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Population context-dependent regulation of membrane lipid composition and downstream activities in mammalian cells: the FAK-ABCA1 system

Final Report Summary - THE FAK-ABCA1 SYSTEM (Population context-dependent regulation of membrane lipid composition and downstream activities in mammalian cells: the FAK-ABCA1 system.)

The FAK-ABCA1 project was aiming at understanding how cells sense and adapt to their microenvironment at a molecular and dynamic level. More precisely the goal was to understand how focal adhesion kinase plays a role as a local crowding sensor and translate such information to the cell to generate proper physiological adaptation, i.e. what molecular partners are involved and what genes are impacted, and on a more dynamic level, what topology rules the system to allow accurate long term adaptation. To our surprise, membrane was found to be key in the process.

I managed to show that Focal Adhesion Kinase (FAK) controls the expression of ABC transporters to impact the membrane composition and signaling using membrane as a scaffold. By doing so, the FAK-ABCA1 system adapts the cell's physiology to the local microenvironment. Microarray
analysis, single molecule FISH, and network analysis show that ABC transporters and especially ABCA1 expressions are controlled by the local crowding, sensed by FAK. Transcription factor screening, western blotting and chromatin immuno-precipitation show that TAL1 and Fox03 are key controllers of ABCA1 expression upon FAK-PI3K-AKT signaling. Using lipidomics and high content microscopy, I have demonstrated that this system leads to more disordered membranes in crowded cells and more ordered membranes in sparser cells and that this leads to a general modulation of the cell's signaling state and physiology.

Moreover I have developed a unique approach to simulate the dynamic behaviour of the system using an agent based model of the social interactions of single cells that I use as a scaffold to show that signaling processes, mathematically modeled, must be integrated in the membrane in order to allow
a graded response to the microenvironment. This model have been validated by acquisition of many single cell data showing that active FAK and ABCA1 have specific patterns in populations of single cells that can be accurately predicted.

Conclusions and take home messages are the following:
-ABCA1 and more generally ABC transporters, can impact the membrane composition.
-This membrane composition control seems to be a very efficient relay for modifying the general cell's physiology.
-Patterns of signals in population of single cells can appear without any compound sharing from a cell autonomous system, only if the cues triggering a change, cellular crowding in our case, are reintegrated properly by the cell, through the membrane in order to allow proper feedback control to appear.

We believe this work will show the benefit of having an integrative approach in biology by coupling single cell quantitative measurements, ‘’omics’’ methods, mathematical and agent based models and more classical methods. Most of all, we believe that this study will show that membrane lipids are key for cell physiology, information storage, signal transduction and processing, applicable at all levels of molecular, cellular and developmental biology, especially in integrative approaches (synthetic or systems biology).