IGMM, CNRS Montpellier
"How do environmental cues control cell behaviour or fate decision programs? Learning from Rho and Ras transcriptional effectors."
Environmental cues such as growth factor, hormone, nutrient and cytokine concentrations are essential in regulating cell behaviour and differentiation processes. Cells integrate these external stimuli through signalling pathways to mediate their response. Aberrant signalling processes are a common feature of diseases such as cancer, so understanding them is critical for the development of therapeutic interventions. In our previous work, we have focussed on the Ras and Rho pathways, whose activity is disrupted in a large proportion of human cancers. The Ras pathway is instrumental in control of cancer cell proliferation, while the Rho pathway is a critical player in metastasis. The model we have used is the fibroblast serum response, a classical model for cell cycle re-entry and wound healing. The transcriptional response to serum is in its large part controlled by the Serum Response Factor (SRF). SRF functions in partnership with members of two families of signal-regulated cofactors: the MRTFs (myocardin-related transcription factors; MRTF-A, MRTF-B, and myocardin itself) and the TCF (ternary complex factor) family of Ets domain proteins (SAP-1, Elk-1, and Net). The MRTFs, which bind G-actin, respond to fluctuations in G-actin concentration induced by Rho GTPase, while TCF activity is controlled by Ras–ERK signaling. Investigating at the genomic scale the serum response, we have described how transcription and epigenetic rearrangement are regulated. We have defined the regulatory elements and genes that are regulated by Rho and Ras signalling pathways and explored how SRF and its coactivators modulate the circadian rhythm, the response to mechanical signals and control the balance between cell proliferation and invasion. In addition to soluble biochemical messengers, cells also need to respond to physical constraints i.e. external forces or mechanical cues such as stretch, compression and changes in the stiffness of the extracellular matrix (ECM). Although they are of critical patho-physiological importance, the molecular events elicited in response to mechanical cues have remained elusive. Indeed, during oncogenesis progression, the extracellular matrix (ECM) surrounding the tumour is stiffening due to matrix remodelling. It can arise from fibrosis or in response to tumour compression and cytoskeletal tension. Mechanosensation and tumour progression are paired: ECM stiffening supports the metastatic program and promotes cytoskeletal rearrangements required during cell invasion. Moreover, normal cellular differentiation has also been shown to be critically dependent on integration of mechanical cues. Mesenchymal Stem Cells (MSCs) are multipotent cells, which are able to differentiate into a variety of connective tissues. In this process, mechanical cues are determinant drivers of the lineage choice: the bone marrow is composed of discrete regions of variable matrix compositional properties, exposing MSCs to low tension conditions favour adipogenesis, while higher tensions favour myogenesis and the highest tensions drive differentiation to osteogenesis. Similarly, physical cues from the microenvironment regulate epidermal stem cell fate decisions. In that case, actin cytoskeleton rearrangement induces keratinocyte differentiation. However, while Rho and Ras signalling pathways have been identified in the response to matrix stiffness, how mechanosensation signals are transduced, integrated by the cell, how they impact on the transcriptional or epigenetic programs, what are the transcription factor networks involved apart from SRF/MRTF and YAP/TAZ and how such cues regulate cell behaviour are still open questions that I further aim to address.