Human tumors exhibit plasticity and evolving capacity over time. It is difficult to study the mechanisms of how tumors change over time in human patients, in particular during the early stages when a few oncogenic cells are barely detectable. Here, we used a Drosophila tumor model caused by loss of scribble (scrib), a highly conserved apicobasal cell polarity gene, to investigate the spatial-temporal dynamics of early tumorigenesis events. The fly scrib mutant tumors have been successfully used to model many aspects of tumorigenesis processes. However, it is still unknown whether Drosophila scrib mutant tumors exhibit plasticity and evolvability along the temporal axis. We found that scrib mutant tumors displayed different growth rates and cell cycle profiles over time, indicative of a growth arrest-to-proliferation transition as the scrib mutant tumors progress. Longitudinal bulk and single-cell transcriptomic analysis of scrib mutant tumors revealed that the MAPK pathway, including JNK and ERK signaling activities, showed quantitative changes over time. We found that high JNK signaling activity caused G2/M cell cycle arrest in early scrib mutant tumors. In addition, JNK signaling activity displayed a radial polarity with the JNK^high cells located at the periphery of scrib mutant tumors, providing an inherent mechanism that leads to an overall decrease in JNK signaling activity over time. We also found that ERK signaling activity, in contrast to JNK activity, increased over time and promoted growth in late-stage scrib mutant tumors. Furthermore, high JNK signaling activity repressed ERK signaling activity in early scrib mutant tumors. Together, these data demonstrate that dynamic MAPK signaling activity, fueled by intratumor heterogeneity derived from tissue topological differences, drives a growth arrest-to-proliferation transition in scrib mutant tumors.This article has an associated First Person interview with the joint first authors of the paper.

中文翻译：

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动态MAPK信号活性是果蝇随意突变突变体中从生长停滞到增殖的过渡的基础。

人肿瘤随时间显示可塑性和进化能力。很难研究人类患者肿瘤如何随时间变化的机制，尤其是在几乎无法检测到一些致癌细胞的早期阶段。在这里，我们使用了果蝇造成的损失肿瘤模型乱画（Scrib的），高度保守的apicobasal细胞极性基因，为了研究肿瘤发生的早期事件的时空动力学。蝇scrib突变体肿瘤已成功用于建模肿瘤发生过程的许多方面。但是，果蝇scrib突变肿瘤是否沿时轴显示可塑性和可进化性仍是未知的。我们发现scrib随着时间的推移，突变型肿瘤显示出不同的生长速率和细胞周期特征，表明随着scrib突变型肿瘤的进展，生长停滞向增殖过渡。对scrib突变肿瘤的纵向批量和单细胞转录组学分析显示，MAPK途径（包括JNK和ERK信号传导活性）随时间变化。我们发现高JNK信号活性导致早期scrib突变肿瘤中的G2 / M细胞周期停滞。此外，JNK信号活动表现出径向极性，JNK^高细胞位于scrib的外围突变的肿瘤，提供了一种内在的机制，该机制会导致JNK信号转导活性随时间整体下降。我们还发现，与JNK活性相反，ERK信号活性随时间增加，并促进晚期scrib突变型肿瘤的生长。此外，高的JNK信号传导活性抑制了早期scrib突变体肿瘤中的ERK信号传导活性。总之，这些数据表明，由组织拓扑差异产生的肿瘤内异质性推动了动态MAPK信号传导活性，推动了scrib突变型肿瘤的生长停滞向增殖过渡。纸。