(PQA-2) Reprogramming of circulating adipose stromal cells by mechanical stress

描述(申请人提供)：脂肪基质细胞(ASCs)是一些脂肪组织来源的促肿瘤因子的主要来源，包括雌激素和各种细胞因子。新的证据表明，循环中的ASCs与肥胖者，特别是肥胖的癌症患者有明显的相关性。在功能上，循环中的ASCs可以运动到远处器官中的肿瘤间质，促进肿瘤的进展。然而，由于循环中的ASCs相对罕见，它们的数量不太可能超过肿瘤间质中经常大量存在的常驻ASCs。循环中的ASCs与从未接触过循环的常住ASCs有什么不同？“血液之旅”本身是否赋予循环中的ASCs某些持久的特征，进而增强其促进肿瘤的活性？ 高顺应性或低刚性是一种显著的机械性能，使液体组织与 固体组织。相应地，在这两个机械上不同的矩阵中，细胞采用不同的大小和形状。我们的初步工作表明，顺应性基质和/或圆形细胞形状，两者都让人想起血液中的机械表型，极大地刺激ASCs产生雌激素，并反过来促进这些基质细胞促进雌激素受体的增殖？(ER)阳性的乳腺癌细胞。在目前的提案中，我们将测试血液中机械顺应性环境诱导循环ASCs转录和表观遗传重新编程的假设。这一过程可能会导致循环ASCs的内分泌输出和促肿瘤活性增加，从而使它们能够在远处含有肿瘤的实体组织中“胜过”常驻的ASCs。我们将结合互补系统(细胞培养、动物模型和临床样本)、跨学科专业知识(生物工程、脂肪/癌症生物学和表观遗传学)和尖端技术(单细胞分离和分析)来检验这一新假设。 富含脂肪的脂肪细胞一直是肥胖相关癌症风险研究的主要焦点。通过探索机械顺应性、表观遗传重新编程和循环ASCs内分泌输出之间的联系，拟议的工作整合了历史上分离的研究领域，并有望为研究不足的肥胖相关细胞群体提供新的见解。此外，机械诱导重编程的新概念可能会对与癌症进展和转移有关的其他循环细胞类型的研究产生深远影响。

DESCRIPTION (provided by applicant): Adipose stromal cells (ASCs) are the major source for some adipose tissue-derived, tumor-promoting factors including estrogens and various cytokines. Emerging evidence indicates that circulating ASCs are distinctly associated with obese individuals, in particular obese cancer patients. Functionally, circulating ASCs can travel to tumor stroma in distant organs to promote tumor progression. However, as circulating ASCs are relatively rare, they are unlikely to outnumber resident ASCs that are often abundantly present in tumor stroma. Are circulating ASCs different from resident ASCs that have never been exposed to circulation? Does the "blood journey" per se endow certain enduring features to circulating ASCs, which in turn enhances their tumor-promoting activity? High compliance or low rigidity is a salient mechanical property that sets liquid tissue apart from solid tissue. Correspondingly, cells adopt different sizes and shapes in these two mechanically different matrices. Our preliminary work indicates that a compliant matrix and/or a round cell shape, both of which are reminiscent of the mechanical phenotype in blood, substantially stimulate estrogen production in ASCs and in turn the ability of these stromal cells to promote proliferation of estrogen receptor ? (ER)-positive breast cancer cells. In the current proposal, we will test the hypothesis that the mechanically compliant environment in blood induces transcriptional and epigenetic reprogramming of circulating ASCs. This process may result in elevated endocrine output and tumor-promoting activity of circulating ASCs, thus enabling them to "outperform" resident ASCs at a distant tumor-containing solid tissue. We will combine complementary systems (cell culture, animal models, and clinical samples), cross-disciplinary expertise (bioengineering, adipose/cancer biology, and epigenetics), and cutting-edge technologies (single-cell isolation and analysis) to test this novel hypothesis. Fat-laden adipocyte has been the primary focus in studies of obesity-related cancer risk. By exploring a link between mechanical compliance, epigenetic reprogramming, and endocrine output of circulating ASCs, the proposed work integrates historically separate areas of research and promises to offer new insights into an under-investigated, obesity-associated cell population. In addition, the novel concept of mechanically induced reprogramming may have a far-reaching impact on studies of other circulating cell types that are involved in cancer progression and metastasis.