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Low junctional adhesion molecule-A expression is associated with an epithelial to mesenchymal transition and poorer outcomes in high-grade serous carcinoma of uterine adnexa

Abstract

High-grade serous carcinoma of uterine adnexa (HGSC) is the most frequent histotype of epithelial ovarian cancer and has a poor 5-year survival rate due to late-stage diagnosis and the poor efficacy of standard treatments. Novel biomarkers of cancer outcome are needed to identify new targetable pathways and improve personalized treatments. Cell-surface screening of 26 HGSC cell lines by high-throughput flow cytometry identified junctional adhesion molecule 1 (JAM-A, also known as F11R) as a potential biomarker. Using a multi-labeled immunofluorescent staining coupled with digital image analysis, protein levels of JAM-A were quantified in tissue microarrays from three HGSC patient cohorts: a discovery cohort (n = 101), the Canadian Ovarian Experimental Unified Resource cohort (COEUR, n = 1158), and the Canadian Cancer Trials Group OV16 cohort (n = 267). Low JAM-A level was associated with poorer outcome in the three cohorts by Kaplan–Meier (p = 0.023, p < 0.001, and p = 0.036, respectively) and was an independent marker of shorter survival in the COEUR cohort (HR = 0.517 (0.381–703), p < 0.001). When analyses were restricted to patients treated by taxane–platinum-based chemotherapy, low JAM-A protein expression was associated with poorer responses in the COEUR (p < 0.001) and OV16 cohorts (p = 0.006) by Kaplan–Meier. Decreased JAM-A gene expression was an indicator of poor outcome in gene expression datasets including The Cancer Genome Atlas (n = 606, p = 0.002) and Kaplan–Meier plotter (n = 1816, p = 0.024). Finally, we observed that tumors with decreased JAM-A expression exhibited an enhanced epithelial to mesenchymal transition (EMT) signature. Our results demonstrate that JAM-A expression is a robust prognostic biomarker of HGSC and may be used to discriminate tumors responsive to therapies targeting EMT.

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Fig. 1: Identification of new HGSC biomarkers by cell-surface marker screening.
Fig. 2: JAM-A protein expression is a biomarker of favorable outcome in the discovery cohort.
Fig. 3: JAM-A protein expression is a biomarker of favorable outcome in the COEUR cohort.
Fig. 4: JAM-A protein and mRNA expression is a biomarker of favorable outcome in independent cohorts.
Fig. 5: Low JAM-A expression is associated with EMT signature.

References

  1. 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.

    PubMed  Google Scholar 

  2. 2.

    Committee CCSA. Canadian Cancer Statistics 2018. Toronto, ON: Canadian Cancer Society; 2018.

    Google Scholar 

  3. 3.

    Lheureux S, Gourley C, Vergote I, Oza AM. Epithelial ovarian cancer. Lancet. 2019;393:1240–53.

    PubMed  PubMed Central  Google Scholar 

  4. 4.

    Prat J. Ovarian carcinomas: five distinct diseases with different origins, genetic alterations, and clinicopathological features. Virchows Arch. 2012;460:237–49.

    PubMed  Google Scholar 

  5. 5.

    Tothill RW, Tinker AV, George J, Brown R, Fox SB, Lade S, et al. Novel molecular subtypes of serous and endometrioid ovarian cancer linked to clinical outcome. Clin Cancer Res. 2008;14:5198–208.

    CAS  PubMed  Google Scholar 

  6. 6.

    Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609–15.

    Google Scholar 

  7. 7.

    Tan TZ, Miow QH, Huang RY, Wong MK, Ye J, Lau JA, et al. Functional genomics identifies five distinct molecular subtypes with clinical relevance and pathways for growth control in epithelial ovarian cancer. EMBO Mol Med. 2013;5:1051–66.

    PubMed  Google Scholar 

  8. 8.

    Konecny GE, Wang C, Hamidi H, Winterhoff B, Kalli KR, Dering J, et al. Prognostic and therapeutic relevance of molecular subtypes in high-grade serous ovarian cancer. J Natl Cancer Inst. 2014;106.

  9. 9.

    Lheureux S, Braunstein M, Oza AM. Epithelial ovarian cancer: evolution of management in the era of precision medicine. CA Cancer J Clin. 2019.

  10. 10.

    Medrano M, Communal L, Brown KR, Iwanicki M, Normand J, Paterson J, et al. Interrogation of functional cell-surface markers identifies CD151 dependency in high-grade serous ovarian cancer. Cell Rep. 2017;18:2343–58.

    CAS  PubMed  Google Scholar 

  11. 11.

    Paterson J, Ailles LE. High throughput flow cytometry for cell surface profiling. Methods Mol Biol. 2018;1678:111–38.

    CAS  PubMed  Google Scholar 

  12. 12.

