Cell Polarity, Migration and Cancer Unit, Institut Pasteur, CNRS UMR3691, Université Paris Cité, Équipe Labellisée Ligue Contre le Cancer, F-75015, Paris, France.
Collège doctoral, Sorbonne Université, F-75005, Paris, France.
Nat Commun. 2022 Aug 11;13(1):4528. doi: 10.1038/s41467-022-31842-y.
Pten is one of the most frequently mutated tumour suppressor gene in cancer. PTEN is generally altered in invasive cancers such as glioblastomas, but its function in collective cell migration and invasion is not fully characterised. Herein, we report that the loss of PTEN increases cell speed during collective migration of non-tumourous cells both in vitro and in vivo. We further show that loss of PTEN promotes LKB1-dependent phosphorylation and activation of the major metabolic regulator AMPK. In turn AMPK increases VASP phosphorylation, reduces VASP localisation at cell-cell junctions and decreases the interjunctional transverse actin arcs at the leading front, provoking a weakening of cell-cell contacts and increasing migration speed. Targeting AMPK activity not only slows down PTEN-depleted cells, it also limits PTEN-null glioblastoma cell invasion, opening new opportunities to treat glioblastoma lethal invasiveness.
PTEN 是癌症中最常发生突变的肿瘤抑制基因之一。PTEN 通常在浸润性癌症如神经胶质瘤中发生改变，但它在细胞集体迁移和侵袭中的功能尚未完全阐明。在此，我们报告在体外和体内非肿瘤细胞的集体迁移中，PTEN 的缺失会增加细胞的迁移速度。我们进一步表明，PTEN 的缺失会促进 LKB1 依赖性磷酸化和主要代谢调节剂 AMPK 的激活。反过来，AMPK 增加 VASP 的磷酸化，减少 VASP 在细胞-细胞连接处的定位，并减少前导前沿处细胞-细胞连接处的横向肌动蛋白弧，导致细胞-细胞连接变弱，迁移速度加快。靶向 AMPK 活性不仅可以减缓 PTEN 缺失细胞的迁移速度，还可以限制 PTEN 缺失的神经胶质瘤细胞的侵袭，为治疗神经胶质瘤的致命侵袭性提供了新的机会。
