Investigation of growth control mechanisms mediated by apicobasal cell polarity proteins

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 the fly scrib mutant tumors exhibit plasticity and evolvability along the temporal axis. Here we first found that the scrib mutant tumors display 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 the scrib mutant tumors revealed that the MAPK pathway, including the JNK and ERK signaling activities, shows quantitative changes over time. We found that high JNK signaling activity causes G2/M cell cycle arrest in the early scrib mutant tumors. In addition, JNK signaling activity displays a radial polarity with the JNK^high cells located at the periphery of the scrib mutant tumors, providing an inherent mechanism that leads to an overall JNK signaling activity decrease over time. We also found that the ERK signaling activity, in contrast to JNK activity, increases over time and promotes growth in the late-stage scrib mutant tumors. Finally, high JNK signaling activity represses ERK signaling activity in the early scrib mutant tumors. Together, these data demonstrated that dynamic MAPK signaling activity, fueled by intratumor heterogeneity derived from tissue topological differences, drives a growth arrest-to-proliferation transition in the scrib mutant tumors.

Date of Award	2020
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology