Showing 1 - 3 of 3 results
1.
Automatic detection of spatio-temporal signalling patterns in cell collectives.
Abstract:
An increasing experimental evidence points to physiological importance of space-time correlations in signalling of cell collectives. From wound healing to epithelial homeostasis to morphogenesis, coordinated activation of bio-molecules between cells allows the collectives to perform more complex tasks and better tackle environmental challenges. To understand this information exchange and to advance new theories of emergent phenomena, we created ARCOS, a computational method to detect and quantify collective signalling. We demonstrate ARCOS on cell and organism collectives with space-time correlations on different scales in 2D and 3D. We make a new observation that oncogenic mutations in the MAPK/ERK and PIK3CA/Akt pathways of MCF10A epithelial cells induce ERK activity waves with different size, duration, and frequency. The open-source implementations of ARCOS are available as R and Python packages, and as a plugin for napari image viewer to interactively quantify collective phenomena without prior programming experience.
2.
The rate of information transmission through the MAPK/ERK signaling pathway stimulated in a pulsatile manner.
Abstract:
Many intracellular signaling pathways, including the MAPK/ERK cascade, respond to an external stimulus in a yes-or-no manner. This has been reflected in estimates of the amount of information a single cell can transmit about the amplitude of an applied (and sustained) input signal, which turns out to only slightly exceed 1 bit. More information, however, can potentially be transmitted in response to time-varying stimulation. In this work, we find a lower bound of the MAPK/ERK signaling channel capacity. We use an epithelial cell line expressing an ERK activity reporter and an optogenetically modified fibroblast growth factor receptor, which allows triggering eventual ERK activity by short light pulses. We observe that it is possible to reconstruct the stimulatory input pattern with five-minute delay and one-minute resolution. By stimulating the cells with random pulse trains we demonstrate that the information transmission rate through the MAPK/ERK pathway can exceed 6 bits per hour. Such high information transmission rate allows the MAPK/ERK pathway to coordinate multiple processes including cell movement.
3.
Spatio-temporal Control of ERK Pulse Frequency Coordinates Fate Decisions during Mammary Acinar Morphogenesis.
Abstract:
The signaling events controlling proliferation, survival, and apoptosis during mammary epithelial acinar morphogenesis remain poorly characterized. By imaging single-cell ERK activity dynamics in MCF10A acini, we find that these fates depend on the frequency of ERK pulses. High pulse frequency is observed during initial acinus growth, correlating with rapid cell motility. Subsequent decrease in motility correlates with lower ERK pulse frequency and quiescence. Later, during lumen formation, coordinated ERK waves emerge across multiple cells of an acinus, correlating with high and low ERK pulse frequency in outer surviving and inner dying cells respectively. A PIK3CA H1047R mutation, commonly observed in breast cancer, increases ERK pulse frequency and inner cell survival, causing loss of lumen formation. Optogenetic entrainment of ERK pulses causally connects high ERK pulse frequency with inner cell survival. Thus, fate decisions during acinar morphogenesis are fine-tuned by different spatio-temporal coordination modalities of ERK pulse frequency.