    Martin-Padura I, Lostaglio S, Schneemann M, Williams L, Romano M, Fruscella P, et al. Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol. 1998;142:117–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Zhao C, Lu F, Chen H, Zhao X, Sun J, Chen H. Dysregulation of JAM-A plays an important role in human tumor progression. Int J Clin Exp Pathol. 2014;7:7242–8.

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Mandell KJ, Babbin BA, Nusrat A, Parkos CA. Junctional adhesion molecule 1 regulates epithelial cell morphology through effects on beta1 integrins and Rap1 activity. J Biol Chem. 2005;280:11665–74.

    CAS  PubMed  Google Scholar 

  15. 15.

    Martin TA. The role of tight junctions in cancer metastasis. Semin Cell Dev Biol. 2014;36:224–31.

    CAS  PubMed  Google Scholar 

  16. 16.

    Ghislin S, Obino D, Middendorp S, Boggetto N, Alcaide-Loridan C, Deshayes F. Junctional adhesion molecules are required for melanoma cell lines transendothelial migration in vitro. Pigment Cell Melanoma Res. 2011;24:504–11.

    CAS  PubMed  Google Scholar 

  17. 17.

    Gutwein P, Schramme A, Voss B, Abdel-Bakky MS, Doberstein K, Ludwig A, et al. Downregulation of junctional adhesion molecule-A is involved in the progression of clear cell renal cell carcinoma. Biochem Biophys Res Commun. 2009;380:387–91.

    CAS  PubMed  Google Scholar 

  18. 18.

    Koshiba H, Hosokawa K, Kubo A, Tokumitsu N, Watanabe A, Honjo H. Junctional adhesion molecule A [corrected] expression in human endometrial carcinoma. Int J Gynecol Cancer. 2009;19:208–13.

    PubMed  Google Scholar 

  19. 19.

    Fong D, Spizzo G, Mitterer M, Seeber A, Steurer M, Gastl G, et al. Low expression of junctional adhesion molecule A is associated with metastasis and poor survival in pancreatic cancer. Ann Surg Oncol. 2012;19:4330–6.

    PubMed  Google Scholar 

  20. 20.

    Zhang M, Luo W, Huang B, Liu Z, Sun L, Zhang Q, et al. Overexpression of JAM-A in non-small cell lung cancer correlates with tumor progression. PLoS One. 2013;8:e79173.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Tian Y, Tian Y, Zhang W, Wei F, Yang J, Luo X, et al. Junctional adhesion molecule-A, an epithelial-mesenchymal transition inducer, correlates with metastasis and poor prognosis in human nasopharyngeal cancer. Carcinogenesis. 2015;36:41–48.

    CAS  PubMed  Google Scholar 

  22. 22.

    Lathia JD, Li M, Sinyuk M, Alvarado AG, Flavahan WA, Stoltz K, et al. High-throughput flow cytometry screening reveals a role for junctional adhesion molecule a as a cancer stem cell maintenance factor. Cell Rep. 2014;6:117–29.

    CAS  PubMed  Google Scholar 

  23. 23.

    Solimando AG, Brandl A, Mattenheimer K, Graf C, Ritz M, Ruckdeschel A, et al. JAM-A as a prognostic factor and new therapeutic target in multiple myeloma. Leukemia. 2018;32:736–43.

    CAS  PubMed  Google Scholar 

  24. 24.

    Ikeo K, Oshima T, Shan J, Matsui H, Tomita T, Fukui H, et al. Junctional adhesion molecule-A promotes proliferation and inhibits apoptosis of gastric cancer. Hepatogastroenterology. 2015;62:540–5.

    CAS  PubMed  Google Scholar 

  25. 25.

    Huang JY, Xu YY, Sun Z, Wang ZN, Zhu Z, Song YX, et al. Low junctional adhesion molecule A expression correlates with poor prognosis in gastric cancer. J Surg Res. 2014;192:494–502.

    CAS  PubMed  Google Scholar 

  26. 26.

    Naik MU, Naik TU, Suckow AT, Duncan MK, Naik UP. Attenuation of junctional adhesion molecule-A is a contributing factor for breast cancer cell invasion. Cancer Res. 2008;68:2194–203.

    CAS  PubMed  Google Scholar 

  27. 27.

    McSherry EA, McGee SF, Jirstrom K, Doyle EM, Brennan DJ, Landberg G, et al. JAM-A expression positively correlates with poor prognosis in breast cancer patients. Int J Cancer. 2009;125:1343–51.

    CAS  PubMed  Google Scholar 

  28. 28.

    Murakami M, Giampietro C, Giannotta M, Corada M, Torselli I, Orsenigo F, et al. Abrogation of junctional adhesion molecule-A expression induces cell apoptosis and reduces breast cancer progression. PLoS One. 2011;6:e21242.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Ivana B, Emina M, Marijana MK, Irena J, Zoran B, Radmila J. High expression of junctional adhesion molecule-A is associated with poor survival in patients with epithelial ovarian cancer. Int J Biol Markers. 2019. https://doi.org/10.1177/1724600819850178.

