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.

Musella, M., Guarracino, A., Manduca, N., Galassi, C., Ruggiero, E., Potenza, A., Maccafeo, E., Manic, G., Mattiello, L., Soliman Abdel Rehim, S., Signore, M., Pietrosanto, M., Helmer-Citterich, M., Pallocca, M., Fanciulli, M., Bruno, T., De Nicola, F., Corleone, G., Di Benedetto, A., Ercolani, C., Pescarmona, E., Pizzuti, L., Guidi, F., Sperati, F., Vitale, S., Macchia, D., Spada, M., Schiavoni, G., Mattei, F., De Ninno, A., Businaro, L., Lucarini, V., Bracci, L., Aricò, E., Ziccheddu, G., Facchiano, F., Rossi, S., Sanchez, M., Boe, A., Biffoni, M., De Maria Marchiano, R., Vitale, I., Sistigu, A., Type I IFNs promote cancer cell stemness by triggering the epigenetic regulator KDM1B, <<NATURE IMMUNOLOGY>>, 2022; 23 (9): 1379-1392. [doi:10.1038/s41590-022-01290-3] [https://hdl.handle.net/10807/231537]

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

Musella, Martina;Manduca, Nicoletta;Maccafeo, Ester;Guidi, Francesco;Vitale, Sara;De Maria Marchiano, Ruggero
;
Sistigu, Antonella
2022

Abstract

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.
2022
Inglese
Musella, M., Guarracino, A., Manduca, N., Galassi, C., Ruggiero, E., Potenza, A., Maccafeo, E., Manic, G., Mattiello, L., Soliman Abdel Rehim, S., Signore, M., Pietrosanto, M., Helmer-Citterich, M., Pallocca, M., Fanciulli, M., Bruno, T., De Nicola, F., Corleone, G., Di Benedetto, A., Ercolani, C., Pescarmona, E., Pizzuti, L., Guidi, F., Sperati, F., Vitale, S., Macchia, D., Spada, M., Schiavoni, G., Mattei, F., De Ninno, A., Businaro, L., Lucarini, V., Bracci, L., Aricò, E., Ziccheddu, G., Facchiano, F., Rossi, S., Sanchez, M., Boe, A., Biffoni, M., De Maria Marchiano, R., Vitale, I., Sistigu, A., Type I IFNs promote cancer cell stemness by triggering the epigenetic regulator KDM1B, <<NATURE IMMUNOLOGY>>, 2022; 23 (9): 1379-1392. [doi:10.1038/s41590-022-01290-3] [https://hdl.handle.net/10807/231537]
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