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.

癌症干细胞（Cancer stem cells, CSCs）是肿瘤内部未成熟且具备无限增殖能力的细胞，可耐受治疗压力，并介导局部及远处的肿瘤复发。尽管非遗传性获得耐药机制的相关研究报道日益增多，但针对该进化过程的分子层面认知仍存在显著缺口。本研究证实，I型干扰素（Type I interferons, IFNs-I）在免疫原性化疗过程中作为耐药性的分子枢纽发挥作用：其可激活表观遗传调控因子KDM1B，介导癌细胞发生适应性且可逆的转录重编程，促使细胞向干细胞样表型转化并获得免疫逃逸能力。相应地，无论体外还是体内实验中，对KDM1B进行药物抑制均可拮抗I型干扰素适配型癌症干细胞的产生。值得注意的是，此类I型干扰素适配型癌症干细胞在多药耐药性、细胞可塑性、侵袭性及免疫原性方面均存在异质性。此外，在接受蒽环类药物化疗的乳腺癌患者中，I型干扰素与KDM1B的基因特征与癌症干细胞及免疫逃逸相关标志物呈正相关。本研究明确了I型干扰素-KDM1B轴是癌细胞重编程的关键驱动引擎，并提出将靶向KDM1B作为免疫原性药物的极具潜力的辅助治疗策略，以阻止癌症干细胞扩增并提升治疗的长期获益。
实验整体设计：
ATAC测序（ATAC-seq）：共3组样本（CD44LOW、CD44HIGH及其PARENTAL），每组设置2次生物学重复；另有2组样本（MCA Kdm1bOVER与MCA Kdm1bKD），每组设置1次生物学重复；
RNA测序（RNA-seq）：共3组样本（CD44LOW、CD44HIGH及其PARENTAL），每组设置2次生物学重复；
染色质免疫沉淀测序（CHIP-seq）：共1组样本（CD44HIGH），设置2次生物学重复。