Collective cancer cell invasion requires RNA accumulation at the invasive front.
Collective cancer cell invasion requires RNA accumulation at the invasive front.
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DOI：
10.1073/pnas.2010872117
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发表时间：
2020-11-03
影响因子：
11.1
通讯作者：
Mili S
中科院分区：
文献类型：
--
作者：
Chrisafis G;Wang T;Moissoglu K;Gasparski AN;Ng Y;Weigert R;Lockett SJ;Mili S
特定的 RNA 在迁移细胞的突出区域富集。这种定位对于二维表面上的细胞迁移很重要。然而，在体内，肿瘤细胞通常以集体形式在复杂的 3D 环境中导航。在这里，我们研究了集体 3D 入侵过程中富含突起的 RNA。我们发现特定的 RNA 在侵入性前导细胞的前端表现出惊人的积累。我们深入了解了侵袭前沿 RNA 积累的机制，并进一步证明了它是肿瘤细胞有效 3D 侵袭所必需的。我们还观察到体内肿瘤侵袭部位的 RNA 富集，支持了该机制的生理相关性，并提出了扰乱癌细胞侵袭的靶向机会。 RNA 在细胞突出区域的定位对于单细胞在二维表面上的迁移非常重要。富含突起的 RNA 编码与癌症进展相关的因子，例如 RAB13 GTPase 和 NET1 鸟嘌呤核苷酸交换因子，并受到肿瘤抑制蛋白 APC 的调节。然而，体内的肿瘤细胞通常不会像单个细胞一样移动，而是利用集体的侵袭和传播模式。在这里，我们开发了一种三维（3D）集体入侵的诱导系统来研究富含突起的RNA的行为和重要性。令人惊讶的是，我们发现 RAB13 和 NET1 RNA 都专门富集在侵入细胞链中前导细胞的侵入前沿。这种定位需要微管并且与高层粘连蛋白浓度的位点一致。事实上，层粘连蛋白结合和整合素结合对于RNA在侵入前沿的积累是必需的。重要的是，干扰 RNA 积累会减少集体 3D 入侵。对体内肿瘤的检查揭示了 RAB13 和 NET1 RNA 在潜在侵袭部位的相似定位，表明这种机制可以为干扰集体癌细胞侵袭提供靶向机会。
Specific RNAs are enriched at protrusive regions of migrating cells. This localization is important for cell migration on 2D surfaces. However, in vivo, tumor cells navigate complex 3D environments often in collective groups. Here, we investigated protrusion-enriched RNAs during collective 3D invasion. We show that specific RNAs exhibit a striking accumulation at the front of invasive leader cells. We provide insights into the mechanism underlying RNA accumulation at the invasive front, and we further demonstrate that it is required for efficient 3D invasion of tumor cells. We additionally observe RNA enrichment at invasive sites of in vivo tumors, supporting the physiological relevance of this mechanism and suggesting a targeting opportunity for perturbing cancer cell invasion. Localization of RNAs at protrusive regions of cells is important for single-cell migration on two-dimensional surfaces. Protrusion-enriched RNAs encode factors linked to cancer progression, such as the RAB13 GTPase and the NET1 guanine nucleotide exchange factor, and are regulated by the tumor-suppressor protein APC. However, tumor cells in vivo often do not move as single cells but rather utilize collective modes of invasion and dissemination. Here, we developed an inducible system of three-dimensional (3D) collective invasion to study the behavior and importance of protrusion-enriched RNAs. We find that, strikingly, both the RAB13 and NET1 RNAs are enriched specifically at the invasive front of leader cells in invasive cell strands. This localization requires microtubules and coincides with sites of high laminin concentration. Indeed, laminin association and integrin engagement are required for RNA accumulation at the invasive front. Importantly, perturbing RNA accumulation reduces collective 3D invasion. Examination of in vivo tumors reveals a similar localization of the RAB13 and NET1 RNAs at potential invasive sites, suggesting that this mechanism could provide a targeting opportunity for interfering with collective cancer cell invasion.
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DOI：
10.1083/jcb.201704053
发表时间：
2017-11-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Erdogan B;Ao M;White LM;Means AL;Brewer BM;Yang L;Washington MK;Shi C;Franco OE;Weaver AM;Hayward SW;Li D;Webb DJ
通讯作者：
Webb DJ
EMT亚型影响上皮可塑性和细胞迁移模式。
影响因子：
11.8
作者：
Aiello NM;Maddipati R;Norgard RJ;Balli D;Li J;Yuan S;Yamazoe T;Black T;Sahmoud A;Furth EE;Bar-Sagi D;Stanger BZ
通讯作者：
Stanger BZ
影响因子：
64.5
作者：
de Hoog, CL;Foster, LJ;Mann, M
通讯作者：
Mann, M
影响因子：
64.8
作者：
Chicurel, ME;Singer, RH;Ingber, DE
通讯作者：
Ingber, DE
影响因子：
5.3
作者：
Carr, Heather S.;Zuo, Yan;Frost, Jeffrey A.
通讯作者：
Frost, Jeffrey A.