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Agent-based model of multicellular tumor spheroid evolution including cell metabolism

  • Fabrizio CleriEmail author
Regular Article
  • 25 Downloads

Abstract.

Computational models aiming at the spatio-temporal description of cancer evolution are a suitable framework for testing biological hypotheses from experimental data, and generating new ones. Building on our recent work (J. Theor. Biol. 389, 146 (2016)) we develop a 3D agent-based model, capable of tracking hundreds of thousands of interacting cells, over time scales ranging from seconds to years. Cell dynamics is driven by a Monte Carlo solver, incorporating partial differential equations to describe chemical pathways and the activation/repression of “genes”, leading to the up- or down-regulation of specific cell markers. Each cell-agent of different kind (stem, cancer, stromal etc.) runs through its cycle, undergoes division, can exit to a dormant, senescent, necrotic state, or apoptosis, according to the inputs from its systemic network. The basic network at this stage describes glucose/oxygen/ATP cycling, and can be readily extended to cancer-cell specific markers. Eventual accumulation of chemical/radiation damage to each cell’s DNA is described by a Markov chain of internal states, and by a damage-repair network, whose evolution is linked to the cell systemic network. Aimed at a direct comparison with experiments of tumorsphere growth from stem cells, the present model will allow to quantitatively study the role of transcription factors involved in the reprogramming and variable radio-resistance of simulated cancer-stem cells, evolving in a realistic computer simulation of a growing multicellular tumorsphere.

