GSE173851
Type I IFNs promote cancer cell stemness by triggering the epigenetic regulator KDM1B
Cancer stem cells (CSCs) are immature, immortal cells within tumors, adept at resisting therapeutic pressure and responsible for local and distant disease recurrence. Non-genetic mechanisms of acquired resistance are increasingly being described, however molecular insights into this evolutionary process still lack. Here, we showed that Type I interferons (IFNs-I) act as molecular hubs of resistance during immunogenic chemotherapy, as they trigger the epigenetic regulator KDM1B, responsible for an adaptive, yet reversible, transcriptional rewiring of cancer cells towards stemness and immune escape. Accordingly, KDM1B pharmacological inhibition antagonizes the appearance of IFN-I-adapted CSCs, both in vitro and in vivo. Notably, IFN-I-adapted CSCs are heterogeneous in terms of multidrug resistance, plasticity, invasiveness and immunogenicity. Moreover, in breast cancer patients receiving anthracycline-based chemotherapy, IFN-I and KDM1B signatures positively correlate with CSC and immune evasion markers. Our study identifies IFN-I?KDM1B axis as a potent engine of cancer cell reprogramming and recommends KDM1B targeting an attractive adjunctive to immunogenic drugs to prevent CSC expansion and increase the long-term benefit of therapy. Overall design: ATAC-seq: 3 samples (CD44LOW, CD44HIGH and their PARENTAL) with 2 replicates for each sample; 2 samples (MCA Kdm1bOVER and MCA Kdm1bKD) with 1 replicate for each sample; RNA-seq: 3 samples (CD44LOW, CD44HIGH and their PARENTAL), with 2 replicates for each sample. CHIP-seq: 1 sample (CD44HIGH), with 2 replicates.