Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 60 Murray Street, Toronto, ON, M5T 3L9, Canada.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
Sci Rep. 2021 Mar 23;11(1):6630. doi: 10.1038/s41598-021-85812-3.
Androgens are a major driver of prostate cancer (PCa) and continue to be a critical treatment target for advanced disease, which includes castration therapy and antiandrogens. However, resistance to these therapies leading to metastatic castration-resistant prostate cancer (mCRPC), and the emergence of treatment-induced neuroendocrine disease (tNEPC) remains an ongoing challenge. Instability of the DNA methylome is well established as a major hallmark of PCa development and progression. Therefore, investigating the dynamics of the methylation changes going from the castration sensitive to the tNEPC state would provide insights into novel mechanisms of resistance. Using an established xenograft model of CRPC, genome-wide methylation analysis was performed on cell lines representing various stages of PCa progression. We confirmed extensive methylation changes with the development of CRPC and tNEPC using this model. This included key genes and pathways associated with cellular differentiation and neurodevelopment. Combined analysis of methylation and gene expression changes further highlighted genes that could potentially serve as therapeutic targets. Furthermore, tNEPC-related methylation signals from this model were detectable in circulating cell free DNA (cfDNA) from mCRPC patients undergoing androgen-targeting therapies and were associated with a faster time to clinical progression. These potential biomarkers could help with identifying patients with aggressive disease.
雄激素是前列腺癌（PCa）的主要驱动因素，仍然是晚期疾病的关键治疗靶点，包括去势治疗和抗雄激素治疗。然而，这些治疗方法的耐药性导致转移性去势抵抗性前列腺癌（mCRPC），以及治疗诱导的神经内分泌疾病（tNEPC）的出现仍然是一个持续的挑战。DNA 甲基化组的不稳定性已被确立为 PCa 发生和发展的主要标志之一。因此，研究从去势敏感到 tNEPC 状态的甲基化变化的动态将为耐药的新机制提供深入了解。使用已建立的 CRPC 异种移植模型，对代表 PCa 进展各个阶段的细胞系进行了全基因组甲基化分析。我们使用该模型证实了 CRPC 和 tNEPC 发展过程中的广泛甲基化变化，其中包括与细胞分化和神经发育相关的关键基因和途径。甲基化和基因表达变化的联合分析进一步突出了可能作为治疗靶点的基因。此外，来自该模型的 tNEPC 相关甲基化信号可在接受雄激素靶向治疗的 mCRPC 患者的循环无细胞 DNA（cfDNA）中检测到，并且与更快的临床进展时间相关。这些潜在的生物标志物可能有助于识别具有侵袭性疾病的患者。
