Deciphering the Code for Senescence Escape During Cancer Progression in Humans

大多数癌症是由于遗传和表观遗传变化在体细胞中积累而产生的进化过程。 使它们能够逃脱控制细胞生长的增殖抑制。近年来，它已经成为 显然，癌症进展的一个关键障碍是被称为细胞衰老的增殖停滞。我们的 研究表明，某些人类癌症前驱病变不活跃的原因是， 如黑色素细胞痣、乳腺导管增生症和结肠腺瘤，是因为 这些损伤经历了端粒功能障碍诱导的衰老(TDIS)。然而，鉴于其中的细胞 这些病变偶尔会继续增殖，从而使这些肿瘤进展到更多 对于晚期癌症，很可能细胞在长时间不活动后可以逃脱TDIs。的确，我们的 初步数据表明，根据衰老细胞中激活的信号通路，TDIS是 并不总是稳定的，细胞在长时间衰老后可以逃脱这种增殖停滞。 令人惊讶的是，衰老细胞获得了部分类似于干细胞的基因表达特征， 这表明衰老细胞经历了表观遗传变化，为细胞提供了类干细胞 特点。为了更好地了解促进逃脱衰老的分子变化 并预测哪些病变几乎无限期地保持非活动状态，哪些病变有可能进展到 更晚期的癌症阶段，我们建议识别乳房、结肠和(黑色素细胞)皮肤的阶段。 端粒启动的衰老反应失活的癌症进展。我们将使用这个 改善诊断和预后工具的知识，以评估癌症的分期和潜在的癌症 进展，开发癌症分期的新生物标记物，并促进患者治疗决策。 此外，我们还将比较正常、衰老和 从细胞培养和从人体组织中分离的衰老逃逸细胞，以表征 导致TDIs肿瘤抑制功能失活的最早变化。一次彻底的 了解促进衰老逃逸的变化将使我们能够促进小说的发展 抗癌策略和/或改进现有策略。最后，我们将使用细胞培养和小鼠模型 更详细地描述从端粒引发的细胞衰老中逃脱的系统 生理上相关的环境。这些模型系统将使我们不仅能够区分 这些是衰老逃避的结果，但它们也将提供一个平台 测试在早期阶段针对恶性肿瘤生长的药物和疗法。

Most cancers arise by an evolutionary process as genetic and epigenetic changes accumulate in somatic cells allowing them to escape the proliferative restrains that control cell growth. In recent years it has become evident that one critical barrier to cancer progression is a proliferative arrest termed cellular senescence. Our studies have demonstrated that the reasons for the inactive nature of certain human cancer precursor lesions, such as melanocytic nevi, ductal hyperplasias of the breast, and colonic adenomas is because cells within these lesions had undergone telomere dysfunction-induced senescence (TDIS). Yet, given that cells within these lesions occasionally continue to proliferate and thereby allow these neoplasms to progress to more advanced cancer stages, it is likely that cells can escape TDIS following a long period of inactivity. Indeed, our preliminary data demonstrate that, depending on the signaling pathways activated in senescent cells, TDIS is not always stable and cells can escape this proliferative arrest following a prolonged period in senescence. Surprisingly, senescent cells acquire a gene expression signature that in part resembles that of stem cells, suggesting that senescent cells undergo epigenetic changes that provide cells with stem cell-like characteristics. In order to better understand the molecular changes that promote escape from senescence and to predict which lesions remain inactive virtually indefinitely and which have the potential to progress to more advanced cancer stages, we propose to identify the stages during breast, colon, and (melanocytic) skin cancer development in which the telomere-initiated senescence responses are inactivated. We will use this knowledge to improve diagnostic and prognostic tools that evaluate cancer stage and potential for cancer progression, develop novel biomarkers for cancer stage, and facilitate decision making for patient treatment. Additionally, we will compare transcriptomes, epigenomes, and exomes from normal, senescent, and senescence-escaped cells, both from cell cultures and isolated from human tissue, in order to characterize the earliest changes that result in inactivation of the tumor suppressing functions of TDIS. A thorough understanding of the changes that promote senescence escape will allow us to facilitate development of novel anti cancer strategies and/or improving existing ones. Finally, we will use cell culture and mouse model systems to characterize escape from telomere-initiated cellular senescence in greater detail and in a physiologically relevant setting. These model systems will allow us to not only differentiate changes that are causative from those that are a consequence of senescence escape, but they will also provide a platform for testing drugs and therapies that target malignant cancer growth at its earliest stages.