Genito Urinary Cancer Research Group, Division of Cancer Sciences, Faculty of Biology, Medicine & Health, The University of Manchester and FASTMAN, Prostate Cancer UK & Movember Centre of Excellence, Manchester, UK.
Department of Surgery, The Christie NHS Foundation Trust, Manchester, UK.
Br J Cancer. 2022 Oct;127(7):1254-1262. doi: 10.1038/s41416-022-01914-3. Epub 2022 Jul 22.
The key process of mesenchymal to amoeboid transition (MAT), which enables prostate cancer (PCa) transendothelial migration and subsequent development of metastases in red bone marrow stroma, is driven by phosphorylation of EphA2 by pAkt, which is induced by the omega-6 polyunsaturated fatty acid arachidonic acid. Here we investigate the influence of EphA2 signalling in PCa progression and long-term survival.
The mechanisms underpinning metastatic biopotential of altered EphA2 signalling in relation to PTEN status were assessed in vitro using canonical (EphA2) and non-canonical (EphA2) PC3-M mutants, interrogation of publicly available PTEN-stratified databases and clinical validation using a PCa TMA (n = 177) with long-term follow-up data. Spatial heterogeneity of EphA2 was assessed using a radical prostatectomy cohort (n = 67).
Non-canonical EphA2 signalling via pEphA2 is required for PCa transendothelial invasion of bone marrow endothelium. High expression of EphA2 or pEphA2 in a PTEN background is associated with poor overall survival. Expression of EphA2, pEphA2 and the associated MAT marker pMLC2 are spatially regulated with the highest levels found within lesion areas within 500 µm of the prostate margin.
EphA2 MAT-related signalling confers transendothelial invasion. This is associated with a substantially worse prognosis in PTEN-deficient PCa.
间质到阿米巴样转变（MAT）的关键过程，使前列腺癌（PCa）穿透血管内皮迁移，并随后在红骨髓基质中发展转移，是由 EphA2 被 pAkt 磷酸化驱动的，这是由 ω-6 多不饱和脂肪酸花生四烯酸诱导的。在这里，我们研究了 EphA2 信号在 PCa 进展和长期生存中的影响。
使用经典（EphA2）和非经典（EphA2）PC3-M 突变体，在体外评估改变的 EphA2 信号与 PTEN 状态相关的转移性生物潜能的机制，查询公开的 PTEN 分层数据库，并使用具有长期随访数据的 PCa TMA（n=177）进行临床验证。使用根治性前列腺切除术队列（n=67）评估 EphA2 的空间异质性。
通过 pEphA2 的非经典 EphA2 信号对于 PCa 穿透骨髓内皮的血管内皮侵袭是必需的。在 PTEN 背景下 EphA2 或 pEphA2 的高表达与总体生存不良相关。EphA2、pEphA2 和相关的 MAT 标志物 pMLC2 的表达具有空间调节性，在距前列腺边缘 500µm 以内的病变区域内发现最高水平。
EphA2 MAT 相关信号赋予了跨内皮侵袭的能力。这与 PTEN 缺失的 PCa 预后显著恶化相关。
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