Exosome secretion in breast cancer progression

外泌体是通过旁分泌驱动癌症转移的小细胞外囊泡（EV）。 和自分泌信号。虽然特定的外泌体货物在这一过程中的作用并不清楚， 应理解，整合素粘附受体已被证明参与选择 转移部位这是如何发生的还不完全清楚，但可能涉及外泌体的结合- 在远处组织中携带整合素至同源细胞外基质（ECM）配体。另一个非- 唯一的可能性是外泌体整合素和其他粘附受体直接启动 组装ECM以允许癌细胞在原发肿瘤部位存活和侵袭， 远处转移部位的定殖。我们将研究这些可能的功能， 外泌体在乳腺癌转移中的作用 在之前的资助周期中，我们确定了癌症- 和基质来源的外泌体控制肿瘤侵袭性，包括：1）自分泌促进 2）成纤维细胞外泌体是诱导组装所必需且足够的 纤连蛋白和其他基质基质蛋白，在体外和体内; 3）和成纤维细胞- 分泌的外来体促进原发性乳腺肿瘤的生长和转移。此外，本发明还提供了一种方法， 我们发现，粘附受体在来自癌细胞的小EV上富集， 成纤维细胞基于这些其他的发现，我们提出了一个中心假设， 乳腺癌和成纤维细胞外泌体携带的分子驱动多个步骤， 转移级联反应为了检验这一假设，我们将：1）检验这一假设， 外泌体内的整合素和多配体蛋白聚糖介导纤连蛋白（FN）组装; 2）测试外泌体内的整合素和多配体蛋白聚糖的表达。 假设乳腺癌细胞外泌体携带独特粘附分子， 3）确定外泌体粘附受体在上皮型ECM组装中的作用; 促进乳腺癌转移。

Exosomes are small extracellular vesicles (EVs) that drive cancer metastasis through paracrine and autocrine signaling. While the role of specific exosome cargoes in this process is not well understood, integrin adhesion receptors have been shown to be involved in the choice of metastatic site. How this occurs is not entirely clear, but could involve binding of exosome- carried integrins to cognate extracellular matrix (ECM) ligands in distant tissues. Another non- exclusive possibility is that exosomal integrins and other adhesion receptors directly initiate assembly of ECM to allow cancer cell survival and invasion at primary tumor sites and colonization of distant metastatic sites. We will investigate these possible functions of exosomes in breast cancer metastasis. In the prior grant cycle, we identified fundamental mechanisms by which both cancer- and stromal-derived exosomes control tumor aggressiveness, including: 1) autocrine promotion of cancer cell migration; 2) fibroblast exosomes are necessary and sufficient to induce assembly of fibronectin and other stromal matrix proteins, both in vitro and in vivo; 3) and fibroblast- secreted exosomes promote both growth and metastasis of primary breast tumors. In addition, we find that adhesion receptors are enriched on small EVs from both cancer cells and fibroblasts. Based on these other findings, we propose the central hypothesis that adhesion molecules carried by breast cancer and fibroblast exosomes drive multiple steps of the metastatic cascade. To test this hypothesis, we will: 1) Test the hypothesis that clustering of integrins and syndecans within exosomes mediates fibronectin (FN) assembly; 2) Test the hypothesis that breast cancer cell exosomes carry unique adhesion molecules that can induce assembly of epithelial-type ECM; 3) Determine the role of exosomal adhesion receptors in promoting breast cancer metastasis.