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Gene expression signatures of site-specificity in cancer metastases

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Abstract

We have previously shown that metastases are generally characterized by a core program of gene expression that induces the oxidative energy metabolism, activates vascularization/tissue remodeling, silences extracellular matrix interactions, and alters ion homeostasis. This core program distinguishes metastases from their originating primary tumors as well as from their target host tissues. We hypothesized that organ preference is reflected in additional, site-selective components within the metastatic gene expression programs. Expanding our prior analysis of 653 human gene expression profiles plus data from a murine model, we find that the release from the primary tumor is associated with a suppression of functions that are important for the identity of the organ of origin, such as a down-regulation of steroid hormone responsiveness in the disseminated foci derived from prostate cancer. Metastases adjust to their target microenvironment by up-regulating—even overexpressing—genes and genetic programs that are characteristic of that organ. Finally, alterations in RNA and protein processing as well as immune deviation are common. In the clinic, metastases are mostly treated with the chemotherapy protocols devised for their primary tumors. Adjustments that account for the gene expression differences between primary and metastatic cancers have the potential to improve the currently dismal success rates.

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References

  1. Weber GF (2007) Molecular mechanisms of cancer. Springer, Dordrecht

    Google Scholar 

  2. Fidler IJ (1975) Biological behavior of malignant melanoma cells correlated to their survival in vivo. Cancer Res 35:218–224

    CAS  PubMed  Google Scholar 

  3. Weber GF, Ashkar S (2000) Stress response genes—the genes that make cancer metastasize. J Mol Med 78:404–408

    CAS  PubMed  Google Scholar 

  4. Zhang G, He B, Weber GF (2003) Growth factor signaling induces metastasis genes in transformed cells. A molecular connection between Akt kinase and osteopontin in breast cancer. Mol Cell Biol 23:6507–6519

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Whalen KA, Weber GF, Benjamin TL, Schaffhausen BS (2008) Polyomavirus middle T antigen induces the transcription of osteopontin, a gene important for migration of transformed cells. J Virol 82:4946–4954

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Mesa C Jr, Mirza M, Mitsutake N, Sartor M, Medvedovic M, Tomlinson C, Knauf JA, Weber GF, Fagin JA (2006) Conditional activation of the RET/PTC3 and B-RAFV600E oncoproteins in thyroid cells is associated with unique patterns of gene expression that predict distinct functional properties and a preferential role of BRAF in extracellular matrix remodeling. Cancer Res 66:6521–6529

    CAS  PubMed  Google Scholar 

  7. Weber GF (2008) Molecular mechanisms of metastasis. Cancer Lett 270:181–190

    CAS  PubMed  Google Scholar 

  8. Turpeenniemi-Hujanen T, Thorgeirsson UP, Hart IR, Grant SS, Liotta LA (1985) Expression of collagenase IV (basement membrane collagenase) activity in murine tumor cell hybrids that differ in metastatic potential. J Natl Cancer Inst 75:99–103

    CAS  PubMed  Google Scholar 

  9. Matrisian LM, Bowden GT, Krieg P, Furstenberger G, Briand JP, Leroy P, Breathnach R (1986) The mRNA coding for the secreted protease transin is expressed more abundantly in malignant than in benign tumors. Proc Natl Acad Sci USA 83:9413–9417

    CAS  PubMed  Google Scholar 

  10. Günthert U, Hofmann M, Rudy W, Reber S, Zöller M, Hausmann I, Matzku S, Wenzel A, Ponta H, Herrlich P (1991) A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell 65:13–24

    PubMed  Google Scholar 

  11. Senger DR, Perruzzi CA, Papadopoulos A (1989) Elevated expression of secreted phosphoprotein I (osteopontin, 2ar) as a consequence of neoplastic transformation. Anticancer Res 9:1291–1299

    CAS  PubMed  Google Scholar 

  12. Steeg PS, Bevilacqua G, Kopper L (1988) Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst 80:200–204

    CAS  PubMed  Google Scholar 

  13. Alvarez OA, Carmichael DF, DeClerck YA (1990) Inhibition of collagenolytic activity and metastasis of tumor cells by a recombinant human tissue inhibitor of metalloproteinases. J Natl Cancer Inst 82:589–595

    CAS  PubMed  Google Scholar 

  14. Hartung F, Wang Y, Aronow B, Weber GF (2017) A core program of gene expression characterizes cancer metastases. Oncotarget 8:102161–102175

    PubMed  PubMed Central  Google Scholar 

  15. Mueller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E, Zlotnik A (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410:50–56

    Google Scholar 

  16. Streeter PR, Berg EL, Rouse BT, Bargatze RF, Butcher EC (1988) A tissue-specific endothelial cell molecule involved in lymphocyte homing. Nature 331:41–46

