Deciphering the Code for Senescence Escape During Cancer Progression in Humans

破译人类癌症进展过程中逃避衰老的密码

基本信息

批准号：
10083711
负责人：
Utz Herbig
金额：
$ 37.65万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-09 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10083711
关键词：
ATAC-seq Advanced Malignant Neoplasm Affect Animal Model Area Automobile Driving Benign Biological Models Breast Breast Adenoma Cell Aging Cell Culture Techniques Cells ChIP-seq Characteristics Chromatin Code Colon Colon Carcinoma Colonic Adenoma Colonic Neoplasms Cultured Cells Data Decision Making Development Diagnostic Disease Disseminated Malignant Neoplasm Ductal Breast Hyperplasia Entropy Epigenetic Process Failure Family member Functional disorder Gene Expression Profile Gene Expression Profiling Genes Genetic Genome Gland Growth Human Immunofluorescence Immunologic Knowledge Lesion Malignant - descriptor Malignant Neoplasms Mammary Neoplasms Melanocytic nevus Modeling Molecular Mus Mutation Nature Neoplasms Noninfiltrating Intraductal Carcinoma Oncogenes Oncogenic Patients Pharmacotherapy Physiological Precancerous melanosis Process Prognostic Marker Proliferating Research Risk Assessment Signal Pathway Signal Transduction Skin Skin Cancer Somatic Cell Telomerase Testing Time Time Series Analysis Up-Regulation Xenograft Model anti-cancer base c-myc Genes cancer biomarkers cancer therapy cell growth chromatin remodeling drug testing epigenome exome exome sequencing experimental study gene therapy genome-wide human tissue improved malignant breast neoplasm mouse model neoplastic novel novel anticancer drug novel marker premalignant prevent prognostic tool promoter repaired response reverse genetics self-renewal senescence stem cells stem-like cell stemness targeted treatment telomere tissue culture transcription factor transcriptome transcriptomics tumor tumor progression virtual

项目摘要

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.

大多数癌症是随着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。近年来已成为显然，癌症进展的一个关键障碍是称为细胞衰老的增殖停滞。我们的研究表明，某些人类癌症前兆病变不活跃的原因，例如黑素细胞痣、乳腺导管增生和结肠腺瘤是因为细胞内这些病变经历了端粒功能障碍诱导的衰老（TDIS）。然而，鉴于细胞内这些病变偶尔会继续增殖，从而使这些肿瘤进展到更多晚期癌症阶段，细胞很可能在长时间不活动后逃脱 TDIS。确实，我们的初步数据表明，根据衰老细胞中激活的信号通路，TDIS 并不总是稳定的，细胞可以在长时间的衰老后逃脱这种增殖停滞。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，表明衰老细胞经历表观遗传变化，为细胞提供干细胞样特征。为了更好地理解促进逃避衰老的分子变化并预测哪些病变几乎无限期地保持不活动状态以及哪些病变有可能进展为对于更晚期的癌症阶段，我们建议确定乳腺癌、结肠癌和（黑素细胞）皮肤的阶段癌症发展过程中，端粒引发的衰老反应失活。我们将使用这个改进评估癌症阶段和癌症潜力的诊断和预后工具的知识进展，开发癌症阶段的新型生物标志物，并促进患者治疗的决策。此外，我们将比较正常、衰老和衰老的转录组、表观基因组和外显子组。来自细胞培养物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。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开发抗癌策略和/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相关的设置。这些模型系统将使我们不仅能够区分那些因衰老逃逸而产生的原因，但它们也将为测试针对恶性癌症生长最早阶段的药物和疗法。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Irreparable telomeric DNA damage and persistent DDR signalling as a shared causative mechanism of cellular senescence and ageing.

不可修复的端粒 DNA 损伤和持续的 DDR 信号传导是细胞衰老和老化的共同致病机制。

DOI：
发表时间：
2014-06
期刊：
影响因子：
4
作者：
Rossiello, Francesca;Herbig, Utz;Longhese, Maria Pia;Fumagalli, Marzia;d'Adda di Fagagna, Fabrizio
通讯作者：
d'Adda di Fagagna, Fabrizio

Telomeric DNA damage is irreparable and causes persistent DNA-damage-response activation.

端粒 DNA 损伤是不可修复的，会导致持续的 DNA 损伤反应激活。

DOI：
发表时间：
2012-03-18
期刊：
影响因子：
21.3
作者：
Fumagalli, Marzia;Rossiello, Francesca;Clerici, Michela;Barozzi, Sara;Cittaro, Davide;Kaplunov, Jessica M;Bucci, Gabriele;Dobreva, Miryana;Matti, Valentina;Beausejour, Christian M;Herbig, Utz;Longhese, Maria Pia;d'Adda di Fagagna, Fabrizio
通讯作者：
d'Adda di Fagagna, Fabrizio

New intranasal and injectable gene therapy for healthy life extension.

新的鼻内和注射基因疗法可延长健康寿命。

DOI：
发表时间：
2022-05-17
期刊：
影响因子：
11.1
作者：
Jaijyan, Dabbu Kumar;Selariu, Anca;Cruz;Tong, Mingming;Yang, Shaomin;Stefa, Alketa;Kekich, David;Sadoshima, Junichi;Herbig, Utz;Tang, Qiyi;Church, George;Parrish, Elizabeth L;Zhu, Hua
通讯作者：
Zhu, Hua

AP-1 imprints a reversible transcriptional programme of senescent cells.

AP-1 印记了衰老细胞的可逆转录程序。

DOI：
发表时间：
2020-07
期刊：
影响因子：
21.3
作者：
Martínez;Roux, Pierre;de Freitas, José Américo N L F;Robinson, Lucas;Doré, Gregory;Sun, Bin;Belenki, Dimitri;Milanovic, Maja;Herbig, Utz;Schmitt, Clemens A;Gil, Jesús;Bischof, Oliver
通讯作者：
Bischof, Oliver

Senescence is an endogenous trigger for microRNA-directed transcriptional gene silencing in human cells.

衰老是人类细胞中 microRNA 介导的转录基因沉默的内源性触发因素。