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Significance of Trask protein interactions in brain metastatic cohorts of lung cancers

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Tumor Biology

Abstract

A class of adhesion protein that occurs in the membrane with both extracellular and intracellular domain and play vital role in maintaining multicellularity is TRASK, also called CUB-domain containing protein1, CD318 (CDCP1). Specifically, in the current study, documented aggressive grades of lung cancers and distant metastatic tissues were examined for protein interactions of Trask and compared with lung cancer variants in situ. The intracellular domain of Trask has the ability to undergo tyrosine phosphorylation and thereafter undergo increased genomic expression, as well as interact with cytoskeletal proteins in the cell periphery and other local signal transduction machinery to induce invadopodia formation and distant metastasis. We incorporated proximity ligation assay to examine protein interactions of Trask in metastatic lung cancer tissues and compare with advanced and low-grade lung cancers restricted to the primary site of origins. Here, we provide direct evidence that activated Trask, which is a phosphorylated form, binds with cytoskeletal proteins actin and spectrin. These interactions were not seen in locally growing lung cancer and cancer in situ. These interactions may be responsible for invadopodia formation and breaking free from a multicellular environment. Functional studies demonstrated interaction between Trask and the STOCs Orai1 and Stim1. Calcium release from internal stores was highest in metastatic lung cancers, suggesting this mechanism as an initial stimulus for the cells to respond chaotically to external growth factor stimulation, especially in aggressive metastatic variants of lung cancers. Recently, inhibitors of STOCs have been identified, and preclinical evidence may be obtained whether these drugs may be of benefit in preventing the deadly consequences of lung cancer.

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References

  1. Chen VW, Ruiz BA, Hsieh MC, Wu XC, Ries LA, Lewis DR. Analysis of stage and clinical/prognostic factors for lung cancer from SEER registries: AJCC staging and collaborative stage data collection system. Cancer. 2014;120 Suppl 23:3781–92.

    Article  PubMed  PubMed Central  Google Scholar 

  2. El-Sherief AH, Lau CT, Wu CC, Drake RL, Abbott GF, Rice TW. International association for the study of lung cancer (IASLC) lymph node map: radiologic review with CT illustration. Radiographics. 2014;34:1680–91.

    Article  PubMed  Google Scholar 

  3. Oyewumi MO, Alazizi A, Wehrung D, Manochakian R, Safadi FF. Emerging lung cancer therapeutic targets based on the pathogenesis of bone metastases. Int J Cell Biol. 2014;2014:236246.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Huang Q, Ouyang X. Predictive biochemical-markers for the development of brain metastases from lung cancer: clinical evidence and future directions. Cancer Epidemiol. 2013;37:703–7.

    Article  CAS  PubMed  Google Scholar 

  5. Eichler AF, Chung E, Kodack DP, Loeffler JS, Fukumura D, Jain RK. The biology of brain metastases-translation to new therapies. Nat Rev Clin Oncol. 2011;8:344–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Krishnan K, Khanna C, Helman LJ. The molecular biology of pulmonary metastasis. Thorac Surg Clin. 2006;16:115–24.

    Article  PubMed  Google Scholar 

  7. Schuette W. Treatment of brain metastases from lung cancer: chemotherapy. Lung Cancer. 2004;45 Suppl 2:S253–7.

    Article  PubMed  Google Scholar 

  8. Puduvalli VK. Brain metastases: biology and the role of the brain microenvironment. Curr Oncol Rep. 2001;3:467–75.

    Article  CAS  PubMed  Google Scholar 

  9. Nicolson GL. Paracrine and autocrine growth mechanisms in tumor metastasis to specific sites with particular emphasis on brain and lung metastasis. Cancer Metastasis Rev. 1993;12:325–43.

    Article  CAS  PubMed  Google Scholar 

  10. D'Antonio C, Passaro A, Gori B, Del Signore E, Migliorino MR, Ricciardi S, et al. Bone and brain metastasis in lung cancer: recent advances in therapeutic strategies. Ther Adv Med Oncol. 2014;6:101–14.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Wood SL, Pernemalm M, Crosbie PA, Whetton AD. The role of the tumor-microenvironment in lung cancer-metastasis and its relationship to potential therapeutic targets. Cancer Treat Rev. 2014;40:558–66.

    Article  CAS  PubMed  Google Scholar 

  12. Yamanaka R. Medical management of brain metastases from lung cancer (review). Oncol Rep. 2009;22:1269–76.

    Article  CAS  PubMed  Google Scholar 

  13. Chen G, Davies MA. Emerging insights into the molecular biology of brain metastases. Biochem Pharmacol. 2012;83:305–14.

    Article  CAS  PubMed  Google Scholar 

  14. Nathoo N, Chahlavi A, Barnett GH, Toms SA. Pathobiology of brain metastases. J Clin Pathol. 2005;58:237–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hanibuchi M, Kim SJ, Fidler IJ, Nishioka Y. The molecular biology of lung cancer brain metastasis: an overview of current comprehensions and future perspectives. J Med Investig. 2014;61:241–53.

    Article  Google Scholar 

  16. Spassov DS, Wong CH, Wong SY, Reiter JF, Moasser MM. Trask loss enhances tumorigenic growth by liberating integrin signaling and growth factor receptor cross-talk in unanchored cells. Cancer Res. 2013;73:1168–79.

