Abstract：
With the widespread use of anti-androgen therapy, such as abiraterone and enzalutamide, the incidence of neuroendocrine prostate cancer (NEPC) is increasing. NEPC is a lethal form of prostate cancer (PCa), with a median overall survival of less than one year after diagnosis. In addition to the common bone metastases seen in PCa, NEPC exhibits characteristics of visceral metastases, notably liver metastasis, which serves as an indicator of a poor prognosis clinically. Key factors driving the neuroendocrine plasticity of PCa have been identified, yet the underlying mechanism behind liver metastasis remains unclear. In this study, we identified PROX1 as a driver of neuroendocrine plasticity in PCa, responsible for promoting liver metastases. Mechanistically, anti-androgen therapy alleviates transcriptional inhibition of PROX1. Subsequently, elevated PROX1 levels drive both neuroendocrine plasticity and liver-specific transcriptional reprogramming, promoting liver metastases. Moreover, liver metastases in PCa induced by PROX1 depend on reprogrammed lipid metabolism, a disruption that effectively reduces the formation of liver metastases.
摘要：
随着抗雄激素治疗的广泛使用,如阿比特龙和恩扎鲁他胺，神经内分泌前列腺癌（NEPC）的发病率正在增加。NEPC是一种致命形式的前列腺癌（PCa），诊断后中位总生存期不到一年。除了在PCa中看到的常见骨转移，NEPC表现出内脏转移的特征，尤其是肝转移，作为临床预后不良的指标。已经确定了驱动PCa神经内分泌可塑性的关键因素，然而，肝转移背后的潜在机制仍不清楚。在这项研究中,我们确定PROX1是PCa神经内分泌可塑性的驱动因素，负责促进肝转移。机械上,抗雄激素治疗减轻PROX1的转录抑制。随后，升高的PROX1水平驱动神经内分泌可塑性和肝脏特异性转录重编程，促进肝转移。此外，PROX1诱导的PCa肝转移依赖于重新编程的脂质代谢，有效减少肝转移形成的破坏。
