Centrosome amplification mediates small extracellular vesicle secretion via lysosome disruption.
Centrosome amplification mediates small extracellular vesicle secretion via lysosome disruption.
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DOI：
10.1016/j.cub.2021.01.028
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发表时间：
2021-04-12
期刊：
影响因子：
--
通讯作者：
Godinho SA
中科院分区：
文献类型：
--
作者：
Adams SD;Csere J;D'angelo G;Carter EP;Romao M;Arnandis T;Dodel M;Kocher HM;Grose R;Raposo G;Mardakheh F;Godinho SA
细胞与其周围环境之间的双向通信在正常和病理环境中都是至关重要的。细胞外囊泡（EVs）是细胞间通讯的重要组成部分，它可以促进细胞间分子的水平传递。在癌症中，EV分泌的改变有助于肿瘤细胞的生长和转移。然而，这些变化背后的机制在很大程度上仍然未知。在这里，我们表明，中心体扩增与胰腺癌细胞中的小细胞外囊泡（SEV）分泌有关，并足以促进SEV分泌。这是溶酶体功能障碍的直接结果，由额外中心体下游的活性氧（ROS）增加引起。我们认为溶酶体功能的缺陷可以促进多泡体与质膜的融合，从而增强SEV的分泌。此外，我们发现响应于扩增的中心体而分泌的SEV在功能上是不同的，并且激活胰腺星状细胞（PSC）。这些活化的PSC促进胰腺癌细胞在异型3D培养物中的侵袭。我们认为，由具有扩增的中心体的癌细胞分泌的SEV影响肿瘤细胞与周围间质之间的双向通信以促进恶性。中心体扩增诱导SEV分泌蛋白质组学分析表明分泌的SEV是内吞来源的溶酶体功能障碍导致具有额外中心体的细胞中的SEV分泌具有额外中心体的PDAC分泌的SEV激活胰腺星状细胞亚当斯等人.证明了中心体扩增下游的溶酶体功能障碍增加了小细胞外囊泡（SEV）的分泌。这些SEV在功能上是不同的，并激活成纤维细胞样细胞，这表明具有扩增中心体的癌细胞可以改变肿瘤微环境。
Bidirectional communication between cells and their surrounding environment is critical in both normal and pathological settings. Extracellular vesicles (EVs), which facilitate the horizontal transfer of molecules between cells, are recognized as an important constituent of cell-cell communication. In cancer, alterations in EV secretion contribute to the growth and metastasis of tumor cells. However, the mechanisms underlying these changes remain largely unknown. Here, we show that centrosome amplification is associated with and sufficient to promote small extracellular vesicle (SEV) secretion in pancreatic cancer cells. This is a direct result of lysosomal dysfunction, caused by increased reactive oxygen species (ROS) downstream of extra centrosomes. We propose that defects in lysosome function could promote multivesicular body fusion with the plasma membrane, thereby enhancing SEV secretion. Furthermore, we find that SEVs secreted in response to amplified centrosomes are functionally distinct and activate pancreatic stellate cells (PSCs). These activated PSCs promote the invasion of pancreatic cancer cells in heterotypic 3D cultures. We propose that SEVs secreted by cancer cells with amplified centrosomes influence the bidirectional communication between the tumor cells and the surrounding stroma to promote malignancy. Centrosome amplification induces SEV secretion Proteomic analysis suggests that secreted SEVs are of endocytic origin Lysosomal dysfunction leads to SEV secretion in cells with extra centrosomes SEVs secreted by PDAC with extra centrosome activate pancreatic stellate cells Adams et al. demonstrate that lysosome dysfunction downstream of centrosome amplification increases the secretion of small extracellular vesicles (SEVs). These SEVs are functionally distinct and activate fibroblast-like cells, suggesting that cancer cells with amplified centrosomes could change the tumor microenvironment.
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影响因子：
11.8
作者：
Arnandis T;Monteiro P;Adams SD;Bridgeman VL;Rajeeve V;Gadaleta E;Marzec J;Chelala C;Malanchi I;Cutillas PR;Godinho SA
通讯作者：
Godinho SA
影响因子：
7.5
作者：
Bonifacino JS;Neefjes J
通讯作者：
Neefjes J
影响因子：
9.2
作者：
Chan JY
通讯作者：
Chan JY
影响因子：
21.3
作者：
Costa-Silva B;Aiello NM;Ocean AJ;Singh S;Zhang H;Thakur BK;Becker A;Hoshino A;Mark MT;Molina H;Xiang J;Zhang T;Theilen TM;García-Santos G;Williams C;Ararso Y;Huang Y;Rodrigues G;Shen TL;Labori KJ;Lothe IM;Kure EH;Hernandez J;Doussot A;Ebbesen SH;Grandgenett PM;Hollingsworth MA;Jain M;Mallya K;Batra SK;Jarnagin WR;Schwartz RE;Matei I;Peinado H;Stanger BZ;Bromberg J;Lyden D
通讯作者：
Lyden D
影响因子：
4
作者：
Colombo, Marina;Moita, Catarina;Raposo, Graca
通讯作者：
Raposo, Graca