Adipose MSC suppress breast cancer progression, metastasis and inhibit EMT pathways via exosomal-miRNAs following co-culture interaction

Introduction: Mesenchymal stem cells (MSCs) are commonly known to influence the progression of cancer due to their ability to migrate to the tumor microenvironment and interact with cancer cells. Exosomes have been found secreted by most cell types and have been shown to act as cargo carrying biomolecules including microRNA (miRNAs). Thus, understanding interaction between MSCs and cancer cells via exosomal miRNAs is crucial in determining the therapeutic role of MSC in treating breast cancer cells and relapse. Methods: Exosomes were harvested from the medium of indirect co-culture of MCF7-luminal and MDA-MB-231-basal breast cancer cells (BCCs) subtypes with adipose MSCs and profiled for miRNAs using next-generation sequencing. Results: The interaction resulted in the changes of exosomal miRNAs profiles that modulate essential signalling pathways and cell cycle arrest into dormancy via inhibition of epithelial-to-mesenchymal transition (EMT). The maintenance and induction of epithelial features in MCF7 and MDA cells have led to a positive correlation with the reduction of proliferation and metastasis as well as increased drug resistance. Overall, adipose MSCs mediated delivery of consensus miRNAs particularly miR-200 family in MCF7, miR-146a in MDA and miR-941 in both BCCs subtypes via exosomes. Overall design: miRNA profiles of breast cancer cells subtypes co-cultured with adipose MSC were generated using next-generation sequencing.

引言：间充质干细胞（Mesenchymal stem cells, MSCs）因具备向肿瘤微环境迁移并与癌细胞相互作用的能力，素来被认为可影响癌症进展。目前已证实，绝大多数细胞类型均可分泌外泌体（exosomes），且外泌体可作为携带包括微小RNA（microRNA, miRNAs）在内的生物分子的载体。因此，阐明间充质干细胞与癌细胞通过外泌体微小RNA介导的相互作用，对于明确间充质干细胞在治疗乳腺癌细胞及抑制肿瘤复发中的治疗作用至关重要。
方法：本研究从脂肪来源间充质干细胞与MCF7腔面型、MDA-MB-231基底型乳腺癌细胞（breast cancer cells, BCCs）的间接共培养培养基中分离收获外泌体，并通过下一代测序（next-generation sequencing）技术对其中的微小RNA进行表达谱分析。
结果：共培养相互作用可改变外泌体的微小RNA表达谱，通过抑制上皮间质转化（epithelial-to-mesenchymal transition, EMT）调控关键信号通路，并诱导细胞周期阻滞进入休眠状态。MCF7与MDA-MB-231细胞株上皮特征的维持与诱导，与细胞增殖能力、转移能力的降低及药物抗性的增强呈显著正相关。总体而言，脂肪来源间充质干细胞可通过外泌体介导共识微小RNA的递送：具体包括MCF7细胞中的miR-200家族、MDA-MB-231细胞中的miR-146a，以及两种乳腺癌细胞亚型均表达的miR-941。
整体实验设计：本数据集通过下一代测序技术，构建了与脂肪来源间充质干细胞共培养的乳腺癌细胞亚型的微小RNA表达谱。