Non-canonical EphA2 activation underpins PTEN-mediated metastatic migration and poor clinical outcome in prostate cancer
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Authors
Sachdeva, AshwinHart, C. A.
Kim, K.
Tawadros, T.
Oliveira, Pedro
Shanks, Jonathan H
Brown, M.
Clarke, Noel W
Affiliation
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, UKIssue Date
2022
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Background: 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 EphA2S897 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. Methods: The mechanisms underpinning metastatic biopotential of altered EphA2 signalling in relation to PTEN status were assessed in vitro using canonical (EphA2D739N) and non-canonical (EphA2S897G) 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). Results: Non-canonical EphA2 signalling via pEphA2S897 is required for PCa transendothelial invasion of bone marrow endothelium. High expression of EphA2 or pEphA2S897 in a PTENlow background is associated with poor overall survival. Expression of EphA2, pEphA2S897 and the associated MAT marker pMLC2 are spatially regulated with the highest levels found within lesion areas within 500 µm of the prostate margin. Conclusion: EphA2 MAT-related signalling confers transendothelial invasion. This is associated with a substantially worse prognosis in PTEN-deficient PCa.Citation
Sachdeva A, Hart CA, Kim K, Tawadros T, Oliveira P, Shanks J, et al. Non-canonical EphA2 activation underpins PTEN-mediated metastatic migration and poor clinical outcome in prostate cancer. British journal of cancer. 2022 Jul 22. PubMed PMID: 35869144. Epub 2022/07/23. eng.Journal
British Journal of CancerDOI
10.1038/s41416-022-01914-3PubMed ID
35869144Additional Links
https://dx.doi.org/10.1038/s41416-022-01914-3Type
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1038/s41416-022-01914-3