Type I IFNs promote cancer cell stemness by triggering the epigenetic regulator KDM1B.
Type I IFNs promote cancer cell stemness by triggering the epigenetic regulator KDM1B.
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DOI：
10.1038/s41590-022-01290-3
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发表时间：
2022-09
影响因子：
30.5
通讯作者：
Sistigu, Antonella
中科院分区：
文献类型：
--
作者：
Musella, Martina;Guarracino, Andrea;Manduca, Nicoletta;Galassi, Claudia;Ruggiero, Eliana;Potenza, Alessia;Maccafeo, Ester;Manic, Gwenola;Mattiello, Luca;Rehim, Sara Soliman Abdel;Signore, Michele;Pietrosanto, Marco;Helmer-Citterich, Manuela;Pallocca, Matteo;Fanciulli, Maurizio;Bruno, Tiziana;De Nicola, Francesca;Corleone, Giacomo;Di Benedetto, Anna;Ercolani, Cristiana;Pescarmona, Edoardo;Pizzuti, Laura;Guidi, Francesco;Sperati, Francesca;Vitale, Sara;Macchia, Daniele;Spada, Massimo;Schiavoni, Giovanna;Mattei, Fabrizio;De Ninno, Adele;Businaro, Luca;Lucarini, Valeria;Bracci, Laura;Arico, Eleonora;Ziccheddu, Giovanna;Facchiano, Francesco;Rossi, Stefania;Sanchez, Massimo;Boe, Alessandra;Biffoni, Mauro;De Maria, Ruggero;Vitale, Ilio;Sistigu, Antonella
癌症干细胞（CSC）是癌细胞的一个亚群，具有高致瘤性、耐药性和转移性。人们越来越多地发现获得性耐药的非遗传机制，但对 CSC 进化过程的分子洞察仍然有限。在这里，我们表明，I 型干扰素 (IFN-I) 在免疫原性化疗期间充当耐药分子中枢，触发表观遗传调节剂去甲基化酶 1B (KDM1B) 促进癌细胞适应性但可逆的转录重连，从而实现干细胞性和免疫逃逸。因此，KDM1B 抑制可防止 IFN-I 诱导的 CSC 出现，无论是在体外还是在体内。值得注意的是，IFN-I诱导的CSC在多药耐药性、可塑性、侵袭性和免疫原性方面具有异质性。此外，在接受蒽环类化疗的乳腺癌 (BC) 患者中，KDM1B 与 CSC 特征呈正相关。我们的研究确定 IFN-I → KDM1B 轴是癌细胞重编程的强大引擎，支持 KDM1B 靶向作为免疫原性药物的有吸引力的辅助剂，以防止 CSC 扩张并增加治疗的长期益处。 I 型干扰素已被描述为具有促肿瘤或抗肿瘤功能，具体取决于具体情况。在这里，作者展示了 I 型干扰素的促肿瘤功能，因为它们通过上调染色质重塑因子 KDM1B 来促进癌症干细胞。
Cancer stem cells (CSCs) are a subpopulation of cancer cells endowed with high tumorigenic, chemoresistant and metastatic potential. Nongenetic mechanisms of acquired resistance are increasingly being discovered, but molecular insights into the evolutionary process of CSCs are limited. Here, we show that type I interferons (IFNs-I) function as molecular hubs of resistance during immunogenic chemotherapy, triggering the epigenetic regulator demethylase 1B (KDM1B) to promote an adaptive, yet reversible, transcriptional rewiring of cancer cells towards stemness and immune escape. Accordingly, KDM1B inhibition prevents the appearance of IFN-I-induced CSCs, both in vitro and in vivo. Notably, IFN-I-induced CSCs are heterogeneous in terms of multidrug resistance, plasticity, invasiveness and immunogenicity. Moreover, in breast cancer (BC) patients receiving anthracycline-based chemotherapy, KDM1B positively correlated with CSC signatures. Our study identifies an IFN-I → KDM1B axis as a potent engine of cancer cell reprogramming, supporting KDM1B targeting as an attractive adjunctive to immunogenic drugs to prevent CSC expansion and increase the long-term benefit of therapy. Type I interferons have been described to have protumor or antitumor functions depending on context. Here the authors show a protumor function for type I interferons in that they promote cancer stem cells by upregulating the chromatin remodeling factor KDM1B.
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影响因子：
64.5
作者：
Acharyya S;Oskarsson T;Vanharanta S;Malladi S;Kim J;Morris PG;Manova-Todorova K;Leversha M;Hogg N;Seshan VE;Norton L;Brogi E;Massagué J
通讯作者：
Massagué J
影响因子：
10.1
作者：
Castiello, Luciano;Sestili, Paola;Arico, Eleonora
通讯作者：
Arico, Eleonora
DOI：
10.1073/pnas.1815345116
发表时间：
2019-01-02
影响因子：
11.1
作者：
Bocci, Federico;Gearhart-Serna, Larisa;Jolly, Mohit Kumar
通讯作者：
Jolly, Mohit Kumar
影响因子：
64.5
作者：
Hugo W;Zaretsky JM;Sun L;Song C;Moreno BH;Hu-Lieskovan S;Berent-Maoz B;Pang J;Chmielowski B;Cherry G;Seja E;Lomeli S;Kong X;Kelley MC;Sosman JA;Johnson DB;Ribas A;Lo RS
通讯作者：
Lo RS
影响因子：
15.9
作者：
Chen, Jianzhou;Cao, Yunhong;Muschel, Ruth J.
通讯作者：
Muschel, Ruth J.