Ketchen Sophie E, Gamboa-Esteves Filomena O, Lawler Sean E, Nowicki Michal O, Rohwedder Arndt, Knipp Sabine, Prior Sally, Short Susan C, Ladbury John E, Brüning-Richardson Anke
Light Laboratories, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.
Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds LS9 7TF, UK.
Biomedicines. 2021 Dec 22;10(1):9. doi: 10.3390/biomedicines10010009.
Cancer cell invasion is a precondition for tumour metastasis and represents one of the most devastating characteristics of cancer. The development of drugs targeting cell migration, known as migrastatics, may improve the treatment of highly invasive tumours such as glioblastoma (GBM). In this study, investigations into the role of the cell adhesion protein Cellular communication network factor 1 (CCN1, also known as CYR61) in GBM cell migration uncovered a drug resistance mechanism adopted by cells when treated with the small molecule inhibitor CCG-1423. This inhibitor binds to importin α/β inhibiting the nuclear translocation of the transcriptional co-activator MKL1, thus preventing downstream effects including migration. Despite this reported role as an inhibitor of cell migration, we found that CCG-1423 treatment did not inhibit GBM cell migration. However, we could observe cells now migrating by mesenchymal-amoeboid transition (MAT). Furthermore, we present evidence that CCN1 plays a critical role in the progression of GBM with increased expression in higher-grade tumours and matched blood samples. These findings support a potential role for CCN1 as a biomarker for the monitoring and potentially early prediction of GBM recurrence, therefore as such could help to improve treatment of and increase survival rates of this devastating disease.
癌细胞侵袭是肿瘤转移的前提条件，也是癌症最具破坏性的特征之一。开发针对细胞迁移的药物（即迁移抑制剂）可能会改善对高度侵袭性肿瘤（如胶质母细胞瘤，GBM）的治疗。在本研究中，对细胞粘附蛋白细胞通讯网络因子1（CCN1，也称为CYR61）在GBM细胞迁移中的作用进行研究时，发现了细胞在用小分子抑制剂CCG - 1423处理时所采用的一种耐药机制。这种抑制剂与输入蛋白α/β结合，抑制转录共激活因子MKL1的核转位，从而防止包括迁移在内的下游效应。尽管有报道称其具有抑制细胞迁移的作用，但我们发现CCG - 1423处理并未抑制GBM细胞迁移。然而，我们观察到细胞现在通过间充质 - 阿米巴样转变（MAT）进行迁移。此外，我们提供的证据表明，CCN1在GBM进展中起关键作用，在高级别肿瘤和匹配的血液样本中表达增加。这些发现支持CCN1作为GBM复发监测和潜在早期预测生物标志物的潜在作用，因此有助于改善这种毁灭性疾病的治疗并提高生存率。
