Non-cell-autonomous cancer progression from chromosomal instability.
Non-cell-autonomous cancer progression from chromosomal instability.
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DOI：
10.1038/s41586-023-06464-z
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发表时间：
2023-08
期刊：
影响因子：
64.8
通讯作者：
Bakhoum, Samuel F
中科院分区：
文献类型：
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作者：
Li, Jun;Hubisz, Melissa J;Earlie, Ethan M;Duran, Mercedes A;Hong, Christy;Varela, Austin A;Lettera, Emanuele;Deyell, Matthew;Tavora, Bernardo;Havel, Jonathan J;Phyu, Su M;Amin, Amit Dipak;Budre, Karolina;Kamiya, Erina;Cavallo, Julie-Ann;Garris, Christopher;Powell, Simon;Reis-Filho, Jorge S;Wen, Hannah;Bettigole, Sarah;Khan, Atif J;Izar, Benjamin;Parkes, Eileen E;Laughney, Ashley M;Bakhoum, Samuel F
染色体不稳定(CIN)是癌症转移的驱动因素，但这种影响在多大程度上依赖于免疫系统仍不清楚。使用ContactTracing-一种新开发、验证和基准的工具，从单细胞转录数据推断细胞-细胞相互作用的性质和条件依赖性-我们表明，CIN诱导的cGAS-STING途径的慢性激活促进了癌细胞中下游信号的重新连接，导致了有利于转移的肿瘤微环境。这种重新连接表现为I型干扰素选择性地在STING下游发生快速反应，并在应激反应中癌细胞衍生的内质网(ER)相应增加。CIN的逆转、癌细胞刺痛的耗竭或ER应激反应信号的抑制取消了CIN对肿瘤微环境的依赖作用，并抑制了免疫活性环境中的转移，但不是严重的免疫损害。使用刺痛抑制剂治疗黑色素瘤、乳腺癌和结直肠癌可减少CIN驱动的转移，其方式依赖于肿瘤细胞固有的刺痛。最后，我们发现CIN和微核中普遍存在的cGAS激活与ER应激信号、免疫抑制和人类三阴性乳腺癌的转移有关，强调了一种可行的策略来识别和治疗干预由CIN诱导的炎症刺激的肿瘤。肿瘤的染色体不稳定与内质网应激信号、免疫抑制和转移有关，cGAS-STING通路是通过抑制cGAS-STING通路减少转移的。
Chromosomal instability (CIN) is a driver of cancer metastasis, yet the extent to which this effect depends on the immune system remains unknown. Using ContactTracing—a newly developed, validated and benchmarked tool to infer the nature and conditional dependence of cell–cell interactions from single-cell transcriptomic data—we show that CIN-induced chronic activation of the cGAS–STING pathway promotes downstream signal re-wiring in cancer cells, leading to a pro-metastatic tumour microenvironment. This re-wiring is manifested by type I interferon tachyphylaxis selectively downstream of STING and a corresponding increase in cancer cell-derived endoplasmic reticulum (ER) stress response. Reversal of CIN, depletion of cancer cell STING or inhibition of ER stress response signalling abrogates CIN-dependent effects on the tumour microenvironment and suppresses metastasis in immune competent, but not severely immune compromised, settings. Treatment with STING inhibitors reduces CIN-driven metastasis in melanoma, breast and colorectal cancers in a manner dependent on tumour cell-intrinsic STING. Finally, we show that CIN and pervasive cGAS activation in micronuclei are associated with ER stress signalling, immune suppression and metastasis in human triple-negative breast cancer, highlighting a viable strategy to identify and therapeutically intervene in tumours spurred by CIN-induced inflammation. Chromosomal instability in cancer is linked to endoplasmic reticulum stress signalling, immune suppression and metastasis, which is mediated by the cGAS–STING pathway, suppression of which can reduce metastasis.