The role of epigenetic memory in endocrine therapy induced dormancy

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Hormone dependent breast cancer (HDBC) represent over 70% of all breast cancer. While in other cancer types the probability of relapse decrease with time from primary treatment, women with HDBC maintain a constant probability of relapse which is independent from the time elapsed from surgery. This clinical behaviour suggest that micro disseminated dormant cancer cells maintain the ability of spontaneously awaken for years after diagnosis. Ongoing studies in the MagnaniLab have demonstrated a role for endocrine therapy in triggering dormancy in a stochastic fashion in survivor persister cells. Dormant cells awaken spontaneously with a dynamic of months. During dormancy, cancer cells converge on a well defined and metastable phenotype which is sustained for a large period of time. Awakening does not have genetic features suggesting that spontaneous changes in the epigenome might favor the transition from cell cycle arrest to cell cycle re-entry. The overarching hypothesis of this PhD project is that epigenetic decay involve specific epigenetic marks, and interfering with decay can be leveraged to prolong dormancy or eradicate dormant cells. The PhD will leverage epigenomics, CRISPR-screen , single cell transcriptomics, lineage tracing, proteomics and quantitative single cell live imaging to identify which epigenetic modifications play a central role in entering, maintaining and exiting dormancy.