Cell/extracellular matrix interaction during cell cycle progression: a novel role in controlling nucleotide metabolism?

The deregulation of cell cycle progression is a common feature of cancer formation and progression. Cell/extracellular matrix (ECM) interaction is widely known to support the progression of the cells through the cell cycle. Recent data from our lab indicate that the internalisation of ECM components is promoted during the G1 phase of the cell cycle and this process is associated with an increased activation of mTOR signalling. Furthermore, we have shown that ECM uptake is, at least in part, mediated by 1 integrin, which internalisation seems to be induced when the cells are synchronised in G1 phase. These observations have been validated using the FUCCI system, a fluorescence-based reporter system which allow the visualisation of the different phases of the cell cycle without inducing any perturbation. Interestingly, cells in G1 strongly increase nucleotide synthesis, in preparation for DNA replication in S phase and our preliminary data suggest that ECM endocytosis might support nucleotide metabolism. This raises the intriguing hypothesis that ECM internalisation might support nucleotide synthesis in G1. In order to investigate this, this project will characterise:

1. The expression of known regulators of ECM internalisation and ECM receptors in the different phases of the cell cycle, to define the molecular mechanisms promoting ECM uptake in G1

2. The metabolic changes occurring in the different phases of the cell cycle, using a metabolomics approach, with a focus on nucleotide metabolism

3. The impact of ECM internalisation in controlling nucleotide synthesis

Overall, this project will shed new light on how cell cycle progression is regulated, potentially identify novel therapeutic targets for the development of anti-cancer therapies.

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