School of Human Sciences, The University of Western Australia, Crawley, 6009, WA, Australia.
Mechanobiology Institute, National University of Singapore, 117411, Singapore, Singapore.
Commun Biol. 2023 Feb 3;6(1):145. doi: 10.1038/s42003-023-04528-4.
Cancer cells experience confinement as they navigate the tumour microenvironment during metastasis. Recent studies have revealed that the nucleus can function as a 'ruler' for measuring physical confinement via membrane tension, allowing for compression-sensitive changes in migration. Cell nuclei contain many nuclear bodies that form when their components phase separate and condense within permissive local regions within the nucleus. However, how sub-nuclear organisation and phase separation changes with cell confinement and compression is largely unknown. Here we focus on paraspeckles, stress-responsive subnuclear bodies that form by phase separation around the long non-coding RNA NEAT1. As cells entered moderate confinement, a significant increase in paraspeckle number and size was observed compared to unconfined cells. Paraspeckle polarization bias towards the leading edge was also observed in confinement, correlating with regions of euchromatin. Increasing paraspeckle abundance resulted in increases in confined migration likelihood, speed, and directionality, as well as an enhancement of paraspeckle polarization towards the leading edge. This polarization of paraspeckle condensates may play a key role in regulating confined migration and invasion in cancer cells, and illustrates the utility of microchannel-based assays for identifying phenomena not observed on 2D or 3D bulk substrates.
癌细胞在转移过程中穿越肿瘤微环境时会受到限制。最近的研究表明，细胞核可以作为一种“尺子”，通过膜张力来测量物理限制，从而允许在迁移过程中发生压缩敏感的变化。细胞核包含许多核体，当它们的成分相分离并在细胞核内允许的局部区域内浓缩时，就会形成核体。然而，细胞核内的亚核组织和相分离如何随细胞限制和压缩而变化，在很大程度上尚不清楚。在这里，我们关注的是副核仁，这是一种应激响应的亚核体，由长链非编码 RNA NEAT1 周围的相分离形成。当细胞进入适度限制时，与未受限制的细胞相比，副核仁的数量和大小显著增加。在限制条件下，还观察到副核仁向前沿的极化偏向，这与常染色质区域相关。增加副核仁的丰度会导致受限迁移的可能性、速度和方向性增加，以及副核仁向前沿的极化增强。这种副核仁凝聚物的极化可能在调节癌细胞的受限迁移和侵袭中发挥关键作用，并说明了基于微通道的测定法在识别 2D 或 3D 基质上未观察到的现象方面的效用。
