Exosome secretion in breast cancer progression

 描述（由申请人提供）：细胞分泌胞外外泌体囊泡可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，外泌体被认为是肿瘤进展的重要介质。然而，外泌体在肿瘤中的确切功能知之甚少。虽然最初并不认为是特定的外泌体货物，但细胞外基质分子经常与外泌体相关，并可能深刻影响肿瘤行为。Weaver实验室最近证明，基质分子纤连蛋白通过与整合素受体相互作用特异性靶向外泌体。此外，他们发现携带纤连蛋白的外泌体的分泌促进粘附形成和癌细胞运动。最后，他们的初步数据表明，外泌体分泌对基质基质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泌体分泌的自分泌和旁分泌通信驱动对齐的基质基质和侵袭性肿瘤行为的产生。为了验证这一假设，我们将确定外泌体在驱动乳腺癌细胞持续细胞迁移中的作用。我们还将检验自分泌外泌体分泌对成纤维细胞的基质基质组装和排列至关重要的假设。最后，我们将确定乳腺癌成纤维细胞外泌体串扰在促进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.