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Disruptions in cell fate decisions and transformed enteroendocrine cells drive intestinal tumorigenesis in Drosophila.
bioRxiv - Cancer Biology Pub Date : 2022-09-26 , DOI: 10.1101/2022.09.25.509404
Maria Quintero , Erdem Bangi

Most epithelial tissues are maintained by stem cells that produce the different cell lineages required for proper tissue function. Constant communication between different cell types that make up a tissue is essential to ensure that all cell lineages are produced at appropriate numbers and to mount regenerative responses to injury, infection, and other environmental stresses. Cancer-driving alterations change the intrinsic properties of transformed cells and disrupt stem cell regulation, cell fate decisions, and cell-cell communication within transformed tissue. However, mechanisms by which these processes are disrupted and co-opted to support tumorigenesis are not well understood. Here, we report a novel genetic platform, PromoterSwitch, that allows targeting of genetic manipulations to a small subset of cells of any tissue or cell type of interest and all their subsequent progeny. We use this technology to generate large, transformed clones derived from individual stem/progenitor cells in the adult Drosophila intestine. We show that cancer-driving genetic alterations representing common colon tumor genome landscapes drive disruptions in cell fate decisions within transformed clones and changes in the relative abundance of different intestinal cell lineages. We also uncover a critical, context-dependent role for the differentiated, hormone-producing enteroendocrine (EE) cells in the growth and maintenance of transformed clones. Our analysis in different genetic contexts provides insights into how the intrinsic properties of transformed cells —dictated by the genetic alterations they carry— determine their response to their environment and dependence on niche signals. A better mechanistic understanding of disruptions of cell-cell communication, stem cell regulation, and cell fate decisions within tumors could reveal novel vulnerabilities and druggable regulatory nodes that can be exploited for therapy. Understanding how tissues respond to the emergence of cells with cancer-driving genetic alterations also provides insights into stem cell biology and epithelial homeostasis.

中文翻译:

细胞命运决定的破坏和转化的肠内分泌细胞驱动了果蝇的肠道肿瘤发生。

大多数上皮组织由干细胞维持,这些干细胞产生正常组织功能所需的不同细胞谱系。组成组织的不同细胞类型之间的持续交流对于确保所有细胞谱系都以适当的数量产生以及对损伤、感染和其他环境压力产生再生反应至关重要。癌症驱动的改变会改变转化细胞的内在特性,并破坏干细胞调节、细胞命运决定和转化组织内的细胞间通讯。然而,这些过程被破坏和增选以支持肿瘤发生的机制尚不清楚。在这里,我们报告了一个新的遗传平台,PromoterSwitch,这允许将基因操作靶向到任何感兴趣的组织或细胞类型的一小部分细胞及其所有后续后代。我们使用这项技术从成年果蝇肠道中的单个干/祖细胞中生成大型转化克隆。我们表明,代表常见结肠肿瘤基因组景观的癌症驱动基因改变会破坏转化克隆内的细胞命运决定,并改变不同肠细胞谱系的相对丰度。我们还揭示了分化的、产生激素的肠内分泌 (EE) 细胞在转化克隆的生长和维持中的关键、依赖于环境的作用。我们在不同遗传背景下的分析提供了关于转化细胞的内在特性(由它们携带的遗传改变决定)如何决定它们对环境的反应和对生态位信号的依赖的见解。更好地理解肿瘤内细胞间通讯中断、干细胞调控和细胞命运决定的机制,可以揭示新的脆弱性和可用于治疗的药物调控节点。了解组织如何对具有癌症驱动基因改变的细胞的出现做出反应,还可以提供对干细胞生物学和上皮稳态的见解。肿瘤内的细胞命运决定可以揭示新的脆弱性和可用于治疗的药物调节节点。了解组织如何对具有癌症驱动基因改变的细胞的出现做出反应,还可以提供对干细胞生物学和上皮稳态的见解。肿瘤内的细胞命运决定可以揭示新的脆弱性和可用于治疗的药物调节节点。了解组织如何对具有癌症驱动基因改变的细胞的出现做出反应,还可以提供对干细胞生物学和上皮稳态的见解。
更新日期:2022-09-27
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