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胰腺癌起始细胞外泌体信息传递至非起始细胞：CD44v6 在重编程中的重要性。

Pancreatic cancer-initiating cell exosome message transfer into noncancer-initiating cells: the importance of CD44v6 in reprogramming.

机构信息

Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China.

Pancreas Section, University Hospital of Surgery, Im Neuenheimer Feld 110, D69120, Heidelberg, Germany.

出版信息

J Exp Clin Cancer Res. 2019 Mar 19;38(1):132. doi: 10.1186/s13046-019-1129-8.

DOI:10.1186/s13046-019-1129-8
PMID:30890157
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6425561/
Abstract

BACKGROUND

Cancer-initiating cell (CIC) exosomes (CIC-TEX) are suggested reprogramming Non-CIC. Mode of message transfer and engagement of CIC-markers being disputed, we elaborated the impact of CD44v6 and Tspan8 on the response of Non-CIC.

METHODS

Non-metastasizing CD44v6- and Tspan8-knockdown (kd) pancreatic cancer cells served as Non-CIC. CIC-TEX coculture-induced changes were evaluated by deep-sequencing and functional assays. Tumor progression was surveyed during in vivo CIC-TEX treatment.

RESULTS

Deep-sequencing of CIC-TEX-cocultured CD44v6kd-Non-CIC revealed pronounced mRNA changes in signaling, transport, transcription and translation; altered miRNA affected metabolism, signaling and transcription. CIC-TEX coculture-induced changes in Tspan8kd-Non-CIC mostly relied on CIC-TEX-Tspan8 being required for targeting. CIC-TEX transfer supported apoptosis resistance and significantly promoted epithelial mesenchymal transition, migration, invasion and (lymph)angiogenesis of the kd Non-CIC in vitro and in vivo, deep-sequencing allowing individual mRNA and miRNA assignment to altered functions. Importantly, CIC-TEX act as a hub, initiated by CD44v6-dependent RTK, GPCR and integrin activation and involving CD44v6-assisted transcription and RNA processing. Accordingly, a kinase inhibitor hampered CIC-TEX-fostered tumor progression, which was backed by an anti-Tspan8 blockade of CIC-TEX binding.

CONCLUSIONS

This in depth report on the in vitro and in vivo impact of CIC-TEX on CD44v6kd and Tspan8kd Non-CIC unravels hub CIC-TEX activity, highlighting a prominent contribution of the CIC-markers CD44v6 to signaling cascade activation, transcription, translation and miRNA processing in Non-CIC and of Tspan8 to CIC-TEX targeting. Blocking CIC-TEX binding/uptake and uptake-initiated target cell activation significantly mitigated the deleterious CIC-TEX impact on CD44v6kd and Tspan8kd Non-CIC.

摘要

背景

癌症起始细胞（CIC）外泌体（CIC-TEX）被认为可以重新编程非 CIC。消息传递模式和 CIC 标志物的参与仍存在争议，我们详细阐述了 CD44v6 和 Tspan8 对非 CIC 反应的影响。

方法

非转移性 CD44v6 和 Tspan8 敲低（kd）胰腺癌细胞作为非 CIC。通过深度测序和功能测定评估 CIC-TEX 共培养诱导的变化。在体内 CIC-TEX 治疗期间调查肿瘤进展。

结果

深度测序显示，CIC-TEX 共培养的 CD44v6kd-非 CIC 中，信号转导、运输、转录和翻译的 mRNA 变化明显；改变的 miRNA 影响代谢、信号转导和转录。Tspan8kd-非 CIC 中 CIC-TEX 共培养诱导的变化主要依赖于 CIC-TEX-Tspan8 靶向。CIC-TEX 转移支持凋亡抵抗，并显著促进体外和体内 kd 非 CIC 的上皮间质转化、迁移、侵袭和（淋巴）血管生成，深度测序允许将单个 mRNA 和 miRNA 分配到改变的功能上。重要的是，CIC-TEX 作为一个枢纽，由 CD44v6 依赖性 RTK、GPCR 和整合素激活启动，并涉及 CD44v6 辅助的转录和 RNA 加工。相应地，一种激酶抑制剂阻碍了 CIC-TEX 促进的肿瘤进展，这得到了抗 Tspan8 阻断 CIC-TEX 结合的支持。

结论

本研究深入报道了 CIC-TEX 对 CD44v6kd 和 Tspan8kd 非 CIC 的体外和体内影响，揭示了枢纽 CIC-TEX 活性，突出了 CIC 标志物 CD44v6 在非 CIC 中信号级联激活、转录、翻译和 miRNA 处理中的重要作用，以及 Tspan8 在 CIC-TEX 靶向中的作用。阻断 CIC-TEX 结合/摄取和摄取引发的靶细胞激活显著减轻了 CIC-TEX 对 CD44v6kd 和 Tspan8kd 非 CIC 的有害影响。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3537/6425561/a4ecb990a679/13046_2019_1129_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3537/6425561/bf870fc7cd0f/13046_2019_1129_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3537/6425561/79005ad5982c/13046_2019_1129_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3537/6425561/333028a9e72d/13046_2019_1129_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3537/6425561/aa0af4078a4f/13046_2019_1129_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3537/6425561/9b23e272e3ae/13046_2019_1129_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3537/6425561/1ebce858e94e/13046_2019_1129_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3537/6425561/53c358f2c103/13046_2019_1129_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3537/6425561/a4ecb990a679/13046_2019_1129_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3537/6425561/bf870fc7cd0f/13046_2019_1129_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3537/6425561/79005ad5982c/13046_2019_1129_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3537/6425561/333028a9e72d/13046_2019_1129_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3537/6425561/aa0af4078a4f/13046_2019_1129_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3537/6425561/9b23e272e3ae/13046_2019_1129_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3537/6425561/1ebce858e94e/13046_2019_1129_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3537/6425561/53c358f2c103/13046_2019_1129_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3537/6425561/a4ecb990a679/13046_2019_1129_Fig8_HTML.jpg

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