染色体不稳定性(CIN)驱动癌细胞进化、转移和治疗耐药性，并与不良预后相关1。CIN导致微核，破裂后将DNA释放到细胞质中，从而触发cGAS和STING介导的炎症信号的激活。这两种蛋白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在癌症中很少失活，虽然它们与转移有关，但尚不清楚为什么在原发肿瘤中没有出现功能丧失突变。

cGAS STING信号的失活选择性地损害了显示CIN的三阴性乳腺癌细胞的生存。CIN触发IL-6 stat3介导的信号通路，依赖于cGAS STING通路和非典型NF-κB通路。通过tocilizumab阻断IL-6信号，一种临床使用的药物，靶向IL-6受体(IL-6R)，有选择性地损害培养的三阴性乳腺癌细胞的生长，显示CIN。此外，与不显示CIN的肿瘤相比，染色体不稳定肿瘤的生长明显延迟。

研究证明cGAS STING信号通路的致瘤特性，并解释cGAS STING通路在原发肿瘤中很少失活的原因。重新使用托珠单抗可能是治疗CIN过表达IL-6R的癌症的一种策略。

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.

原文链接

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

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