Self-organization of MAPK Signaling Dynamics in the Epithelium

Self-organization of MAPK Signaling Dynamics in the Epithelium

Olivier Pertz

Institute of Cell Biology, University of Bern (Swizerland)

Date: 02/02/2023
Time: 12:30 horas
CIC Lecture Hall
Host: David Santamaría
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Cells dynamically sense and respond to ever changing external stimuli through sophisticated signaling networks. Accordingly, signaling dynamics rather than steady states control fate decisions. For many signaling pathways, heterogeneous dynamic signaling states occur within distinct cells, explaining fate variability observed within a cell population. Measuring single cell signaling dynamics is therefore key to understand how cellular responses correlate with specific cell fate decisions. Here, we combine biosensor imaging, optogenetics and mathematical modelling to map how different MAPK signalling network circuitries fine tune ERK activity dynamics at the single cell level. We apply these technologies to study fate determination system in collectives of MCF10A breast epithelial cells. In a process called epithelial homeostasis, this cell collective constantly senses the state of the epithelium, and reacts by spatially tuning survival and proliferation fates to ensure a critical cell density necessary for proper barrier function.

Here, we observe two single-cell ERK signalling modes that consist either of stochastic pulses (in presence of growth factor stimulation), or of co-ordinated ERK waves across multiple cell layers that originate around apoptotic extruding cells (in absence of GFs or in presence of cytotoxic stress). We show that such ERK activity pulses provide a local survival signal for about 4 hours to the cells surrounding the apoptotic extruding cells, allowing to fine tune epithelial homeostasis at the cell population level. We show that this spatial mechanism of ERK activity waves ensures that a critical number of cells is maintained in the epithelium, even in the presence of strong external insults such a chemotherapy.
A higher complexity in spatio-temporal signalling is observed when these cells are grown as 3D epithelial acini that display a specific size and exhibit a lumen. This sequentially involves
initial cell proliferation, followed by quiescence and triggering of apoptosis specifically in the inner cell mass to allow for lumen formation. We show that spatio-temporal self-
organization of ERK frequency within this cell ecosystem serves as a mechanism to locally control proliferation, survival and apoptosis fates during acinus growth and lumen
formation. Our results provide new insight into the self-organization of signaling dynamics in morphogenesis of complex multicellular structures.