MCF10CA Breast Cancer Cells Utilize Hyaluronan-Coated EV-Rich Trails for Coordinated Migration.
MCF10CA Breast Cancer Cells Utilize Hyaluronan-Coated EV-Rich Trails for Coordinated Migration.
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DOI：
10.3389/fonc.2022.869417
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发表时间：
2022
影响因子：
4.7
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中科院分区：
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肿瘤细胞通过间质的侵袭是响应于由细胞外环境提供的迁移线索而协调的。肿瘤微环境中最丰富的分子之一是透明质酸，一种已知促进肿瘤进展的许多标志的糖胺聚糖，包括肿瘤细胞的迁移潜力。引人注目的是，还经常发现透明质酸包覆细胞外囊泡（EV），所述细胞外囊泡源自对迁移至关重要的肿瘤细胞的质膜触手，例如丝状伪足，并且在肿瘤小生境中丰富。因此，透明质酸和透明质酸涂层EV可能在促进迁移方面具有协同作用。在这项工作中，我们比较了透明质酸的合成，EV分泌和迁移行为的正常和侵袭性乳腺细胞系MCF 10系列。单活细胞共聚焦成像，电子显微镜和相关的光学和电子显微镜实验表明，迁移的肿瘤细胞形成富含EV和透明质酸包被的踪迹。这些踪迹促进跟随细胞的寻路行为，这依赖于透明质酸。具体而言，我们证明了在迁移过程中肿瘤细胞留下的质膜突起和EV对CD 9呈强阳性。单细胞追踪显示了领导者-跟随者行为，其在去除细胞周透明质酸后显著降低，表明透明质酸促进跟随者细胞的寻路行为。鸡胚绒毛尿囊膜试验表明，肿瘤细胞在3D条件下表现相似。这项研究加强了细胞外基质的产生和结构在协调肿瘤细胞运动中的重要作用，并验证了EV作为肿瘤基质重要组分和调节剂的作用。结果表明，肿瘤细胞可以修改的细胞外生态位形成的痕迹，他们随后遵循协调。未来的研究将更详细地阐明透明质酸，EV和其他细胞外信号在跟随细胞的协调迁移和寻路行为中的协调作用。
Invasion of tumor cells through the stroma is coordinated in response to migratory cues provided by the extracellular environment. One of the most abundant molecules in the tumor microenvironment is hyaluronan, a glycosaminoglycan known to promote many hallmarks of tumor progression, including the migratory potential of tumor cells. Strikingly, hyaluronan is also often found to coat extracellular vesicles (EVs) that originate from plasma membrane tentacles of tumor cells crucial for migration, such as filopodia, and are abundant in tumor niches. Thus, it is possible that hyaluronan and hyaluronan-coated EVs have a cooperative role in promoting migration. In this work, we compared the hyaluronan synthesis, EV secretion and migratory behavior of normal and aggressive breast cell lines from MCF10 series. Single live cell confocal imaging, electron microscopy and correlative light and electron microscopy experiments revealed that migrating tumor cells form EV-rich and hyaluronan -coated trails. These trails promote the pathfinding behavior of follower cells, which is dependent on hyaluronan. Specifically, we demonstrated that plasma membrane protrusions and EVs left behind by tumor cells during migration are strongly positive for CD9. Single cell tracking demonstrated a leader-follower behavior, which was significantly decreased upon removal of pericellular hyaluronan, indicating that hyaluronan promotes the pathfinding behavior of follower cells. Chick chorioallantoic membrane assays in ovo suggest that tumor cells behave similarly in 3D conditions. This study strengthens the important role of extracellular matrix production and architecture in coordinated tumor cell movements and validates the role of EVs as important components and regulators of tumor matrix. The results suggest that tumor cells can modify the extracellular niche by forming trails, which they subsequently follow coordinatively. Future studies will clarify in more detail the orchestrated role of hyaluronan, EVs and other extracellular cues in coordinated migration and pathfinding behavior of follower cells.
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影响因子：
16
作者：
Menck K;Bleckmann A;Wachter A;Hennies B;Ries L;Schulz M;Balkenhol M;Pukrop T;Schatlo B;Rost U;Wenzel D;Klemm F;Binder C
通讯作者：
Binder C
影响因子：
5.2
作者：
Kyykallio, Heikki;Oikari, Sanna;Rilla, Kirsi
通讯作者：
Rilla, Kirsi
影响因子：
7.5
作者：
Jacquemet, Guillaume;Hamidi, Hellyeh;Ivaska, Johanna
通讯作者：
Ivaska, Johanna
影响因子：
21.3
作者：
Das, Tamal;Safferling, Kai;Spatz, Joachim P.
通讯作者：
Spatz, Joachim P.
影响因子：
--
作者：
Aguilar-Cuenca R;Llorente-Gonzalez C;Vicente C;Vicente-Manzanares M
通讯作者：
Vicente-Manzanares M