OpenLB
Open Library of Bioscience
Advanced Search
British journal of cancer
10, 2022;127 (7): 1254-1262.

Non-canonical EphA2 activation underpins PTEN-mediated metastatic migration and poor clinical outcome in prostate cancer.

Ashwin Sachdeva, Claire A Hart, Kyungmin Kim, Thomas Tawadros, Pedro Oliveira, Jonathan Shanks, Mick Brown, Noel Clarke
Author Information
  1. Ashwin Sachdeva: 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.
  2. Claire A Hart: 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.
  3. Kyungmin Kim: 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.
  4. Thomas Tawadros: 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.
  5. Pedro Oliveira: Department of Pathology, The Christie NHS Foundation Trust, Manchester, UK.
  6. Jonathan Shanks: Department of Pathology, The Christie NHS Foundation Trust, Manchester, UK.
  7. Mick Brown: 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. michael.d.brown@manchester.ac.uk. ORCID
  8. Noel Clarke: 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.
PMID: 35869144 DOI: 10.1038/s41416-022-01914-3

Abstract

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 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.
METHODS: 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).
RESULTS: 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.
CONCLUSION: EphA2 MAT-related signalling confers transendothelial invasion. This is associated with a substantially worse prognosis in PTEN-deficient PCa.

References

  1. James ND, Spears MR, Clarke NW, Dearnaley DP, De Bono JS, Gale J, et al. Survival with newly diagnosed metastatic prostate cancer in the “Docetaxel Era”: data from 917 patients in the control arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019). Eur Urol. 2015;67:1028–38. [PMID: 25301760]
  2. Loberg RD, Logothetis CJ, Keller ET, Pienta KJ. Pathogenesis and treatment of prostate cancer bone metastases: targeting the lethal phenotype. J Clin Oncol. 2005;23:8232–41. [PMID: 16278478]
  3. Diedrich JD, Rajagurubandara E, Herroon MK, Mahapatra G, Huttemann M, Podgorski I. Bone marrow adipocytes promote the Warburg phenotype in metastatic prostate tumors via HIF-1alpha activation. Oncotarget 2016;7:64854–77. [PMID: 27588494]
  4. Hardaway AL, Herroon MK, Rajagurubandara E, Podgorski I. Bone marrow fat: linking adipocyte-induced inflammation with skeletal metastases. Cancer Metastasis Rev. 2014;33:527–43. [PMID: 24398857]
  5. Uehara H, Kobayashi T, Matsumoto M, Watanabe S, Yoneda A, Bando Y. Adipose tissue: critical contributor to the development of prostate cancer. J Med Invest. 2018;65:9–17. [PMID: 29593201]
  6. Huang J, Mondul AM, Weinstein SJ, Derkach A, Moore SC, Sampson JN, et al. Prospective serum metabolomic profiling of lethal prostate cancer. Int J Cancer. 2019;145:3231–43.
  7. Chavarro JE, Stampfer MJ, Li H, Campos H, Kurth T, Ma J. A prospective study of polyunsaturated fatty acid levels in blood and prostate cancer risk. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive. Oncology. 2007;16:1364–70.
  8. Szymanski KM, Wheeler DC, Mucci LA. Fish consumption and prostate cancer risk: a review and meta-analysis. Am J Clin Nutr. 2010;92:1223–33. [PMID: 20844069]
  9. Wynder EL, Rose DP, Cohen LA. Nutrition and prostate cancer: a proposal for dietary intervention. Nutr Cancer. 1994;22:1–10. [PMID: 11304906]
  10. Denizot Y, Desplat V, Dulery C, Trimoreau F, Praloran V. Arachidonic acid and freshly isolated human bone marrow mononuclear cells. Mediators Inflamm. 1999;8:31–5. [PMID: 10704087]
  11. Denizot Y, Dulery C, Trimoreau F, Desplat V, Praloran V. Arachidonic acid and human bone marrow stromal cells. Biochim Biophys Acta. 1998;1402:209–15. [PMID: 9561806]
  12. Sumida T. Clinical and experimental study on fatty acid composition of bone marrow lipid in hematologic disorders. Acta Med Nagasaki. 1965;9:222–41. [PMID: 5841985]
  13. Gazi E, Gardner P, Lockyer NP, Hart CA, Brown MD, Clarke NW. Direct evidence of lipid translocation between adipocytes and prostate cancer cells with imaging FTIR microspectroscopy. J lipid Res. 2007;48:1846–56. [PMID: 17496269]
  14. Brown MD, Hart C, Gazi E, Gardner P, Lockyer N, Clarke N. Influence of omega-6 PUFA arachidonic acid and bone marrow adipocytes on metastatic spread from prostate cancer. Br J Cancer. 2010;102:403–13. [PMID: 19997104]
  15. Brown MD, Hart CA, Gazi E, Bagley S, Clarke NW. Promotion of prostatic metastatic migration towards human bone marrow stoma by Omega 6 and its inhibition by Omega 3 PUFAs. Br J Cancer. 2006;94:842–53. [PMID: 16523199]
  16. Brown M, Roulson JA, Hart CA, Tawadros T, Clarke NW. Arachidonic acid induction of Rho-mediated transendothelial migration in prostate cancer. Br J Cancer. 2014;110:2099–108. [PMID: 24595005]
  17. Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, et al. EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell. 2009;16:9–20. [PMID: 19573808]
  18. Tawadros T, Brown MD, Hart CA, Clarke NW. Ligand-independent activation of EphA2 by arachidonic acid induces metastasis-like behaviour in prostate cancer cells. Br J Cancer. 2012;107:1737–44. [PMID: 23037715]
  19. Cioce M, Fazio VM. EphA2 and EGFR: friends in life, partners in crime. Can EphA2 Be a predictive biomarker of response to anti-EGFR agents? Cancers. 2021;13:700.
  20. Pasquale EB. Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer. 2010;10:165–80. [PMID: 20179713]
  21. Walker-Daniels J, Coffman K, Azimi M, Rhim JS, Bostwick DG, Snyder P, et al. Overexpression of the EphA2 tyrosine kinase in prostate cancer. Prostate. 1999;41:275–80. [PMID: 10544301]
