Prostate cancer extracellular vesicles mediate intercellular communication with bone marrow cells and promote metastasis in a cholesterol-dependent manner.
Prostate cancer extracellular vesicles mediate intercellular communication with bone marrow cells and promote metastasis in a cholesterol-dependent manner.
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DOI：
10.1002/jev2.12042
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发表时间：
2020-12
影响因子：
16
通讯作者：
Thaxton CS
中科院分区：
文献类型：
--
作者：
Henrich SE;McMahon KM;Plebanek MP;Calvert AE;Feliciano TJ;Parrish S;Tavora F;Mega A;De Souza A;Carneiro BA;Thaxton CS
原发肿瘤可以与远处器官建立远程通信，将其转化为循环肿瘤细胞植入和增殖的肥沃土壤，这一过程称为转移前生态位（PMN）形成。肿瘤来源的细胞外囊泡（EV）是PMN形成的有效介质，因为它们具有不同的促恶性分子cargo补体和针对特定细胞类型的倾向（Costa Silva等人，2015；Hoshino等人，2015；Peinado等人，2012；Peinado等人，2017）。虽然在了解前转移性EV在前转移器官部位产生有利于肿瘤的微环境的机制方面已经取得了重大进展，但相对而言，很少有人关注受体细胞固有的因素，这些因素可能会改变前转移性EV信号的接收和转导程度。在这里，我们研究了受体细胞胆固醇稳态在前列腺癌（PCa） EV介导的信号传导和转移中的作用。利用enzalutamide耐药PCa的骨转移模型，我们首先表征了EV介导的PCa细胞与骨髓之间的通信轴，其标志是体外和体内PCa EV被骨髓样细胞摄取、NF - κB信号的激活、破骨细胞分化增强和髓样血栓响应蛋白- 1表达降低。然后，我们采用了一种靶向的仿生方法，在体外和体内降低骨髓细胞胆固醇，然后用PCa ev进行调节。降低髓细胞胆固醇可阻止受体髓细胞对PCa ev的摄取，抑制NF - κB活性和破骨细胞分化，稳定血小板反应蛋白- 1表达，并将转移负担降低77%。这些结果表明，骨髓细胞中的胆固醇稳态通过充当EV信号转导的守门人来调节EV的前转移信号和转移。
Primary tumours can establish long‐range communication with distant organs to transform them into fertile soil for circulating tumour cells to implant and proliferate, a process called pre‐metastatic niche (PMN) formation. Tumour‐derived extracellular vesicles (EV) are potent mediators of PMN formation due to their diverse complement of pro‐malignant molecular cargo and their propensity to target specific cell types (Costa‐Silva et al., 2015; Hoshino et al., 2015; Peinado et al., 2012; Peinado et al., 2017). While significant progress has been made to understand the mechanisms by which pro‐metastatic EVs create tumour‐favouring microenvironments at pre‐metastatic organ sites, comparatively little attention has been paid to the factors intrinsic to recipient cells that may modify the extent to which pro‐metastatic EV signalling is received and transduced. Here, we investigated the role of recipient cell cholesterol homeostasis in prostate cancer (PCa) EV‐mediated signalling and metastasis. Using a bone metastatic model of enzalutamide‐resistant PCa, we first characterized an axis of EV‐mediated communication between PCa cells and bone marrow that is marked by in vitro and in vivo PCa EV uptake by bone marrow myeloid cells, activation of NF‐κB signalling, enhanced osteoclast differentiation, and reduced myeloid thrombospondin‐1 expression. We then employed a targeted, biomimetic approach to reduce myeloid cell cholesterol in vitro and in vivo prior to conditioning with PCa EVs. Reducing myeloid cell cholesterol prevented the uptake of PCa EVs by recipient myeloid cells, abolished NF‐κB activity and osteoclast differentiation, stabilized thrombospondin‐1 expression, and reduced metastatic burden by 77%. These results demonstrate that cholesterol homeostasis in bone marrow myeloid cells regulates pro‐metastatic EV signalling and metastasis by acting as a gatekeeper for EV signal transduction.
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影响因子：
16
作者：
Lötvall J;Hill AF;Hochberg F;Buzás EI;Di Vizio D;Gardiner C;Gho YS;Kurochkin IV;Mathivanan S;Quesenberry P;Sahoo S;Tahara H;Wauben MH;Witwer KW;Théry C
通讯作者：
Théry C
影响因子：
2.9
作者：
Hoop, Cody L.;Sivanandam, V. N.;Kodali, Ravindra;Srnec, Matthew N.;van der Wel, Patrick C. A.
通讯作者：
van der Wel, Patrick C. A.
影响因子：
--
作者：
Kregel S;Chen JL;Tom W;Krishnan V;Kach J;Brechka H;Fessenden TB;Isikbay M;Paner GP;Szmulewitz RZ;Vander Griend DJ
通讯作者：
Vander Griend DJ
影响因子：
2.6
作者：
Hirata T;Park SC;Muldong MT;Wu CN;Yamaguchi T;Strasner A;Raheem O;Kumon H;Sah RL;Cacalano NA;Jamieson CHM;Kane CJ;Masuda K;Kulidjian AA;Jamieson CAM
通讯作者：
Jamieson CAM
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