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Cell cycle clock in nervous system and cancer

Final Report Summary - CYCLOCK (Cell cycle clock in nervous system and cancer)

The team entitled "Cell cycle clock Genomics, C3G" is led by the IRG fellow F. Bienvenu and is dedicated to the understanding of the various activities of Cyclin D1 during development and cancer. Cyclin D1 is instrumental to cell cycle progression. It is involved in retinal development and lactating mammary gland activity. However, Cyclin D1 is over-expressed in the vast majority of human malignancies and alterations in the gene encoding for this protein are very frequent across all human tumors. Therefore, Cyclin D1 is considered as a putative target against cancer.
To investigate the complete repertoire of molecular mechanisms regulated by Cyclin D1, animal models which express in physiological manner FLAG-HA-tagged Cyclin D1 were generated by homologous recombination, Thanks to this animal model, we perform in vivo protein purifications followed by mass spectrometry analysis, Chromatin immunoprecipitation followed by DNA-sequencing (ChIP-seq) and transcription profiling by RNA sequencing (RNA-Seq). This technological setting is used in models of cancer development (breast cancer) and more recently in environmental stress related disorders.

During the last 4 years, the C3G team managed to set up a new technological strategy to target specifically Cyclin D1 in vivo by RNA interference and to detect its relative abundance by a novel TR-FRET approach. This innovation led to a maturation project supported by the CNRS and by a new French technology transfer facility named the SATT AxLR. This commercial value is envisioned in collaboration with a local company named MedesisPharma. The technology has been used to demonstrate in vivo the importance of Cyclin D1 in tumor progression and maintenance. This strategy has highlighted that Cyclin D1 protects cancer cells against stress-induced death. This is of prime importance to propose novel therapies aiming at targeting efficiently cancer cells by chemotherapeutics.

Of even more importance, we have discovered that Cyclin D1 is still expressed in adult post-mitotic tissues and continues to act as a shield to favour cell survival during aging. Decreased expression of Cyclin D1 in healthy adult animals sensitizes them to stress-induced cell death and represents a novel marker of environmental challenge sensitivity. Thus, our results should provide a new diagnosis tool for patients developing resistance to chemotherapy, or on the contrary, developing age-related complications like Parkinson disease. In addition to cancer cells and dopaminergic neurons, we have shown that Cyclin D1 is active in adult heart and testis, opening a wider scope of therapeutic hopes based on Cyclin D1 expression tuning.

The IRG CYCKLOCK project led to a patent filed in September 2014 and to 3 manuscripts submitted for publication in mid 2015.