小柯机器人

荷兰格罗宁根大学医学中心Floris Foijer、Marcel A. T. M. van Vugt和Marco de Bruyn研究团队合作取得进展。他们发现cGAS-STING通路调控了IL-6依赖性染色体不稳定性(CIN)癌症的存活。该研究于2022年6月15日发表于国际学术期刊《自然》杂志。

研究人员发现cGAS-STING信号丢失选择性地损害了由CIN诱导三阴性乳腺癌细胞的存活。CIN诱导IL-6-STAT3介导的信号传导，这取决于cGAS-STING通路和非经典NF-κB通路。托珠单抗是一种临床使用的靶向IL-6受体(IL-6R)的药物，通过阻断IL-6信号传导，选择性地破坏了CIN诱导三阴性乳腺癌细胞的生长。

此外，与不具有CIN的肿瘤相比，染色体不稳定肿瘤的生长明显延迟。值得注意的是，这种可靶向位点在体外和体内高表达IL-6和/或IL-6R的癌症类型中是保守的。总之，该研究工作证明了cGAS-STING信号传导促肿瘤发生的特征，并解释了为什么cGAS-STING通路在原发性肿瘤中很少失活。重新利用托珠单抗可能是治疗过表达IL-6R CIN癌症的一种策略。

据悉，CIN诱导癌细胞进化、转移和产生治疗抗性，并与预后不良有关。CIN导致微核破裂后DNA释放到细胞质，从而激活由cGAS和STING介导的炎症信号通路。这两种蛋白质被认为是肿瘤抑制因子，因为它们促进细胞凋亡和免疫监视。然而，cGAS和STING在癌症细胞中具有活性，尽管它们与转移有关，但尚不清楚为什么原发性肿瘤中不会出现功能丧失突变。

附：英文原文

Title: cGAS–STING drives the IL-6-dependent survival of chromosomally instable cancers

Author: Hong, Christy, Schubert, Michael, Tijhuis, Andra E., Requesens, Marta, Roorda, Maurits, van den Brink, Anouk, Ruiz, Lorena Andrade, Bakker, Petra L., van der Sluis, Tineke, Pieters, Wietske, Chen, Mengting, Wardenaar, Ren, van der Vegt, Bert, Spierings, Diana C. J., de Bruyn, Marco, van Vugt, Marcel A. T. M., Foijer, Floris

Issue&Volume: 2022-06-15

Abstract: Chromosomal instability (CIN) drives cancer cell evolution, metastasis and therapy resistance, and is associated with poor prognosis1. CIN leads to micronuclei that release DNA into the cytoplasm after rupture, which triggers activation of inflammatory signalling mediated by cGAS and STING2,3. These two proteins are considered to be tumour suppressors as they promote apoptosis and immunosurveillance. However, cGAS and STING are rarely inactivated in cancer4, and, although they have been implicated in metastasis5, it is not known why loss-of-function mutations do not arise in primary tumours4. Here we show that inactivation of cGAS–STING signalling selectively impairs the survival of triple-negative breast cancer cells that display CIN. CIN triggers IL-6–STAT3-mediated signalling, which depends on the cGAS–STING pathway and the non-canonical NF-κB pathway. Blockade of IL-6 signalling by tocilizumab, a clinically used drug that targets the IL-6 receptor (IL-6R), selectively impairs the growth of cultured triple-negative breast cancer cells that exhibit CIN. Moreover, outgrowth of chromosomally instable tumours is significantly delayed compared with tumours that do not display CIN. Notably, this targetable vulnerability is conserved across cancer types that express high levels of IL-6 and/or IL-6R in vitro and in vivo. Together, our work demonstrates pro-tumorigenic traits of cGAS–STING signalling and explains why the cGAS–STING pathway is rarely inactivated in primary tumours. Repurposing tocilizumab could be a strategy to treat cancers with CIN that overexpress IL-6R.

DOI: 10.1038/s41586-022-04847-2

Source: https://www.nature.com/articles/s41586-022-04847-2

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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