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.
Cell death and differentiation. 2024 Apr 23 [Epub ahead of print]
Deng Wang, Genyu Du, Xinyu Chen, Jinming Wang, Kaiyuan Liu, Huifang Zhao, Chaping Cheng, Yuman He, Na Jing, Penghui Xu, Wei Bao, Xialian Xi, Yingchao Zhang, Nan Wang, Yiyun Liu, Yujiao Sun, Kai Zhang, Pengcheng Zhang, Wei-Qiang Gao, Helen He Zhu
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, Shanghai Tech University, Shanghai, 201210, China., 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. ., 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. .