  22. Zelinski DP, Zantek ND, Stewart JC, Irizarry AR, Kinch MS. EphA2 overexpression causes tumorigenesis of mammary epithelial cells. Cancer Res. 2001;61:2301–6. [PMID: 11280802]
  23. Miao H, Burnett E, Kinch M, Simon E, Wang B. Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nat Cell Biol. 2000;2:62–9. [PMID: 10655584]
  24. Miao H, Nickel CH, Cantley LG, Bruggeman LA, Bennardo LN, Wang B. EphA kinase activation regulates HGF-induced epithelial branching morphogenesis. J Cell Biol. 2003;162:1281–92. [PMID: 14517207]
  25. Miao H, Wei BR, Peehl DM, Li Q, Alexandrou T, Schelling JR, et al. Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway. Nat Cell Biol. 2001;3:527–30. [PMID: 11331884]
  26. Barquilla A, Lamberto I, Noberini R, Heynen-Genel S, Brill LM, Pasquale EB. Protein kinase A can block EphA2 receptor-mediated cell repulsion by increasing EphA2 S897 phosphorylation. Mol Biol Cell. 2016;27:2757–70. [PMID: 27385333]
  27. Li JY, Xiao T, Yi HM, Yi H, Feng J, Zhu JF, et al. S897 phosphorylation of EphA2 is indispensable for EphA2-dependent nasopharyngeal carcinoma cell invasion, metastasis and stem properties. Cancer Lett. 2019;444:162–74. [PMID: 30583071]
  28. Jamaspishvili T, Berman DM, Ross AE, Scher HI, De Marzo AM, Squire JA, et al. Clinical implications of PTEN loss in prostate cancer. Nat Rev Urol. 2018;15:222–34. [PMID: 29460925]
  29. Coulthard MG, Morgan M, Woodruff TM, Arumugam TV, Taylor SM, Carpenter TC, et al. Eph/Ephrin signaling in injury and inflammation. Am J Pathol. 2012;181:1493–503. [PMID: 23021982]
  30. Gambini L, Salem AF, Udompholkul P, Tan XF, Baggio C, Shah N, et al. Structure-based design of novel EphA2 agonistic agents with nanomolar affinity in vitro and in cell. ACS Chem Biol. 2018;13:2633–44. [PMID: 30110533]
  31. Gomez-Soler M, Petersen Gehring M, Lechtenberg BC, Zapata-Mercado E, Hristova K, Pasquale EB. Engineering nanomolar peptide ligands that differentially modulate EphA2 receptor signaling. J Biol Chem. 2019;294:8791–805.
  32. Moser C, Lorenz JS, Sajfutdinow M, Smith DM. Pinpointed stimulation of EphA2 receptors via DNA-templated oligovalence. Int J Mol Sci. 2018;19:3482.
  33. Maxwell PJ, Coulter J, Walker SM, McKechnie M, Neisen J, McCabe N, et al. Potentiation of inflammatory CXCL8 signalling sustains cell survival in PTEN-deficient prostate carcinoma. Eur Urol. 2013;64:177–88. [PMID: 22939387]
  34. Almeida-Porada G, Ascensao JL. Isolation, characterization, and biologic features of bone marrow endothelial cells. J Lab Clin Med. 1996;128:399–407. [PMID: 8833889]
  35. Hart CA, Brown M, Bagley S, Sharrard M, Clarke NW. Invasive characteristics of human prostatic epithelial cells: understanding the metastatic process. Br J Cancer. 2005;92:503–12. [PMID: 15668715]
  36. Cancer Genome Atlas Research N. The molecular taxonomy of primary prostate cancer. Cell 2015;163:1011–25. [DOI: 10.1016/j.cell.2015.10.025]
  37. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18:11–22. [PMID: 20579941]
  38. Lu TP, Lai LC, Tsai MH, Chen PC, Hsu CP, Lee JM, et al. Integrated analyses of copy number variations and gene expression in lung adenocarcinoma. PLoS ONE. 2011;6:e24829. [PMID: 21935476]
  39. Andor N, Graham TA, Jansen M, Xia LC, Aktipis CA, Petritsch C, et al. Pan-cancer analysis of the extent and consequences of intratumor heterogeneity. Nat Med. 2016;22:105–13. [PMID: 26618723]
  40. Cyll K, Ersvaer E, Vlatkovic L, Pradhan M, Kildal W, Avranden Kjaer M, et al. Tumour heterogeneity poses a significant challenge to cancer biomarker research. Br J Cancer. 2017;117:367–75. [PMID: 28618431]
  41. Lang SH, Clarke NW, George NJ, Allen TD, Testa NG. Interaction of prostate epithelial cells from benign and malignant tumor tissue with bone-marrow stroma. Prostate. 1998;34:203–13. [PMID: 9492849]
  42. Scott LJ, Clarke NW, George NJ, Shanks JH, Testa NG, Lang SH. Interactions of human prostatic epithelial cells with bone marrow endothelium: binding and invasion. Br J Cancer. 2001;84:1417–23. [PMID: 11355957]
  43. Gazi E, Dwyer J, Lockyer NP, Gardner P, Shanks JH, Roulson J, et al. Biomolecular profiling of metastatic prostate cancer cells in bone marrow tissue using FTIR microspectroscopy: a pilot study. Anal Bioanal Chem. 2007;387:1621–31. [PMID: 17268776]
  44. Shen W, Xi H, Zhang K, Cui J, Li J, Wang N, et al. Prognostic role of EphA2 in various human carcinomas: a meta-analysis of 23 related studies. Growth Factors. 2014;32:247–53. [PMID: 25418013]
  45. Dunne PD, Dasgupta S, Blayney JK, McArt DG, Redmond KL, Weir JA, et al. EphA2 expression is a key driver of migration and invasion and a poor prognostic marker in colorectal cancer. Clin Cancer Res. 2016;22:230–42. [PMID: 26283684]
  46. Easty DJ, Guthrie BA, Maung K, Farr CJ, Lindberg RA, Toso RJ, et al. Protein B61 as a new growth factor: expression of B61 and up-regulation of its receptor epithelial cell kinase during melanoma progression. Cancer Res. 1995;55:2528–32. [PMID: 7780963]
  47. Chen P, Huang Y, Zhang B, Wang Q, Bai P. EphA2 enhances the proliferation and invasion ability of LNCaP prostate cancer cells. Oncol Lett. 2014;8:41–6. [PMID: 24959216]
  48. Kurose H, Ueda K, Kondo R, Ogasawara S, Kusano H, Sanada S, et al. Elevated expression of EPHA2 is associated with poor prognosis after radical prostatectomy in prostate cancer. Anticancer Res. 2019;39:6249–57. [PMID: 31704854]
  49. Lin KT, Gong J, Li CF, Jang TH, Chen WL, Chen HJ, et al. Vav3-rac1 signaling regulates prostate cancer metastasis with elevated Vav3 expression correlating with prostate cancer progression and posttreatment recurrence. Cancer Res. 2012;72:3000–9. [PMID: 22659453]

