Exosome secretion in breast cancer progression

 描述(申请人提供)：细胞分泌的胞外外体小泡可以对细胞表型产生深刻的自分泌和旁分泌效应。在肿瘤微环境中，外切体被认为是肿瘤进展的重要介质。然而，外切体在肿瘤中的确切功能还知之甚少。虽然最初不被认为是特定的外切体货物，但细胞外基质分子经常被发现与外切体相关，并可能深刻地影响肿瘤的行为。Weaver实验室最近证实，基质分子纤维连接蛋白通过与整合素受体相互作用而特异性地靶向外体。此外，他们还发现，携带纤维连接蛋白的外切体的分泌促进了黏附的形成和癌细胞的移动。最后，他们的初步数据表明，外切体分泌对基质基质的组装和排列也很重要，Keely实验室已经证明，这是乳腺癌预后不良的重要驱动因素。基于这些数据，该项目的中心假设是，通过成纤维细胞和乳腺癌外小体分泌的自分泌和旁分泌通讯都驱动了排列的基质基质的产生和侵袭性肿瘤行为。为了验证这一假设，我们将确定外切体在驱动乳腺癌细胞持续细胞迁移中的作用。我们还将测试自分泌外体分泌对成纤维细胞的基质组装和排列至关重要的假说。最后，我们将明确乳腺癌-成纤维细胞胞外体串扰在促进基质基质组装和肿瘤侵袭性中的作用。

 DESCRIPTION (provided by applicant): Secretion of extracellular exosome vesicles from cells can have profound autocrine and paracrine effects on cellular phenotype. In the tumor microenvironment, exosomes are thought to be important mediators of tumor progression. However, the exact functions of exosomes in tumors are poorly understood. Although not initially thought to be specific exosome cargos, extracellular matrix molecules are frequently identified in association with exosomes and could profoundly affect tumor behavior. The Weaver laboratory recently demonstrated that the matrix molecule fibronectin is specifically targeted to exosomes by interacting with integrin receptors. Furthermore, they have found that secretion of fibronectin-carrying exosomes promotes adhesion formation and cancer cell motility. Finally, their preliminary data indicates that exosome secretion is also important for stromal matrix assembly and alignment, which the Keely lab has demonstrated is an important driver of poor prognosis in breast cancer. Based on these data, the central hypothesis of this project is that both autocrine and paracrine communication via fibroblast and breast cancer exosome secretion drives generation of aligned stromal matrices and aggressive tumor behavior. To test this hypothesis, we will determine the role of exosomes in driving persistent cell migration by breast cancer cells. We will also test the hypothesis that autocrine exosome secretion is critical for stromal matrix assembly and alignment by fibroblasts. Finally, we will define the role of breast cancer- fibroblast exosomal crosstalk in promoting stromal matrix assembly and tumor aggressiveness.