-of-function studies, along with a model of partial trisomy of chromosome 21q, demonstrated a dosage-dependent effect of the interferon receptor genes cluster as an adaptive mechanism to deleterious chromosomal instability in metastatic progression. This work provides critical knowledge on drivers of renal cell carcinoma progression and defines the primary role of interferon signaling in constraining the propagation of aneuploid clones in cancer evolution.

摘要翻译：

转移性肾癌的分子途径是侵袭性肾癌的关键因素。通过体内CRISPR–Cas9基因编辑，我们生成了体细胞突变的基因工程模型，这些模型精确再现了转移性肾肿瘤。破坏9p21位点是系统性疾病的一个进化驱动力，通过癌细胞快速获得复杂的染色体。跨物种分析发现，重复出现的拷贝数变异模式，包括21q染色体缺失和干扰因子通路失活，是转移势能的主要因素。利用功能丧失研究进行的体外和体内基因组工程，结合部分21q染色体三倍化的模型，显示了干扰因子受体基因簇在转移性进展中对抗染色体异常侵袭的适应机制。这项研究提供了关于肾细胞癌进展的关键知识，并明确了干扰因子信号在限制异常克隆侵袭演化中的主要作用。