The role of epigenetic memory in endocrine therapy induced dormancy

激素依赖性乳腺癌（HDBC）占所有乳腺癌的70%以上。虽然在其他癌症类型中，复发的概率随着初次治疗的时间而降低，但HDBC女性的复发概率保持恒定，这与手术后的时间无关。这种临床表现表明，微播散的休眠癌细胞在诊断后数年内保持自发觉醒的能力。MagnaniLab正在进行的研究已经证明了内分泌治疗在以随机方式触发存活持续细胞休眠中的作用。休眠细胞会自发唤醒，并持续数月。在休眠期间，癌细胞聚集在一个明确定义的亚稳态表型上，该表型持续很长一段时间。觉醒没有遗传特征，这表明表观基因组的自发变化可能有利于从细胞周期停滞到细胞周期重新进入的过渡。这个博士项目的首要假设是，表观遗传衰变涉及特定的表观遗传标记，干扰衰变可以延长休眠或根除休眠细胞。博士将利用表观基因组学，CRISPR筛选，单细胞转录组学，谱系追踪，蛋白质组学和定量单细胞活成像来确定哪些表观遗传修饰在进入，维持和退出休眠中发挥核心作用。

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.