Characterization of a drug-resilient cancer cell phenotype [ATAC-Seq]

Resistance to treatment and post-therapy recurrence due to small populations of resistant cells remain core challenges in cancer therapy. The mechanisms underlying therapy resistance are undefined for many patients. Here, we demonstrate that some cancer cells survive therapeutic stress via a transient state of whole genome doubling. At the onset of the polyploidization program, we identified upregulation of key transcriptional regulators, including the early stress-response protein AP-1 and normoxic stabilization of HIF-2a. Moreover, chromatin accessibility is altered and expression of pRB is ablated, and we identified enrichment of AP-1 motif accessibility along with an upregulation of replication-dependent histone variants. Here we demonstrate that AP-1and HIF-2a regulate a therapy resilient and survivor phenotype in cancer cells. Consistent with this, genetic or pharmacologic targeting of AP-1 and HIF-2a reduced the frequency of surviving cells following treatment with chemotherapy. These results suggest a novel avenue for tackling chemotherapy-induced resistance in cancer. Overall design: To establish a drug resistant populatio we treated cells wit LD50 cisplatin for 72h

癌症治疗中，因少量耐药细胞群体导致的治疗耐药及治疗后复发，仍是该领域的核心挑战。目前多数患者的治疗耐药相关机制仍未阐明。本研究证实，部分癌细胞可通过全基因组倍增的瞬时状态，在治疗应激中存活下来。在多倍体化程序启动阶段，我们发现关键转录调控因子的表达上调，包括早期应激反应蛋白激活蛋白1（AP-1），以及常氧条件下缺氧诱导因子2α（HIF-2α）的稳定性提升。此外，染色质可及性发生改变，视网膜母细胞瘤蛋白（pRB）的表达被沉默，同时我们发现AP-1基序的可及性富集，以及复制依赖性组蛋白变体的表达上调。本研究证实，AP-1与HIF-2α可调控癌细胞的治疗抵抗存活表型。与此一致的是，对AP-1与HIF-2α进行遗传学或药理学靶向干预，可降低化疗处理后存活癌细胞的比例。上述研究结果为解决癌症化疗诱导的耐药问题提供了全新的干预方向。实验整体设计：为构建耐药细胞群体，我们用半数致死剂量（LD50）的顺铂处理细胞72小时。