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，确诊时的平均年龄为 63.排卵和衰老引起输卵管微环境的炎性改变，是大多数 HGSOC。随着时间的推移，细胞开始衰老，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 与癌症宣传有牵连。然而，衰老微环境在卵巢癌发生中的作用是 这一未知因素对这一致命疾病的有效早期发现和预防战略造成了重大障碍。 这项提议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)，推动卵巢癌的形成。间充质基质/干细胞(MSC)具有多潜能 基质祖细胞对整个生命周期的组织动态平衡至关重要。在癌症中，MSCs经历了表观基因组学 重新编程成为致癌相关的间充质干细胞(CA-MSCs)。促肿瘤的CA-MSC 表型是由Wilms Tumor 1(WT1)转录因子的激活驱动的。WT1诱导分泌 CA-MSC来源的BMP4增加了卵巢CICs池。初步数据表明，随着 随着年龄的增长，MSCs可以表达WT1，甚至在癌症开始之前就采用了促癌表型。 我们将这些细胞称为“高危”间充质干细胞(HrMSCs)。初步数据表明hrMSCs(I)概括 CA-MSC的表型，并在癌前上皮细胞间质中丰富，(Ii)分泌SASP样蛋白 既能诱导上皮细胞DNA损伤又能支持DNA损伤的上皮细胞存活的蛋白质 以及(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- MSC/hrMSC形成。在一项临床试验中，增加AMPK的二甲双胍逆转了CA-MSC表型 一些患者与提高存活率有关。初步数据显示，一种更有效的新型AMPK激活剂， BC1618，改变了hrMSC分泌组。我们假设衰老会导致表观遗传变化，这种变化会转化为 MSCs到hrMSCs和hrMSCs创造了一个促进肿瘤形成的微环境，支持 卵巢CICs。我们在衰老、基质干细胞和CICs方面拥有专业知识的协作团队建议：1) 确定年龄对输卵管间充质干细胞表型的影响以及与CICs的空间关系。我们 假设老年间充质干细胞通过DNA甲基化改变获得高危表型并支持邻近 中情局队形。2)探讨老龄hrMSCs对CIC形成和卵巢癌进展的影响。我们 假设衰老的hrMSCs通过WT1介导的BMP4和SASP促进CIC的形成和进展 分泌物。3)以老化的hrMSCs为靶点，限制卵巢癌的形成。我们假设AMPK激活剂， BC1618通过改变年龄相关的MSC表观遗传学改变，将减少hrMSC的形成和卵巢 癌症的开端。这项工作将通过定义卵巢癌的关键作用来拓宽我们对卵巢癌启动的理解 研究CIC形成中的老化间质，并为早期发现和预防策略提供新的途径。

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.