Type I IFNs promote cancer cell stemness by triggering the epigenetic regulator KDM1B

Autor: Martina Musella, Andrea Guarracino, Nicoletta Manduca, Claudia Galassi, Eliana Ruggiero, Alessia Potenza, Ester Maccafeo, Gwenola Manic, Luca Mattiello, Sara Soliman Abdel Rehim, Michele Signore, Marco Pietrosanto, Manuela Helmer-Citterich, Matteo Pallocca, Maurizio Fanciulli, Tiziana Bruno, Francesca De Nicola, Giacomo Corleone, Anna Di Benedetto, Cristiana Ercolani, Edoardo Pescarmona, Laura Pizzuti, Francesco Guidi, Francesca Sperati, Sara Vitale, Daniele Macchia, Massimo Spada, Giovanna Schiavoni, Fabrizio Mattei, Adele De Ninno, Luca Businaro, Valeria Lucarini, Laura Bracci, Eleonora Aricò, Giovanna Ziccheddu, Francesco Facchiano, Stefania Rossi, Massimo Sanchez, Alessandra Boe, Mauro Biffoni, Ruggero De Maria, Ilio Vitale, Antonella Sistigu
Rok vydání: 2022
Předmět:
Zdroj: Nature Immunology. 23:1379-1392
ISSN: 1529-2916
1529-2908
DOI: 10.1038/s41590-022-01290-3
Popis: 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.
Databáze: OpenAIRE
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