Dynamic MAPK signaling activity underlies a transition from growth arrest to proliferation in Drosophila scribble mutant tumors

Tiantian Ji; Lina Zhang; Mingxi Deng; Shengshuo Huang; Ying Wang; Tri Thanh Pham; Andrew Alan Smith; Varun Sridhar; Clemens Cabernard; Jiguang Wang; Yan Yan

doi:10.1242/dmm.040147

Dynamic MAPK signaling activity underlies a transition from growth arrest to proliferation in Drosophila scribble mutant tumors

Dis Model Mech. 2019 Aug 29;12(8):dmm040147. doi: 10.1242/dmm.040147.

Authors

Tiantian Ji^{1

2}, Lina Zhang^{1

2}, Mingxi Deng^{1

2}, Shengshuo Huang^{1

2

3}, Ying Wang^{1

2}, Tri Thanh Pham⁴, Andrew Alan Smith⁴, Varun Sridhar⁴, Clemens Cabernard⁴, Jiguang Wang^{1

2

3}, Yan Yan^{5

2}

Affiliations

¹ Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
² Center of Systems Biology and Human Health, School of Science and Institute for Advanced Study, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
³ Department of Chemical and Biological Engineering, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
⁴ Department of Biology, University of Washington, Life Science Building, Seattle, WA 98195, USA.
⁵ Division of Life Science, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China yany@ust.hk.

Abstract

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.

Keywords: Cell polarity; Drosophila tumor model; ERK; JNK.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Cycle Checkpoints / genetics*
Cell Proliferation
Drosophila Proteins / genetics*
Drosophila melanogaster / cytology*
Drosophila melanogaster / genetics*
MAP Kinase Signaling System*
Membrane Proteins / genetics*
Mutation / genetics*
Neoplasms / enzymology*
Neoplasms / pathology*
Time Factors
Transcriptome / genetics

Substances

Drosophila Proteins
Membrane Proteins
Scrib protein, Drosophila