THESIS
2020
xiv, 115 pages : color illustrations ; 30 cm
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...[
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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.
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