MeSH Term

Arachidonic Acid
Cell Line, Tumor
Humans
Male
PTEN Phosphohydrolase
Phosphorylation
Prostatic Neoplasms
Receptor, EphA2

Chemicals

EPHA2 protein, human
Arachidonic Acid
Receptor, EphA2
PTEN Phosphohydrolase
PTEN protein, human
Journal Article
Article has an altmetric score of 2

Word Cloud

Created with Highcharts 10.0.0EphA2PCasignallingprostatetransendothelialusingpEphA2associatedMATcancermigrationbonemarrowacidlong-termsurvivalmetastaticPTENassessedclinicalNon-canonicalinvasionpoorwithinBACKGROUND:keyprocessmesenchymalamoeboidtransitionenablessubsequentdevelopmentmetastasesredstromadrivenphosphorylationpAktinducedomega-6polyunsaturatedfattyarachidonicinvestigateinfluenceprogressionMETHODS:mechanismsunderpinningbiopotentialalteredrelationstatusvitrocanonicalnon-canonicalPC3-MmutantsinterrogationpubliclyavailablePTEN-stratifieddatabasesvalidationTMAn = 177follow-updataSpatialheterogeneityradicalprostatectomycohortn = 67RESULTS:viarequiredendotheliumHighexpressionbackgroundoverallExpressionmarkerpMLC2spatiallyregulatedhighestlevelsfoundlesionareas500 µmmarginCONCLUSION:MAT-relatedconferssubstantiallyworseprognosisPTEN-deficientactivationunderpinsPTEN-mediatedoutcome

Similar Articles

Cited By (6)