Vimentin filaments drive migratory persistence in polyploidal cancer cells
Vimentin filaments drive migratory persistence in polyploidal cancer cells
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DOI：
10.1073/pnas.2011912117
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发表时间：
2020-10
期刊：
影响因子：
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通讯作者：
Botai Xuan;D. Ghosh;Joy X. Jiang;Rachelle Shao;M. Dawson
中科院分区：
文献类型：
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作者：
Botai Xuan;D. Ghosh;Joy X. Jiang;Rachelle Shao;M. Dawson
多倍体细胞已被证明与临床上不良的患者结局相关，以及与增加的化疗耐药性和致瘤性相关。由于它们的高度迁移表型，它们也与癌症侵袭有关。人们严重缺乏对促使其移徙增加的基本生物物理机制的了解。在这里，我们解决这种缺乏知识，并表明波形蛋白是他们的迁移表型的关键，特别是在细胞干扰的情况下。我们还提出了一种治疗途径，可以在临床上适应，以减轻这些巨大的癌细胞对患者预后的有害影响。多倍体巨癌细胞（PGCC）是在异质性实体瘤中发现的多核化学抗性癌细胞。部分由于其明显的休眠，PGCC对癌症进展的影响在很大程度上尚未研究。最近的研究强调了PGCC作为侵袭性和化学抗性癌细胞的关键作用，以及它们经历无丝分裂出芽以逃避休眠的能力。我们最近的研究证明了PGCC独特的生物物理特性，以及它们不寻常的迁移持久性。在这里，我们揭示了波形蛋白中间丝（VIFs）在维持PGCC结构完整性和增强其迁移持久性方面的关键功能。我们进行了深入的单细胞分析，以研究VIF的分布及其在迁移持久性中的作用。我们发现，PGCC在很大程度上依赖于其独特的分布和极化的VIF网络，以提高他们的过渡，从一个堵塞到一个未堵塞的状态，以允许定向迁移。用丙烯酰胺抑制VIF和波形蛋白的小干扰RNA敲低均显著降低PGCC迁移并导致PGCC体积损失。由于PGCC依赖其VIF网络来指导迁移并维持其扩大的形态，因此靶向波形蛋白或波形蛋白交联蛋白可以提供一种治疗方法，以减轻这些化疗耐药细胞在癌症进展中的影响，并改善化疗患者的结局。
Significance Polyploidal cells have been shown to correlate with poor patient outcomes in the clinic, as well as with increased chemoresistance and tumorigenicity. They are also implicated in cancer aggression due to their highly migratory phenotype. There is a serious lack of understanding of the underlying biophysical mechanisms that drive their increased migration. Here we address this lack of knowledge and show that vimentin is key to their migratory phenotype, especially in the context of cellular jamming. We also propose a therapeutic avenue that can be adapted in the clinic to mitigate the deleterious effects of these giant cancer cells on patient outcomes. Polyploidal giant cancer cells (PGCCs) are multinucleated chemoresistant cancer cells found in heterogeneous solid tumors. Due in part to their apparent dormancy, the effect of PGCCs on cancer progression has remained largely unstudied. Recent studies have highlighted the critical role of PGCCs as aggressive and chemoresistant cancer cells, as well as their ability to undergo amitotic budding to escape dormancy. Our recent study demonstrated the unique biophysical properties of PGCCs, as well as their unusual migratory persistence. Here we unveil the critical function of vimentin intermediate filaments (VIFs) in maintaining the structural integrity of PGCCs and enhancing their migratory persistence. We performed in-depth single-cell analysis to examine the distribution of VIFs and their role in migratory persistence. We found that PGCCs rely heavily on their uniquely distributed and polarized VIF network to enhance their transition from a jammed to an unjammed state to allow for directional migration. Both the inhibition of VIFs with acrylamide and small interfering RNA knockdown of vimentin significantly decreased PGCC migration and resulted in a loss of PGCC volume. Because PGCCs rely on their VIF network to direct migration and to maintain their enlarged morphology, targeting vimentin or vimentin cross-linking proteins could provide a therapeutic approach to mitigate the impact of these chemoresistant cells in cancer progression and to improve patient outcomes with chemotherapy.