Cell plasticity has been found to play a critical role in tumor progression and therapy resistance. However, our understanding of the characteristics and markers of plastic cellular states during cancer cell lineage transition remains limited. In this study, multi-omics analyses show that prostate cancer cells undergo an intermediate state marked by Zeb1 expression with epithelial-mesenchymal transition (EMT), stemness, and neuroendocrine features during the development of neuroendocrine prostate cancer (NEPC). Organoid-formation assays and in vivo lineage tracing experiments demonstrate that Zeb1⁺ epithelioid cells are putative cells of origin for NEPC. Mechanistically, Zeb1 transcriptionally regulates the expression of several key glycolytic enzymes, thereby predisposing tumor cells to utilize glycolysis for energy metabolism. During this process, lactate accumulation-mediated histone lactylation enhances chromatin accessibility and cellular plasticity including induction of neuro-gene expression, which promotes NEPC development. Collectively, Zeb1-driven metabolic rewiring enables the epigenetic reprogramming of prostate cancer cells to license the adeno-to-neuroendocrine lineage transition.

人们发现细胞可塑性在肿瘤进展和治疗耐药性中发挥着关键作用。然而，我们对癌细胞谱系转变过程中可塑性细胞状态的特征和标志物的理解仍然有限。在这项研究中，多组学分析表明，前列腺癌细胞在神经内分泌前列腺癌（NEPC）的发展过程中经历了一个以 Zeb1 表达为标志的中间状态，具有上皮间质转化（EMT）、干性和神经内分泌特征。类器官形成测定和体内谱系追踪实验表明 Zeb1 ⁺上皮样细胞是 NEPC 的假定来源细胞。从机制上讲，Zeb1 转录调节几种关键糖酵解酶的表达，从而使肿瘤细胞倾向于利用糖酵解进行能量代谢。在此过程中，乳酸积累介导的组蛋白乳酰化增强了染色质的可及性和细胞可塑性，包括诱导神经基因表达，从而促进 NEPC 的发育。总的来说，Zeb1驱动的代谢重连使得前列腺癌细胞的表观遗传重编程能够实现腺到神经内分泌谱系的转变。