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

基本信息

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
项目类别：
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&apos -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

项目摘要

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.

年龄是高级别浆液性卵巢癌 (HGSOC) 的主要危险因素，诊断时的平均年龄为 63. 排卵和衰老会引起输卵管微环境的炎症变化，这是大多数疾病的起源。随着时间的推移，细胞会衰老并分泌称为衰老的调节因子。相关分泌表型（SASP）引起的局部微环境变化。然而，衰老微环境在卵巢癌发生中的作用是重要的。未知的情况对这种致命疾病的有效早期检测和预防策略造成了主要障碍。该提案的目标是确定衰老对基质细胞与癌症之间相互作用的影响驱动卵巢癌形成的起始细胞（CIC）是多能的。基质祖细胞对整个生命周期的组织稳态至关重要，间充质干细胞经历表观基因组变化。重编程成为促肿瘤性癌症相关 MSC（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。 CA-MSC 衍生的 BMP4 增加了卵巢 CIC 的数量。随着年龄的增长，间充质干细胞甚至在癌症发生之前就可以表达WT1并采取促癌表型。我们将这些细胞称为“高风险”MSC (hrMSC)。初步数据表明，hrMSC (i) 具有概括性。 CA-MSC 表型并富集于癌前上皮细胞的基质中，(ii) 分泌 SASP 样诱导上皮细胞 DNA 损伤并支持 DNA 受损上皮细胞存活的蛋白质 (iii) 支持已建立的癌细胞生长，AMP 激活蛋白激酶 (AMPK) 可能对 CA- 至关重要。在一项临床试验中，二甲双胍可增加 AMPK，逆转 CA-MSC 表型。一些与改善生存相关的患者的初步数据显示了一种更有效的新型 AMPK 激活剂， BC1618，改变 hrMSC 分泌组，我们发现衰老会诱导表观遗传变化，从而转化。 MSCs 到 hrMSCs，并且 hrMSCs 创造了一个支持肿瘤生长的促肿瘤微环境卵巢 CIC。我们在衰老、基质干细胞和 CIC 方面拥有专业知识的合作团队建议：1) 确定衰老对输卵管 MSC 表型的影响以及与 CIC 的空间关系。取代老化的MSC通过DNA甲基化获得高风险表型并支持邻近的 2) 确定老化的 hrMSC 对 CIC 形成和卵巢癌进展的影响。老化的 hrMSC 通过 WT1 介导的 BMP4 和 SASP 促进 CIC 的形成和进展 3）靶向老化的hrMSCs以限制卵巢癌的形成我们利用了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 的形成和卵巢这项工作将通过定义关键作用来拓宽我们对卵巢癌发生的理解。老化基质在 CIC 形成中的作用，并为早期检测和预防策略提供新途径。