An oncogenic isoform of septin 9 promotes the formation of juxtanuclear invadopodia by reducing nuclear deformability.
An oncogenic isoform of septin 9 promotes the formation of juxtanuclear invadopodia by reducing nuclear deformability.
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DOI：
10.1016/j.celrep.2023.112893
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发表时间：
2023-08-29
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影响因子：
8.8
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中科院分区：
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--
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侵殖体是细胞外基质（ECM）降解结构，促进癌细胞侵袭。细胞核越来越被视为决定迁移策略的机械感觉细胞器。然而，细胞核是如何与内过足交叉的却鲜为人知。在这里，我们报道了致癌的septin 9亚型1 （SEPT9_i1）是乳腺癌浸润性的一个组成部分。SEPT9_i1的缺失减少了invadopodium的形成和invadopodium前体成分TKS5的聚集和接触。这种表型的特征是细胞核变形，核膜有褶皱和凹槽。我们发现sept9_11定位于核膜和近核内过足。此外，外源性层粘连蛋白A可以挽救核形态和核旁TKS5簇。重要的是，表皮生长因子诱导的近核侵过体扩增需要sept9_11。我们假设低变形能力的细胞核以sept9_11依赖的方式有利于近核侵过体的形成，这是克服ECM不可穿透性的可调节机制。侵过性促进转移性癌症的侵袭。细胞核是决定迁移策略的机械感觉细胞器，但它如何与入侵虫相互影响尚不清楚。Okletey等人的研究表明，致癌异构体SEPT9_i1促进了核膜稳定性和质膜近核区侵入性足的形成。
Invadopodia are extracellular matrix (ECM) degrading structures, which promote cancer cell invasion. The nucleus is increasingly viewed as a mechanosensory organelle that determines migratory strategies. However, how the nucleus crosstalks with invadopodia is little known. Here, we report that the oncogenic septin 9 isoform 1 (SEPT9_i1) is a component of breast cancer invadopodia. SEPT9_i1 depletion diminishes invadopodium formation and the clustering of the invadopodium precursor components TKS5 and cortactin. This phenotype is characterized by deformed nuclei and nuclear envelopes with folds and grooves. We show that SEPT9_i1 localizes to the nuclear envelope and juxtanuclear invadopodia. Moreover, exogenous lamin A rescues nuclear morphology and juxtanuclear TKS5 clusters. Importantly, SEPT9_i1 is required for the amplification of juxtanuclear invadopodia, which is induced by the epidermal growth factor. We posit that nuclei of low deformability favor the formation of juxtanuclear invadopodia in a SEPT9_i1-dependent manner, which functions as a tunable mechanism for overcoming ECM impenetrability. Invadopodia promote the invasion of metastatic cancers. The nucleus is a mechanosensory organelle that determines migratory strategies, but how it crosstalks with invadopodia is unknown. Okletey et al. show that the oncogenic isoform SEPT9_i1 promotes nuclear envelope stability and the formation of invadopodia at juxtanuclear areas of the plasma membrane.
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