    CAS  PubMed  Google Scholar 

  17. Ruoslahti E (2000) Targeting tumor vasculature with homing peptides from phage display. Semin Cancer Biol 10:435–442

    CAS  PubMed  Google Scholar 

  18. Lê S, Josse J, Husson F (2008) FactoMineR: an R package for multivariate analysis. J Stat Softw 25:1–18

    Google Scholar 

  19. Lê Cao K-A, Rohart F, McHugh L, Korn O, Wells CA (2014) YuGene: a simple approach to scale gene expression data derived from different platforms for integrated analyses. Genomics 103:239–251

    PubMed  Google Scholar 

  20. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8:e1000412

    PubMed  PubMed Central  Google Scholar 

  21. Huang S, Eleniste PP, Wayakanon K, Mandela P, Eipper BA, Mains RE, Allen MR, Bruzzaniti A (2014) The Rho-GEF Kalirin regulates bone mass and the function of osteoblasts and osteoclasts. Bone 60:235–245

    CAS  PubMed  Google Scholar 

  22. Church RH, Ali I, Tate M, Lavin D, Krishnakumar A, Kok HM, Hombrebueno JR, Dunne PD, Bingham V, Goldschmeding R, Martin F, Brazil DP (2017) Gremlin1 plays a key role in kidney development and renal fibrosis. Am J Physiol Renal Physiol 312:F1141–F1157

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Zhifang M, Liang W, Wei Z, Bin H, Rui T, Nan W, Shuhai Z (2015) The androgen receptor plays a suppressive role in epithelial- mesenchymal transition of human prostate cancer stem progenitor cells. BMC Biochem 16:13

    PubMed  PubMed Central  Google Scholar 

  24. Zhu ML, Kyprianou N (2010) Role of androgens and the androgen receptor in epithelial-mesenchymal transition and invasion of prostate cancer cells. FASEB J 24:769–777

    CAS  PubMed  PubMed Central  Google Scholar 

  25. de Launoit Y, Baert JL, Chotteau-Lelievre A, Monte D, Coutte L, Mauen S, Firlej V, Degerny C, Verreman K (2006) The Ets transcription factors of the PEA3 group: transcriptional regulators in metastasis. Biochim Biophys Acta 1766:79–87

    PubMed  Google Scholar 

  26. Selvaraj A, Prywes R (2004) Expression profiling of serum inducible genes identifies a subset of SRF target genes that are MKL dependent. BMC Mol Biol 5:13

    PubMed  PubMed Central  Google Scholar 

  27. Agarwal P, Verzi MP, Nguyen T, Hu J, Ehlers ML, McCulley DJ, Xu SM, Dodou E, Anderson JP, Wei ML, Black BL (2011) The MADS box transcription factor MEF2C regulates melanocyte development and is a direct transcriptional target and partner of SOX10. Development 138:2555–2565

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Schummer P, Kuphal S, Vardimon L, Bosserhoff AK, Kappelmann M (2016) Specific c-Jun target genes in malignant melanoma. Cancer Biol Ther 17:486–497

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Efimenko E, Padua MB, Manuylov NL, Fox SC, Morse DA, Tevosian SG (2013) The transcription factor GATA4 is required for follicular development and normal ovarian function. Dev Biol 381:144–158

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Heikinheimo M, Ermolaeva M, Bielinska M, Rahman NA, Narita N, Huhtaniemi IT, Tapanainen JS, Wilson DB (1997) Expression and hormonal regulation of transcription factors GATA-4 and GATA-6 in the mouse ovary. Endocrinology 138:3505–3514

    CAS  PubMed  Google Scholar 

  31. Vihma H, Pruunsild P, Timmusk T (2008) Alternative splicing and expression of human and mouse NFAT genes. Genomics 92:279–291

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Rosen CJ, Ackert-Bicknell C, Rodriguez JP, Pino AM (2009) Marrow fat and the bone microenvironment: developmental, functional, and pathological implications. Crit Rev Eukaryot Gene Expr 19:109–124

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Tian L, Yu X (2015) Lipid metabolism disorders and bone dysfunction—interrelated and mutually regulated (Review). Mol Med Rep 12:783–794

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Li M, Li A, Zhou S, Xu Y, Xiao Y, Bi R, Yang W (2018) Heterogeneity of PD-L1 expression in primary tumors and paired lymph node metastases of triple negative breast cancer. BMC Cancer 18:4

    PubMed  PubMed Central  Google Scholar 

  35. Manson QF, Schrijver WAME, Ter Hoeve ND, Moelans CB, van Diest PJ (2019) Frequent discordance in PD-1 and PD-L1 expression between primary breast tumors and their matched distant metastases. Clin Exp Metastasis 36:29–37