  30. 30.

    Le Page C, Rahimi K, Kobel M, Tonin PN, Meunier L, Portelance L, et al. Characteristics and outcome of the COEUR Canadian validation cohort for ovarian cancer biomarkers. BMC Cancer. 2018;18:347.

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Hoskins P, Vergote I, Cervantes A, Tu D, Stuart G, Zola P, et al. Advanced ovarian cancer: phase III randomized study of sequential cisplatin-topotecan and carboplatin-paclitaxel vs carboplatin-paclitaxel. J Natl Cancer Inst. 2010;102:1547–56.

    CAS  PubMed  Google Scholar 

  32. 32.

    Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Disco. 2012;2:401–4.

    Google Scholar 

  34. 34.

    Gyorffy B, Lanczky A, Szallasi Z. Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients. Endocr Relat Cancer. 2012;19:197–208.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Tan TZ, Yang H, Ye J, Low J, Choolani M, Tan DS, et al. CSIOVDB: a microarray gene expression database of epithelial ovarian cancer subtype. Oncotarget. 2015;6:43843–52.

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Tan TZ, Miow QH, Miki Y, Noda T, Mori S, Huang RY, et al. Epithelial-mesenchymal transition spectrum quantification and its efficacy in deciphering survival and drug responses of cancer patients. EMBO Mol Med. 2014;6:1279–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Gedye CA, Hussain A, Paterson J, Smrke A, Saini H, Sirskyj D, et al. Cell surface profiling using high-throughput flow cytometry: a platform for biomarker discovery and analysis of cellular heterogeneity. PLoS One. 2014;9:e105602.

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Liu Y, Nusrat A, Schnell FJ, Reaves TA, Walsh S, Pochet M, et al. Human junction adhesion molecule regulates tight junction resealing in epithelia. J Cell Sci. 2000;113:2363–74.

    CAS  PubMed  Google Scholar 

  39. 39.

    Bazzoni G. The JAM family of junctional adhesion molecules. Curr Opin Cell Biol. 2003;15:525–30.

    CAS  PubMed  Google Scholar 

  40. 40.

    Mandell KJ, Parkos CA. The JAM family of proteins. Adv Drug Deliv Rev. 2005;57:857–67.

    CAS  PubMed  Google Scholar 

  41. 41.

    Xu Z, Jin B. A novel interface consisting of homologous immunoglobulin superfamily members with multiple functions. Cell Mol Immunol. 2010;7:11–19.

    PubMed  PubMed Central  Google Scholar 

  42. 42.

    Cera MR, Fabbri M, Molendini C, Corada M, Orsenigo F, Rehberg M, et al. JAM-A promotes neutrophil chemotaxis by controlling integrin internalization and recycling. J Cell Sci. 2009;122:268–77.

    CAS  PubMed  Google Scholar 

  43. 43.

    Iden S, Misselwitz S, Peddibhotla SS, Tuncay H, Rehder D, Gerke V, et al. aPKC phosphorylates JAM-A at Ser285 to promote cell contact maturation and tight junction formation. J Cell Biol. 2012;196:623–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Severson EA, Parkos CA. Structural determinants of junctional adhesion molecule A (JAM-A) function and mechanisms of intracellular signaling. Curr Opin Cell Biol. 2009;21:701–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Marchini S, Fruscio R, Clivio L, Beltrame L, Porcu L, Fuso Nerini I, et al. Resistance to platinum-based chemotherapy is associated with epithelial to mesenchymal transition in epithelial ovarian cancer. Eur J Cancer. 2013;49:520–30.

    CAS  PubMed  Google Scholar 

  46. 46.

    Deng J, Wang L, Chen H, Hao J, Ni J, Chang L, et al. Targeting epithelial-mesenchymal transition and cancer stem cells for chemoresistant ovarian cancer. Oncotarget. 2016;7:55771–88.

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Mitra T, Prasad P, Mukherjee P, Chaudhuri SR, Chatterji U, Roy SS. Stemness and chemoresistance are imparted to the OC cells through TGFbeta1 driven EMT. J Cell Biochem. 2018;119:5775–87.

    CAS  PubMed  Google Scholar 

  48. 48.

    Klymenko Y, Kim O, Stack MS. Complex determinants of epithelial: mesenchymal phenotypic plasticity in ovarian cancer. Cancers. 2017;9.

  49. 49.

    Antony J, Thiery JP, Huang RY. Epithelial-to-mesenchymal transition: lessons from development, insights into cancer and the potential of EMT-subtype based therapeutic intervention. Phys Biol. 2019.

  50. 50.