Graphical abstract

Keywords

Living systems: Multicellular Systems 

References

  1. 1.
    F. Hirschhaeuser, H. Menne, C. Dittfeld, J. West, W. Mueller-Klieser, L.A. Kunz-Schughart, J. Biotechnol. 148, 3 (2010)CrossRefGoogle Scholar
  2. 2.
    S. Johnson, H. Chen, P.K. Luo, Bio Protoc. 3, e325 (2013)Google Scholar
  3. 3.
    C.H. Lee, C.C. Yu, B.Y. Wang, W.W. Chang, Oncotarget 7, 1215 (2015)Google Scholar
  4. 4.
    F. Pampaloni, E.G. Reynaud, E.H.K. Stelzer, Nat. Rev. Mol. Cell Biol. 8, 839 (2007)CrossRefGoogle Scholar
  5. 5.
    L.B. Weiswald, D. Bellet, V. Dangles-Marie, Neoplasia 17, 1 (2015)CrossRefGoogle Scholar
  6. 6.
    C.M. West, R.M. Sutherland, Radiat. Res. 112, 105 (1987)ADSCrossRefGoogle Scholar
  7. 7.
    P.K. Kreeger, D.A. Lauffenburger, Carcinogenesis 31, 2 (2010)CrossRefGoogle Scholar
  8. 8.
    D. Loessner, J.P. Little, G.J. Pettet, D.W. Hutmacher, J. Cell Sci. 126, 2761 (2013)CrossRefGoogle Scholar
  9. 9.
    A. Sanchez-Reyes, Radiat. Res. 130, 139 (1992)ADSCrossRefGoogle Scholar
  10. 10.
    R.D. Stewart, Radiat. Res. 156, 356 (2001)ADSCrossRefGoogle Scholar
  11. 11.
    A.R. Kansal, S. Torquato, G.R. Harsh, E.A. Chiocca, T.S. Deisboeck, J. Theor. Biol. 203, 367 (2000)CrossRefGoogle Scholar
  12. 12.
    Y. Jiang, J. Pjesivac-Grbovic, C. Cantrell, J.P. Freyer, Biophys. J. 89, 3884 (2005)CrossRefGoogle Scholar
  13. 13.
    T.S. Deisboeck, Z. Wang, P. Macklin, V. Cristini, Annu. Rev. Biomed. Eng. 13, 127 (2011)CrossRefGoogle Scholar
  14. 14.
    Z. Wang, J.D. Butner, R. Kerketta, V. Cristini, T.S. Deisboeck, Semin. Cancer Biol. 30, 70 (2015)CrossRefGoogle Scholar
  15. 15.
    V. Cristini, E.J. Koay, Z. Wang, An Introduction to Physical Oncology, Mathematical and Computational Biology (CRC Press, Boca Raton, FL, 2017)Google Scholar
  16. 16.
    C.S. Hogea, B.T. Murray, J.A. Sethian, J. Math. Biol. 53, 86 (2005)CrossRefGoogle Scholar
  17. 17.
    S.T. Roose, S.J. Chapman, P.K. Maini, SIAM Rev. 49, 179 (2007)ADSMathSciNetCrossRefGoogle Scholar
  18. 18.
    J. Ranft, M. Basan, J. Elgeti, J.F. Joanny, J. Prost, F. Jülicher, Proc. Natl. Acad. Sci. USA 107, 20863 (2010)ADSCrossRefGoogle Scholar
  19. 19.
    A.R. Anderson, M.A. Chaplain, K.A. Rejniak, Single-cell Based Models in Biology and Medicine (Birkhauser Verlag, Basel, 2007)Google Scholar
  20. 20.
    A.S. Silva, R.A. Gatenby, Biol. Direct 5, 25 (2010)CrossRefGoogle Scholar
  21. 21.
    H. Kempf, H. Hatzikirou, M. Bleicher, M. Meyer-Hermann, PLOS Comput. Biol. 9, e1003295 (2013)ADSCrossRefGoogle Scholar
  22. 22.
    G.G. Powathil, D.J. Adamson, M.A. Chaplain, PLOS Comput. Biol. 9, e1003120 (2013)ADSCrossRefGoogle Scholar
  23. 23.
    M. Tomezak, C. Abbadie, E. Lartigau, F. Cleri, J. Theor. Biol. 389, 146 (2016)CrossRefGoogle Scholar
  24. 24.
    V. Turinetto, L. Orlando, C. Giachino, Int. J. Mol. Sci. 18, 1952 (2017)CrossRefGoogle Scholar
  25. 25.
    P.M. Altrock, L.L. Liu, F. Michor, Nat. Rev. Cancer 15, 730 (2015)CrossRefGoogle Scholar
  26. 26.
    A.M. Kellerer, in The Dosimetry of Ionizing Radiation, edited by K. Kase, B. Bjarngard, F. Attix (Academic Press, Orlando (USA), 1985) pp. 78--162Google Scholar
  27. 27.
    N. Albright, Radiat. Res. 118, 1 (1989)ADSCrossRefGoogle Scholar
  28. 28.
    R.K. Sachs, L. Hlatky, P. Hahnfeldt, P.L. Chen, Radiat. Res. 124, 216 (1990)ADSCrossRefGoogle Scholar
  29. 29.
    R. Bridson, Fast Poisson disk sampling in arbitrary dimensions, in ACM SIGGRAPH 2007, San Diego, ACM Trans. Graph. (ACM, New York, 2007) No. 22Google Scholar
  30. 30.
    J.J. Casciari, S.V. Sotirchos, R.M. Sutherland, Cell Prolif. 25, 1 (1992)CrossRefGoogle Scholar
  31. 31.
    W. Mueller-Klieser, J.P. Freyer, R.M. Sutherland, Br. J. Cancer 53, 345 (1986)CrossRefGoogle Scholar