    CAS  PubMed  Google Scholar 

  36. Bissonnette RP, Echeverri F, Mahboubi A, Green DR (1992) Apoptotic cell death induced by c-myc is inhibited by bcl-2. Nature 359:552–554

    CAS  PubMed  Google Scholar 

  37. Koskinen PJ, Alitalo K (1993) Role of myc amplification and overexpression in cell growth, differentiation and death. Semin Cancer Biol 4:3–12

    CAS  PubMed  Google Scholar 

  38. Weber GF (2016) Metabolism in cancer metastasis. Int J Cancer 138:2061–2066

    CAS  PubMed  Google Scholar 

  39. Salami J, Crews CM (2017) Waste disposal—an attractive strategy for cancer therapy. Science 355:1163–1167

    CAS  PubMed  Google Scholar 

  40. Kaplan RN, Riba RD, Zacharoulis S (2005) VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820–827

    CAS  PubMed  PubMed Central  Google Scholar 

  41. McAllister SS, Gifford AM, Greiner AL, Kelleher SP, Saelzler MP, Ince TA, Reinhardt F, Harris LN, Hylander BL, Repasky EA, Weinberg RA (2008) Systemic endocrine instigation of indolent tumor growth requires osteopontin. Cell 133:994–1005

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Hiratsuka S, Watanabe A, Sakurai Y, Akashi-Takamura S, Ishibashi S, Miyake K, Shibuya M, Akira S, Aburatani H, Maru Y (2008) The S100A8-serum amyloid A3-TLR4 paracrine cascade establishes a pre-metastatic phase. Nature Cell Biol 10:1349–1355

    CAS  PubMed  Google Scholar 

  43. Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, Molina H, Kohsaka S, Di Giannatale A, Ceder S, Singh S, Williams C, Soplop N, Uryu K, Pharmer L, King T, Bojmar L, Davies AE, Ararso Y, Zhang T, Zhang H, Hernandez J, Weiss JM, Dumont-Cole VD, Kramer K, Wexler LH, Narendran A, Schwartz GK, Healey JH, Sandstrom P, Labori KJ, Kure EH, Grandgenett PM, Hollingsworth MA, de Sousa M, Kaur S, Jain M, Mallya K, Batra SK, Jarnagin WR, Brady MS, Fodstad O, Muller V, Pantel K, Minn AJ, Bissell MJ, Garcia BA, Kang Y, Rajasekhar VK, Ghajar CM, Matei I, Peinado H, Bromberg J, Lyden D (2015) Tumor exosome integrins determine organotropic metastasis. Nature 527:329–335

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Bae JS, Oh AR, Lee HJ, Ahn YH, Cha JY (2016) Hepatic Elovl6 gene expression is regulated by the synergistic action of ChREBP and SREBP-1c. Biochem Biophys Res Commun 478:1060–1066

    CAS  PubMed  Google Scholar 

  45. Liu Z, Ukomadu C (2008) Fibrinogen-like protein 1, a hepatocyte derived protein is an acute phase reactant. Biochem Biophys Res Commun 365:729–734

    CAS  PubMed  Google Scholar 

  46. Sheftel AD, Stehling O, Pierik AJ, Elsässer HP, Mühlenhoff U, Webert H, Hobler A, Hannemann F, Bernhardt R, Lill R (2010) Humans possess two mitochondrial ferredoxins, Fdx1 and Fdx2, with distinct roles in steroidogenesis, heme, and Fe/S cluster biosynthesis. Proc Natl Acad Sci USA 107:11775–11780

    CAS  PubMed  Google Scholar 

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Acknowledgements

This research was supported by DOD grant PR094070 to GFW. The breast cancer portion also received support from the Marlene Harris-Ride Cincinnati/Pilot Program to GFW. We are thankful to Conover Talbot, The Johns Hopkins School of Medicine, Institute for Basic Biomedical Sciences, for the principal component analysis.

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Authors and Affiliations

  1. University of Cincinnati Academic Health Center, Cincinnati, OH, USA

    Franz Hartung & Georg F. Weber

  2. Bioinformatics Centre, Savitribai Phule Pune University, Pune, Maharashtra, India

    Aditya Patil & Rohan J. Meshram

  3. James L. Winkle College of Pharmacy, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267-0514, USA

    Georg F. Weber

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  1. Franz Hartung
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Correspondence to Georg F. Weber.

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Hartung, F., Patil, A., Meshram, R.J. et al. Gene expression signatures of site-specificity in cancer metastases. Clin Exp Metastasis 37, 159–171 (2020). https://doi.org/10.1007/s10585-019-09995-w

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