本期文章：《自然》：Online/在线发表

美国纪念斯隆凯特琳癌症中心Samuel F. Bakhoum等研究人员合作揭示染色体不稳定导致的非细胞自主性癌症进展。2023年8月23日，国际知名学术期刊《自然》在线发表了这一成果。

利用ContactTracing——一种新开发、经过验证和基准测试的工具，研究人员从单细胞转录组数据中推断出了细胞-细胞相互作用的性质和条件依赖性，结果表明染色体不稳定性（CIN）诱导的cGAS-STING通路慢性激活促进了癌细胞下游信号的重连，从而导致了有利于转移的肿瘤微环境。这种重连表现为STING下游选择性的I型干扰素速效性，以及癌细胞衍生的内质网（ER）应激反应的相应增加。逆转CIN、耗尽癌细胞STING或抑制ER应激反应信号可消除CIN对肿瘤微环境的依赖性影响，并抑制免疫功能正常但免疫功能严重受损情况下的肿瘤转移。

使用STING抑制剂可减少黑色素瘤、乳腺癌和结直肠癌中CIN驱动的转移，其方式依赖于肿瘤细胞内STING。最后，研究人员证明了微核中的CIN和普遍的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，进而突出了一种可行的策略，可用于识别和治疗由CIN诱导的炎症刺激型肿瘤。

据介绍，CIN是癌症转移的驱动因素，但这种效应在多大程度上依赖于免疫系统仍是未知数。

附：英文原文

Title: Non-cell-autonomous cancer progression from chromosomal instability

Author: 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.

Issue&Volume: 2023-08-23

Abstract: Chromosomal instability (CIN) is a driver of cancer metastasis1,2,3,4, 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.

DOI: 10.1038/s41586-023-06464-z