Dynamic MAPK signaling activity underlies a transition from growth arrest to proliferation in Drosophila scribble mutant tumors
| Autor: | Shengshuo Huang, Ying Wang, Mingxi Deng, Lina Zhang, Tiantian Ji, Yan Yan, Clemens Cabernard, Varun Sridhar, Jiguang Wang, Andrew Alan Smith, Tri Thanh Pham |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway SCRIB Mutant Neuroscience (miscellaneous) lcsh:Medicine Medicine (miscellaneous) Biology medicine.disease_cause General Biochemistry Genetics and Molecular Biology Transcriptome 03 medical and health sciences 0302 clinical medicine Immunology and Microbiology (miscellaneous) Cell polarity lcsh:Pathology medicine Transition (genetics) lcsh:R Cell cycle Cell biology ERK 030104 developmental biology Drosophila tumor model JNK Carcinogenesis 030217 neurology & neurosurgery lcsh:RB1-214 |
| Zdroj: | Disease Models & Mechanisms, Vol 12, Iss 8 (2019) |
| ISSN: | 1754-8411 1754-8403 |
| DOI: | 10.1242/dmm.040147 |
| Popis: | 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 JNKhigh 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|