One single molecule to access another scale PAI-1, Microenvironment and Cancer cell migration

International audience; The cancer pathology is a complex process caused by a cellular dysfunction leading to a whole organ or even organism vital perturbation. To better understand this process we need to understand each of the levels involved and what allows the change of scales. A matricellular protein, called PAI-1* has been identified as able to induce cell adhesion, reorganization of actin cytoskeleton and morphological changes, and to promote cell migration. PAI-1 participates in a regulation network linking the extracellular matrix and the cell. The molecular bridge formed by this protein and others is able to transduce biochemical and biomechanical signals to the cell. The cell response can be evaluated in terms of mRNA rate constants. It can further be assessed by the evaluation of migration speed. We are using the game theory and the game network theory to model this dynamic at the cell scale. PAI-1, found closely around the most invasive tumors represents an independent factor of bad prognosis. Cancer cells, having undergone the epithelial-mesenchymal transition (EMT), can use PAI-1 for their migration. However, if the environnement is very rich in PAI-1, the cells undergo a second transition, the so-called mesenchymal-amaeboid transition (MAT) Then their migration becomes "amaeboid" very different from the previous one by the independence towards integrins and proteases activity. This amaeboid state is characterized by a complete reorganisation of actin (with actin rings) and by the activation of the Rho GTPases transduction pathways. Furthermore, in the presence of this particular (i.e. PAI-1 enriched) environment, the cells down-regulate their PAI- I mRNAs rate constants. From the cellular level to the tissue level. Here the regulation network occurs at the cellular/microenvironmental level and includes a PAI- I concentration threshold. However, the consequences of a unique cell MAT can be its escape from the initial tumour, i.e. metastatic migration. If this occurs, the moving cancer cell will meet a microenvironment in which PAI-I progressively decreases, and the cell could return to the mesenchymal condition through an inverse transition (form amaeboid to mesenchymal behaviour). As it is a cancer cell, it will proliferate, produce more PAI- I (a characteristic of the most invasive cells) and perhaps again undergo MAT. The PAI- I negative feed-back in terms of RNAs, described earlier, could help this regulation to occur. We have perhaps identified one of the conditions for a cell to undergo MAT and return. A "grain of sand" The regulation of a cancer cell behaviour by its PAI-1 microenvironment, could then be considered as a cause leading to consequences at the organ or the organism level. And its critical transition point is that one single molecule of PAI-1 could do the job! In avalanches, it is known that at the critical state the output is not proportional to the input, that is, the system is highly nonlinear and gives rise to "non-obvious" effects. Could one molecule of PAI-1 play the role of a "grain of sand" in the "biological avalanche" of cancer? Is the suggestion of self-organised criticality useful to explain such scale changes? *Plasminogen Activator Inhibitor type I