Defining the impact of stromal aging on ovarian cancer initiation

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.排卵和衰老诱导输卵管微环境的炎症变化，这是大多数输卵管炎的起源。 HGSOC。随着时间的推移，细胞变得衰老并分泌称为衰老的调节因子。 相关分泌表型（SASP）。SASP引起的局部微环境的变化已经被 与癌症有关然而，衰老微环境在卵巢癌发生中的作用是 这一未知因素对有效早期发现和预防这一致命疾病的战略构成了重大障碍。 这项提案的目标是确定衰老对基质细胞和癌症之间相互作用的影响 启动细胞（CIC）驱动卵巢癌形成。间充质基质/干细胞（MSC）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。在癌症中，MSC经历表观基因组 重编程以成为促肿瘤发生癌症相关MSC（CA-MSC）。促肿瘤发生CA-MSC 表型由Wilms肿瘤1（WT 1）转录因子的激活驱动。WT 1诱导分泌 CA-MSC衍生的BMP 4增加卵巢CIC的库。初步数据显示， 随着年龄的增长，MSC可以表达WT 1，甚至在癌症开始之前就采用癌症促进表型。 我们将这些细胞称为“高风险”MSC（hrMSC）。初步数据表明，hrMSC（i）概括了 CA-MSC表型，并在恶变前上皮细胞的基质中富集，（ii）分泌SASP样 诱导上皮细胞DNA损伤并支持DNA损伤的上皮细胞存活的蛋白质 和（iii）支持已建立的癌细胞生长。AMP激活的蛋白激酶（AMPK）可能是CA的关键。 MSC/hrMSC形成。在一项临床试验中，增加AMPK的Metabolic逆转了CA-MSC的表型， 一些患者的生存率提高。初步数据显示，一种更有效的新型AMPK激活剂， BC 1618改变hrMSC分泌组。我们假设衰老诱导表观遗传变化， 我们还发现，人骨髓间充质干细胞转化为人骨髓间充质干细胞，人骨髓间充质干细胞创造了一个促肿瘤发生的微环境，支持肿瘤细胞的生长。 卵巢CIC。我们的合作团队在衰老、基质干细胞和CIC方面拥有专业知识，建议：1） 确定老化对输卵管MSC表型的影响以及与CIC的空间关系。我们 假设老化MSC通过改变DNA甲基化获得高风险表型，并支持邻近的 战斗信息中心编队。2)确定老化的hrMSCs对CIC形成和卵巢癌进展的影响。我们 推测老化hrMSCs通过WT 1介导的BMP 4和SASP促进CIC的形成和进展 分泌物3)靶向衰老的hrMSCs以限制卵巢癌的形成。我们假设AMPK激活剂， BC 1618通过改变与年龄相关的MSC表观遗传变化，将减少hrMSC的形成和卵巢功能。 癌症起始。这项工作将扩大我们的理解卵巢癌的启动，通过定义的关键作用 衰老间质在CIC形成中的作用，并为早期检测和预防策略提供了新的途径。

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.