Hysteresis conveys the EMT spread to the neighborhood tumor cells and metastasis
Worldwide Cancer Research
CERCA Institution
Cancer metastasis is a complex process with multiple challenges that disseminated tumour cells need to overcome to form overt metastasis, yet many biological aspects of metastasis are poorly understood. One of the most studied tumour cell phenotypic changes during metastasis is the epithelial-to-mesenchymal transition (EMT). This is a reversible transdifferentiation into a mesenchymal phenotype that favours cancer cell dissemination and cell plasticity to adapt to new conditions. We have recently described the dynamics of EMT at single cell level, by a molecular feedback loop that governs a bistable switch among the epithelial and mesenchymal state, also called hysteresis. However, how the dynamics affects group-decision processes at the cell population level has not been yet well studied. Remarkably, our recent data in 2D cell cultures show that EMT-like cells can spatially spread the EMT induction to the neighbourhood when the recipient cells are wired to undergo EMT by hysteresis. In this proposal, we aim to study the collective effects of hysteretic-EMT that resonates into spreading the EMT across cancer cell populations and its epigenetic mediators. For this purpose, we will use unique models of hysteresis and non-hysteresis cancer cells that we have previously generated, and inducible EMT systems with precise space and time control in 3D cultures in vitro, as well as in vivo breast cancer models. Advanced microscopy imaging, flow-cytometry analysis, ATAC-sequencing, and genome-wide DNA methylation will be used to model and unveil the mechanisms involved in the EMT spreading effect. Overall, this proposal will characterize the ability of cancer cells to amplify the EMT signal received by tumour cells, and the epigenetic mechanisms underlying it. This can lead to specific treatments to disrupt the spreading effect in order to halt cancer metastasis.
2.1 Biological and endogenous factors