School of Pharmacy, University of East Anglia, Norwich, UK.
School of Biological Sciences, University of East Anglia, Norwich, UK.
Life Sci Alliance. 2023 Aug 7;6(10). doi: 10.26508/lsa.202301953. Print 2023 Oct.
Tunneling nanotubes (TNTs) are thin cytoplasmic extensions involved in long-distance intercellular communication and can transport intracellular organelles and signalling molecules. In cancer cells, TNT formation contributes to cell survival, chemoresistance, and malignancy. However, the molecular mechanisms underlying TNT formation are not well defined, especially in different cancers. TNTs are present in non-small cell lung cancer (NSCLC) patients with adenocarcinoma. In NSCLC, hepatocyte growth factor (HGF) and its receptor, c-Met, are mutationally upregulated, causing increased cancer cell growth, survival, and invasion. This study identifies c-Met, β1-integrin, and paxillin as novel components of TNTs in A549 lung adenocarcinoma cells, with paxillin localised at the protrusion site of TNTs. The HGF-induced TNTs in our study demonstrate the ability to transport lipid vesicles and mitochondria. HGF-induced TNT formation is mediated by c-Met and β1-integrin in conjunction with paxillin, followed by downstream activation of MAPK and PI3K pathways and the Arp2/3 complex. These findings demonstrate a potential novel approach to inhibit TNT formation through targeting HGF/c-Met receptor and β1-integrin signalling interactions, which has implications for multi-drug targeting in NSCLC.
隧道纳米管 (TNTs) 是参与长距离细胞间通讯的细细胞质延伸物，可以运输细胞内细胞器和信号分子。在癌细胞中，TNT 的形成有助于细胞存活、化疗耐药性和恶性转化。然而，TNT 形成的分子机制尚未明确，特别是在不同的癌症中。TNTs 存在于患有腺癌的非小细胞肺癌 (NSCLC) 患者中。在 NSCLC 中，肝细胞生长因子 (HGF) 及其受体 c-Met 发生突变性上调，导致癌细胞生长、存活和侵袭增加。本研究鉴定出 c-Met、β1-整合素和桩蛋白是 A549 肺腺癌细胞 TNTs 的新成分，其中桩蛋白定位于 TNTs 的突起部位。本研究中的 HGF 诱导的 TNTs 表现出运输脂质体和线粒体的能力。HGF 诱导的 TNT 形成是通过 c-Met 和 β1-整合素与桩蛋白共同介导的，随后下游激活 MAPK 和 PI3K 途径以及 Arp2/3 复合物。这些发现表明，通过靶向 HGF/c-Met 受体和 β1-整合素信号相互作用来抑制 TNT 形成是一种潜在的新方法，这对 NSCLC 的多药物靶向治疗具有重要意义。