  32. 32.
    R. Heinrich, S.M. Rapoport, T.A. Rapoport, Prog. Biophys. Mol. Biol. 32, 1 (1977)CrossRefGoogle Scholar
  33. 33.
    R. Heinrich, S. Schuster, The Regulation of Cellular Systems (Chapman & Hall, New York, 2012)Google Scholar
  34. 34.
    U. Alon, Nat. Rev. Genet. 8, 450 (2007)CrossRefGoogle Scholar
  35. 35.
    K. Thurley, L.F. Wu, S.J. Altschuler, Cell Syst. 6, 355 (2018)CrossRefGoogle Scholar
  36. 36.
    D.A. Bradbury, T.D. Simmons, K.J. Slater, S.P.M. Crouch, J. Immunol. Methods 240, 79 (2000)CrossRefGoogle Scholar
  37. 37.
    E.N. Maldonado, J.J. LeMasters, Mitochondrion 19A, 78 (2014)CrossRefGoogle Scholar
  38. 38.
    A. Pannuti, K. Foreman, P. Rizzo, C. Osipo, T. Golde, B. Osborne, L. Miele, Clin. Cancer Res. 16, 3141 (2010)CrossRefGoogle Scholar
  39. 39.
    P.K. Lo, D. Kanojia, X. Liu, U.P. Singh, F.G. Berger, Q. Wang, H. Chen, Oncogene 31, 2614 (2012)CrossRefGoogle Scholar
  40. 40.
    J.C. Liu, T. Deng, R.S. Lehal, J. Kim, E. Zacksenhaus, Cancer Res. 67, 8671 (2007)CrossRefGoogle Scholar
  41. 41.
    J. Han, H. Chang, O. Giricz, G.Y. Lee, F.L. Baehner, J.W. Gray, M.J. Bissell, P.A. Kenny, B. Parvin, PLOS Comput. Biol. 6, e1000684 (2010)ADSCrossRefGoogle Scholar
  42. 42.
    A. Carruthers, Physiol. Rev. 70, 1135 (1990)CrossRefGoogle Scholar
  43. 43.
    B.J. Papenburg, L. Vogelaar, L.A. Bolhuis-Versteeg, R.G. Lammertink, D. Stamatialis, M. Wessling, Biomaterials 28, 1998 (2007)CrossRefGoogle Scholar
  44. 44.
    C. Boss, E. Meurville, J.M. Sallese, P. Ryser, J. Membr. Sci. 401-402, 217 (2012)CrossRefGoogle Scholar
  45. 45.
    H. Suhaimi, S. Wang, T. Thornton, D.B. Das, Chem. Eng. Sci. 126, 244 (2015)CrossRefGoogle Scholar
  46. 46.
    I.A. Rodriguez-Brenes, N.L. Komarova, D. Wodarz, Trends Ecol. Evol. 28, 597 (2013)CrossRefGoogle Scholar
  47. 47.
    D.R. Grimes, C. Kelly, K. Bloch, M. Partridge, J. R. Soc. Interface 11, 1124 (2013)Google Scholar
  48. 48.
    J. Crank, The Mathematics of Diffusion (Clarendon Press, Oxford, 1975)Google Scholar
  49. 49.
    J. Folkman, M. Hochberg, J. Exp. Med. 138, 745 (1973)CrossRefGoogle Scholar
  50. 50.
    J.P. Freyer, Cancer Res. 48, 2432 (1988)Google Scholar
  51. 51.
    D.I. Wallace, X. Guo, Front. Oncol. 3, 51 (2013)CrossRefGoogle Scholar
  52. 52.
    E. Marx, W. Mueller-Klieser, P. Vaupel, Int. J. Radiat. Oncol. Biol. Physiol. 14, 947 (1988)CrossRefGoogle Scholar
  53. 53.
    J. Landry, J.P. Freyer, R.M. Sutherland, J. Cell Physiol. 106, 23 (1981)CrossRefGoogle Scholar
  54. 54.
    K. Sakata, S. Okada, H. Majima, N. Suzuki, Strahlenther. Onkol. 167, 723 (1991)Google Scholar
  55. 55.
    G. Hamilton, B. Rath, J. Cancer Metastasis. Treat. 2, 446 (2016)CrossRefGoogle Scholar
  56. 56.
    J.F. Modiano, M.G. Ritt, J. Wojcieszyn, R. Smith, DNA Cell Biol. 18, 357 (1999)CrossRefGoogle Scholar
  57. 57.
    C.H. Choresca, O.J. Koo, H.J. Oh, S.G. Hong, D.K. Gomez, J.H. Kim, B.C. Lee, S.C. Park, Cell Biol. Int. 33, 65 (2009)CrossRefGoogle Scholar
  58. 58.
    S.A. Menchón, C.A. Condat, Eur. Biophys. J. 38, 479 (2009)CrossRefGoogle Scholar
  59. 59.
    G. Hemlinger, P.A. Netti, H. Lichtenbeld, R. Melder, R.K. Jain, Nat. Biotechnol. 15, 778 (1997)CrossRefGoogle Scholar
  60. 60.
    A. Chakrabarti, S. Verbridge, A.D. Stroock, C. Fischbach, J.D. Varner, Ann. Biomed. Eng. 40, 2488 (2012)CrossRefGoogle Scholar

Copyright information

© EDP Sciences, Società Italiana di Fisica and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Institut d’ElectroniqueMicroélectronique et Nanotechnologie (IEMN, UMR Cnrs 8520)Villeneuve d’AscqFrance
  2. 2.Departement de PhysiqueUniversité de LilleVilleneuve d’AscqFrance

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