    Article  CAS  PubMed  Google Scholar 

  17. Spassov DS, Ahuja D, Wong CH, Moasser MM. The structural features of Trask that mediate its anti-adhesive functions. PLoS One. 2011;6:e19154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Spassov DS, Baehner FL, Wong CH, McDonough S, Moasser MM. The transmembrane src substrate Trask is an epithelial protein that signals during anchorage deprivation. Am J Pathol. 2009;174:1756–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Spassov DS, Wong CH, Sergina N, Ahuja D, Fried M, Sheppard D, et al. Phosphorylation of Trask by Src kinases inhibits integrin clustering and functions in exclusion with focal adhesion signaling. Mol Cell Biol. 2011;31:766–82.

    Article  CAS  PubMed  Google Scholar 

  20. Wong CH, Baehner FL, Spassov DS, Ahuja D, Wang D, Hann B, et al. Phosphorylation of the SRC epithelial substrate Trask is tightly regulated in normal epithelia but widespread in many human epithelial cancers. Clin Cancer Res. 2009;15:2311–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lin CY, Chen HJ, Huang CC, Lai LC, Lu TP, Tseng GC, et al. ADAM9 promotes lung cancer metastases to brain by a plasminogen activator-based pathway. Cancer Res. 2014;74:5229–43.

    Article  CAS  PubMed  Google Scholar 

  22. Hansen MC, Nederby L, Henriksen MO, Hansen M, Nyvold CG. Sensitive ligand-based protein quantification using immuno-PCR: a critical review of single-probe and proximity ligation assays. Biotechniques. 2014;56:217–28.

    Article  CAS  PubMed  Google Scholar 

  23. Blokzijl A, Nong R, Darmanis S, Hertz E, Landegren U, et al. Protein biomarker validation via proximity ligation assays. Biochim Biophys Acta. 1844;2014:933–9.

    Google Scholar 

  24. Weibrecht I, Leuchowius KJ, Clausson CM, Conze T, Jarvius M, Howell WM, et al. Proximity ligation assays: a recent addition to the proteomics toolbox. Exp Rev Proteom. 2010;7:401–9.

    Article  CAS  Google Scholar 

  25. Takkunen M, Hukkanen M, Liljeström M, Grenman R, Virtanen I. Podosome-like structures of non-invasive carcinoma cells are replaced in epithelial-mesenchymal transition by actin comet-embedded invadopodia. J Cell Mol Med. 2010;14:1569–93.

    Article  PubMed  Google Scholar 

  26. Sun J, Lu F, He H, Shen J, Messina J, Mathew R, et al. STIM1- and Orai1-mediated Ca2+ oscillation orchestrates invadopodium formation and melanoma invasion. J Cell Biol. 2014;207:535–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Guo A, Villén J, Kornhauser J, Lee KA, Stokes MP, Rikova K, et al. Signaling networks assembled by oncogenic EGFR and c-Met. Proc Natl Acad Sci U S A. 2008;105:692–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Murai R, Tanaka M, Takahashi Y, Kuribayashi K, Kobayashi D, Watanabe N. Stanniocalcin-1 promotes metastasis in a human breast cancer cell line through activation of PI3K. Clin Exp Metastasis. 2014;31:787–94.

    Article  CAS  PubMed  Google Scholar 

  29. Sheridan JT, Gilmore RC, Watson MJ, Archer CB, Tarran R. 17β-Estradiol inhibits phosphorylation of stromal interaction molecule 1 (STIM1) protein: implication for store-operated calcium entry and chronic lung diseases. J Biol Chem. 2013;288:33509–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wang F, Liu DZ, Xu H, Li Y, Wang W, Liu BL, et al. Thapsigargin induces apoptosis by impairing cytoskeleton dynamics in human lung adenocarcinoma cells. Sci World J. 2014;2014:619050.

    Google Scholar 

  31. Hirooka S, Akashi T, Ando N, Suzuki Y, Ishida N, Kurata M, et al. Localization of the invadopodia-related proteins actinin-1 and cortactin to matrix-contact-side cytoplasm of cancer cells in surgically resected lung adenocarcinomas. Pathobiology. 2011;78:10–23.

    Article  CAS  PubMed  Google Scholar 

  32. Wang S, Li E, Gao Y, Wang Y, Guo Z, He J, et al. Study on invadopodia formation for lung carcinoma invasion with a microfluidic 3D culture device. PLoS One. 2013;8:e56448.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Respiratory Medicine, Shaanxi Provincial People’s Hospital, No. 256, Youyi West Road, Beilin District, Xi’an, 710068, Shaanxi, China

    Hua Wu, Li-qun Shang, Rui-lin Chen, Shu-mei Yang, Shui-li Wang, Jun Wang & Gang Sun

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  1. Hua Wu
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  2. Li-qun Shang
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  3. Rui-lin Chen
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Correspondence to Hua Wu.

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Wu, H., Shang, Lq., Chen, Rl. et al. Significance of Trask protein interactions in brain metastatic cohorts of lung cancers. Tumor Biol. 36, 4181–4187 (2015). https://doi.org/10.1007/s13277-015-3053-7

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  • DOI: https://doi.org/10.1007/s13277-015-3053-7

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