State Key Laboratory of Systems Medicine for Cancer, Renji-Med-X Stem Cell Research Center & Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine and School of Biomedical Engineering, Shanghai, 200127, China.
School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, China.
Cell Death Differ. 2024 Jun;31(6):779-791. doi: 10.1038/s41418-024-01295-5. Epub 2024 Apr 23.
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.
细胞可塑性被发现在肿瘤进展和治疗耐药中起着关键作用。然而，我们对于癌症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中间状态，其特征是 Zeb1 表达，并具有上皮-间充质转化（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 的可能起源细胞。在机制上，Zeb1 转录调控几个关键糖酵解酶的表达，从而使肿瘤细胞易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糖化增强了染色质可及性和细胞可塑性，包括诱导神经基因表达，从而促进 NEPC 的发展。总的来说，Zeb1 驱动的代谢重编程使前列腺癌细胞的表观遗传重新编程能够获得腺-神经内分泌谱系转变的许可。
