Department of Urology, Veterans Affairs Medical Center San Francisco and University of California San Francisco, San Francisco, California.
Clin Cancer Res. 2019 Nov 1;25(21):6532-6545. doi: 10.1158/1078-0432.CCR-19-0498. Epub 2019 Aug 1.
Neuroendocrine prostate cancer (NEPC), an aggressive variant of castration-resistant prostate cancer (CRPC), often emerges after androgen receptor-targeted therapies such as enzalutamide or , via trans-differentiation process of neuroendocrine differentiation. The mechanistic basis of neuroendocrine differentiation is poorly understood, contributing to lack of effective predictive biomarkers and late disease recognition. The purpose of this study was to examine the role of novel proneural it-ct-nc-domain transcription factors (TF) in NEPC and examine their potential as noninvasive predictive biomarkers. Prostate cancer patient-derived xenograft models, clinical samples, and cellular neuroendocrine differentiation models were employed to determine the expression of TFs and . levels were modulated in prostate cancer cell lines followed by functional assays. Furthermore, extracellular vesicles (EV) were isolated from patient samples and cell culture models, characterized by nanoparticle tracking analyses, Western blotting, and real-time PCR.
We identify for the first time that: (i) is amplified and overexpressed in NEPC clinical samples and that overexpression drives neuroendocrine differentiation via its interplay with , a TF that was previously implicated in NEPC; (ii) and mRNA are actively released in prostate cancer EVs upon neuroendocrine differentiation induction; and (iii) enzalutamide treatment augments release of and in prostate cancer EVs, promoting neuroendocrine differentiation induction.
Our study identifies a novel TF that drives NEPC and suggests that as adaptive mechanism to enzalutamide treatment, prostate cancer cells express and secrete and in EVs that drive oncogenic reprogramming of prostate cancer cells to NEPC. Importantly, EV-associated and are potential novel noninvasive biomarkers to predict neuroendocrine differentiation in CRPC.
神经内分泌前列腺癌（NEPC）是一种侵袭性的去势抵抗性前列腺癌（CRPC）变体，通常在雄激素受体靶向治疗（如恩扎鲁胺）后出现，通过神经内分泌分化的转化过程。神经内分泌分化的机制基础理解甚少，导致缺乏有效的预测生物标志物和晚期疾病识别。本研究的目的是研究新型原神经 it-ct-nc 结构域转录因子（TF）在 NEPC 中的作用，并研究其作为非侵入性预测生物标志物的潜力。使用前列腺癌患者来源的异种移植模型、临床样本和细胞神经内分泌分化模型来确定 TF 的表达。和。在前列腺癌细胞系中调节水平后进行功能测定。此外，从患者样本和细胞培养模型中分离出细胞外囊泡（EV），通过纳米颗粒跟踪分析、Western blot 和实时 PCR 进行表征。
我们首次发现：（i）在 NEPC 临床样本中扩增和过表达，并且过表达通过其与先前涉及 NEPC 的 TF 的相互作用驱动神经内分泌分化；（ii）在神经内分泌分化诱导时，和 mRNA 被积极释放到前列腺癌细胞 EV 中；（iii）恩扎鲁胺治疗增强前列腺癌细胞 EV 中释放和，促进神经内分泌分化诱导。
我们的研究确定了一种新型 TF，该 TF 驱动 NEPC，并表明作为对恩扎鲁胺治疗的适应机制，前列腺癌细胞在 EV 中表达和分泌和，从而推动前列腺癌细胞向 NEPC 的致癌重编程。重要的是，EV 相关和可能是预测 CRPC 神经内分泌分化的潜在新型非侵入性生物标志物。
