Defining the impact of stromal aging on ovarian cancer initiation

定义基质老化对卵巢癌发生的影响

• 批准号: 10353485
• 负责人: Ronald J Buckanovich
• 金额: $ 46.64万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10353485
• 关键词: 5' -AMP-activated protein kinase; Adopted; Age; Aging; BMP4; Cancer Cell Growth; Cancer Model; Cell Aging; Cell secretion; Cells; Chronic; Clinical Trials; Colon; DNA Damage; DNA Methylation; Data; Development; Diagnosis; Disease; Early Diagnosis; Epigenetic Process; Epithelial Cells; Genetically Engineered Mouse; Goals; Growth; Homeostasis; Human; In Vitro; Inflammation; Inflammatory; Label; Liver; Longevity; Lung; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Mediating; Mesenchymal; Metformin; Modeling; Multipotent Stem Cells; Mus; Organoids; Ovarian; Ovulation; Patients; Pattern; Phenotype; Prevention strategy; Prognostic Factor; Protein Kinase; Proteins; Request for Applications; Risk Factors; Role; Serous; Site; Stromal Cells; Stromal Change; Time; Tissues; Transgenic Mice; WT1 gene; Wild Type Mouse; Woman; Work; age group; age related; aged; anti aging; anti-tumor immune response; cancer cell; cancer initiation; cancer invasiveness; chemokine; epigenomics; high risk; improved; in vivo; mRNA Expression; multipotent stromal progenitor; novel; premalignant; prevent; response; senescence; spatial relationship; stem cells; transcription factor; tumor progression; tumorigenic; wound healing

Age is a major risk factor for high grade serous ovarian cancer (HGSOC) with an average age at diagnosis of 63. Ovulation and aging induce inflammatory changes in the fallopian tube microenvironment, the origin of most HGSOC. Over time, cells become senescent and secrete regulatory factors known as the senescence associated secretory phenotype (SASP). SASP-induced changes in the local microenvironment have been implicated in cancer promotion. However, the role of the aging microenvironment in ovarian cancer initiation is unknown creating a major barrier to effective early detection and prevention strategies for this deadly disease. The goal of this proposal is to define the impact of aging on interactions between stromal cells and cancer initiating cells (CIC) that drive ovarian cancer formation. Mesenchymal stromal/stem cell (MSC) are multipotent stromal progenitor cells critical to tissue homeostasis across the lifespan. In cancer, MSCs undergo epigenomic reprogramming to become pro-tumorigenic cancer associated MSCs (CA-MSCs). The pro-tumorigenic CA-MSC phenotype is driven by the activation of the Wilms tumor 1 (WT1) transcription factor. WT1 induces the secretion of CA-MSC derived BMP4 which increases the pool of ovarian CICs. Preliminary data demonstrate that with increasing age, MSCs can express WT1 and adopt a cancer promoting phenotype even before cancer starts. We have termed these cells ‘high risk’ MSCs (hrMSCs). Preliminary data indicate that hrMSCs (i) recapitulate the CA-MSC phenotype and are enriched in the stroma of pre-malignant epithelial cells, (ii) secrete SASP-like proteins which both induce epithelial cell DNA damage and support the survival of DNA damaged epithelial cells and (iii) support established cancer cell growth. AMP-activated protein kinase (AMPK) may be critical to CA- MSC/hrMSC formation. In a clinical trial Metformin, which increases AMPK, reversed the CA-MSC phenotype in some patients correlating with improved survival. Preliminary data shows a more potent, novel AMPK activator, BC1618, alters the hrMSC secretome. We hypothesize that aging induces epigenetic changes which convert MSCs to hrMSCs and that hrMSCs create a pro-tumorigenic microenvironment that supports the growth of ovarian CICs. Our collaborative team with expertise in aging, stromal stem cells and CICs propose to: 1) Determine the impact of aging on the fallopian tube MSC phenotype and spatial relationship to CICs. We hypothesize that aged MSCs obtain a high risk phenotype through altered DNA methylation and support adjacent CIC formation. 2) Determine the impact of aged hrMSCs on CIC formation and ovarian cancer progression. We hypothesize that aged hrMSCs promote CIC formation and progression via WT1-mediated BMP4 and SASP secretion. 3) Target aging hrMSCs to limit ovarian cancer formation. We hypothesize that the AMPK activator, BC1618, through altering age-related MSC epigenetic changes, will decrease hrMSC formation and ovarian cancer initiation. This work will broaden our understanding of ovarian cancer initiation by defining the critical role of aging stroma in CIC formation and offer new avenues for early detection and prevention strategies.

年龄是高级浆液卵巢癌（HGSOC）的主要危险因素，诊断为平均年龄 63。排卵和衰老引起输卵管微环境的炎症变化，大多数的起源 HGSOC。随着时间的流逝，细胞成为感官和秘密调节因子称为感应的因素 相关的秘密表型（SASP）。 SASP引起的局部微环境的变化已经 在癌症促进中实施。但是，衰老微环境在卵巢癌开始中的作用是 未知为这种致命疾病的有效早期发现和预防策略创造了主要障碍。 该提案的目的是定义衰老对基质细胞与癌症之间相互作用的影响 启动驱动卵巢癌形成的细胞（CIC）。间充质基质/干细胞（MSC）是多能 基质祖细胞对整个寿命至关重要的组织稳态至关重要。在癌症中，MSC经历表观基因组学 重新编程成为促肿瘤癌相关的MSC（CA-MSC）。亲瘤的CA-MSC 表型是由Wilms肿瘤1（WT1）转录因子的激活驱动的。 WT1诱导分泌物 CA-MSC衍生的BMP4增加了卵巢CIC的库。初步数据证明了 随着年龄的增长，MSC甚至在癌症开始之前就可以表达WT1并采用癌症促进表型。 我们称这些细胞为“高风险” MSC（HRMSC）。初步数据，表明HRMSC（i）概括 CA-MSC表型，并富集在恶性上皮细胞的基质中，（ii）秘密SASP样 蛋白质都诱导上皮细胞DNA损伤并支持DNA损坏的上皮细胞的存活 （iii）支持确定的癌细胞生长。 AMP激活的蛋白激酶（AMPK）对CA-可能至关重要 MSC/HRMSC形成。在增加AMPK的临床试验二甲双胍中，逆转了CA-MSC表型 一些患者与提高生存率相关。初步数据显示了更潜在的新型AMPK激活剂， BC1618，改变了HRMSC分泌组。我们假设衰老会引起表观遗传变化，这些变化转化了 MSC到HRMSC，HRMSC创建了一个亲氧化微环境，以支持增长 卵巢CICS。我们在衰老，基质干细胞和CICS建议方面具有专业知识的合作团队：1） 确定衰老对输卵管MSC表型的影响以及与CICS的空间关系。我们 假设老化的MSC通过改变DNA甲基化并支持粘合剂获得高风险表型 CIC组。 2）确定老化的HRMSC对CIC形成和卵巢癌进展的影响。我们 假设老化的HRMSC通过WT1介导的BMP4和SASP促进CIC的形成和进展 分泌。 3）目标衰老的HRMSC限制卵巢癌的形成。我们假设AMPK激活剂， BC1618通过改变与年龄相关的MSC表观遗传变化，将减少HRMSC形成和卵巢 癌症开始。这项工作将通过定义关键作用来扩大我们对卵巢癌开始的理解 CIC形成中衰老基质的衰老，并为早期检测和预防策略提供了新的途径。