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Ji, Tiantian; Zhang, Lina; Deng, Mingxi; Huang, Shengshuo; Wang, Ying; Pham, Tri Thanh; Smith, Andrew Alan; Sridhar, Varun; Cabernard, Clemens; Wang, Jiguang; Yan, Yan
Disease models & mechanisms, 08/2019, Letnik: 12, Številka: 8Journal Article
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 tumor model caused by loss of ( ), a highly conserved apicobasal cell polarity gene, to investigate the spatial-temporal dynamics of early tumorigenesis events. The fly mutant tumors have been successfully used to model many aspects of tumorigenesis processes. However, it is still unknown whether mutant tumors exhibit plasticity and evolvability along the temporal axis. We found that mutant tumors displayed different growth rates and cell cycle profiles over time, indicative of a growth arrest-to-proliferation transition as the mutant tumors progress. Longitudinal bulk and single-cell transcriptomic analysis of 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 mutant tumors. In addition, JNK signaling activity displayed a radial polarity with the JNK cells located at the periphery of 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 mutant tumors. Furthermore, high JNK signaling activity repressed ERK signaling activity in early 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 mutant tumors.This article has an associated First Person interview with the joint first authors of the paper.
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