    Moffitt L, Karimnia N, Stephens A, Bilandzic M. Therapeutic targeting of collective invasion in ovarian cancer. Int J Mol Sci. 2019;20.

  51. 51.

    Bilyk O, Coatham M, Jewer M, Postovit LM. Epithelial-to-mesenchymal transition in the female reproductive tract: from normal functioning to disease pathology. Front Oncol. 2017;7:145.

    PubMed  PubMed Central  Google Scholar 

  52. 52.

    Zhou J, Du Y, Lu Y, Luan B, Xu C, Yu Y, et al. CD44 expression predicts prognosis of ovarian cancer patients through promoting epithelial-mesenchymal transition (EMT) by regulating snail, ZEB1, and caveolin-1. Front Oncol. 2019;9:802.

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Bonome T, Levine DA, Shih J, Randonovich M, Pise-Masison CA, Bogomolniy F, et al. A gene signature predicting for survival in suboptimally debulked patients with ovarian cancer. Cancer Res. 2008;68:5478–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Verhaak RG, Tamayo P, Yang JY, Hubbard D, Zhang H, Creighton CJ, et al. Prognostically relevant gene signatures of high-grade serous ovarian carcinoma. J Clin Invest. 2013;123:517–25.

    CAS  Google Scholar 

  55. 55.

    Newsted D, Banerjee S, Watt K, Nersesian S, Truesdell P, Blazer LL, et al. Blockade of TGF-beta signaling with novel synthetic antibodies limits immune exclusion and improves chemotherapy response in metastatic ovarian cancer models. Oncoimmunology 2019;8:e1539613.

    PubMed  Google Scholar 

  56. 56.

    Komiyama S, Kurahashi T, Ishikawa M, Tanaka K, Komiyama M, Mikami M, et al. Expression of TGFss1 and its receptors is associated with biological features of ovarian cancer and sensitivity to paclitaxel/carboplatin. Oncol Rep. 2011;25:1131–8.

    CAS  PubMed  Google Scholar 

  57. 57.

    Cao L, Shao M, Schilder J, Guise T, Mohammad KS, Matei D. Tissue transglutaminase links TGF-beta, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer. Oncogene. 2012;31:2521–34.

    CAS  PubMed  Google Scholar 

  58. 58.

    Wang Y, Lui WY. Transforming growth factor-beta1 attenuates junctional adhesion molecule-A and contributes to breast cancer cell invasion. Eur J Cancer. 2012;48:3475–87.

    CAS  PubMed  Google Scholar 

  59. 59.

    Alsina-Sanchis E, Figueras A, Lahiguera A, Gil-Martin M, Pardo B, Piulats JM, et al. TGFbeta controls ovarian cancer cell proliferation. Int J Mol Sci. 2017;18.

  60. 60.

    Szender JB, Emmons T, Belliotti S, Dickson D, Khan A, Morrell K, et al. Impact of ascites volume on clinical outcomes in ovarian cancer: a cohort study. Gynecol Oncol. 2017;146:491–7.

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

LC, MM, and FS were supported by the Selective Therapy Program from the TFRI and the Ontario Institute for Cancer Research. LC was supported by a post-doctoral fellowship from the Fond de recherche Québec—Santé (FRQS). MM was supported by Ovarian Cancer Canada’s Teal Heart Scholarship. A-MMM and DP are researchers of CRCHUM/ICM, which receive support from the FRQS and the Réseau de Recherche sur le cancer (RR cancer). We thank Jacqueline Chung for English editing. We thank Anne-Marie Fortier, Senthil Muthuswamy, and Shakeel Virk for helpful discussions and information. We thank the molecular pathology core facility of the CRCHUM for performing the discovery and COEUR TMA construction and tissue scanning. We thank the Department of Pathology and Molecular Biology at the Queen’s University for performing the OV16 TMA construction. Tumor banking for the discovery cohort was supported by the Banque de tissus et de données of the RR cancer of the FRQS affiliated with the Canadian Tumor Repository Network. Tumor banking for the OV16 cohort was performed by the CCTG Tumor Tissue Data Repository. This study uses resources provided by the COEUR biobank funded by the TFRI and managed and supervised by the CHUM. The Consortium acknowledges contributions to its COEUR biobank from Institutions across Canada (for a full list see www.tfri.ca/COEUR/members). We thank the generosity of patients included in this study.

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Correspondence to Anne-Marie Mes-Masson.

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AO is a consultant/advisory board member for Immunogen, AstraZeneca, Tesaro, and Clovis. The other authors declare that they have no conflict of interest.

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Communal, L., Medrano, M., Sircoulomb, F. et al. Low junctional adhesion molecule-A expression is associated with an epithelial to mesenchymal transition and poorer outcomes in high-grade serous carcinoma of uterine adnexa. Mod Pathol 33, 2361–2377 (2020). https://doi.org/10.1038/s41379-020-0586-0

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