Dynamic MAPK signaling activity underlies a transition from growth arrest to proliferation in Drosophila scribble mutant tumors
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...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
The Company of Biologists
2019-08-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/12/8/dmm040147 |
| _version_ | 1818434741179777024 |
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| author | Tiantian Ji Lina Zhang Mingxi Deng Shengshuo Huang Ying Wang Tri Thanh Pham Andrew Alan Smith Varun Sridhar Clemens Cabernard Jiguang Wang Yan Yan |
| author_facet | Tiantian Ji Lina Zhang Mingxi Deng Shengshuo Huang Ying Wang Tri Thanh Pham Andrew Alan Smith Varun Sridhar Clemens Cabernard Jiguang Wang Yan Yan |
| author_sort | Tiantian Ji |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T16:41:48Z |
| format | Article |
| id | doaj.art-fdd637ac196145378976af35c82d0b97 |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-14T16:41:48Z |
| publishDate | 2019-08-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-fdd637ac196145378976af35c82d0b972022-12-21T22:54:19ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112019-08-0112810.1242/dmm.040147040147Dynamic MAPK signaling activity underlies a transition from growth arrest to proliferation in Drosophila scribble mutant tumorsTiantian Ji0Lina Zhang1Mingxi Deng2Shengshuo Huang3Ying Wang4Tri Thanh Pham5Andrew Alan Smith6Varun Sridhar7Clemens Cabernard8Jiguang Wang9Yan Yan10 Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China Department of Biology, University of Washington, Life Science Building, Seattle, WA 98195, USA Department of Biology, University of Washington, Life Science Building, Seattle, WA 98195, USA Department of Biology, University of Washington, Life Science Building, Seattle, WA 98195, USA Department of Biology, University of Washington, Life Science Building, Seattle, WA 98195, USA Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China 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.http://dmm.biologists.org/content/12/8/dmm040147Cell polarityDrosophila tumor modelJNKERK |
| spellingShingle | Tiantian Ji Lina Zhang Mingxi Deng Shengshuo Huang Ying Wang Tri Thanh Pham Andrew Alan Smith Varun Sridhar Clemens Cabernard Jiguang Wang Yan Yan Dynamic MAPK signaling activity underlies a transition from growth arrest to proliferation in Drosophila scribble mutant tumors Disease Models & Mechanisms Cell polarity Drosophila tumor model JNK ERK |
| title | Dynamic MAPK signaling activity underlies a transition from growth arrest to proliferation in Drosophila scribble mutant tumors |
| title_full | Dynamic MAPK signaling activity underlies a transition from growth arrest to proliferation in Drosophila scribble mutant tumors |
| title_fullStr | Dynamic MAPK signaling activity underlies a transition from growth arrest to proliferation in Drosophila scribble mutant tumors |
| title_full_unstemmed | Dynamic MAPK signaling activity underlies a transition from growth arrest to proliferation in Drosophila scribble mutant tumors |
| title_short | Dynamic MAPK signaling activity underlies a transition from growth arrest to proliferation in Drosophila scribble mutant tumors |
| title_sort | dynamic mapk signaling activity underlies a transition from growth arrest to proliferation in drosophila scribble mutant tumors |
| topic | Cell polarity Drosophila tumor model JNK ERK |
| url | http://dmm.biologists.org/content/12/8/dmm040147 |
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