Linking changes in epithelial morphogenesis to cancer mutations using computational modeling

Katarzyna A. Rejniak, Shizhen E. Wang, Nicole S. Bryce, Hang Chang, Bahram Parvin, Jerome Jourquin, Lourdes Estrada, Joe W. Gray, Carlos L. Arteaga, Alissa M. Weaver, Vito Quaranta, Alexander R.A. Anderson

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Most tumors arise from epithelial tissues, such as mammary glands and lobules, and their initiation is associated with the disruption of a finely defined epithelial architecture. Progression from intraductal to invasive tumors is related to genetic mutations that occur at a subcellular level but manifest themselves as functional and morphological changes at the cellular and tissue scales, respectively. Elevated proliferation and loss of epithelial polarization are the two most noticeable changes in cell phenotypes during this process. As a result, many three-dimensional cultures of tumorigenic clones show highly aberrant morphologies when compared to regular epithelial monolayers enclosing the hollow lumen (acini). In order to shed light on phenotypic changes associated with tumor cells, we applied the bio-mechanical IBCell model of normal epithelial morphogenesis quantitatively matched to data acquired from the non-tumorigenic human mammary cell line, MCF10A. We then used a high-throughput simulation study to reveal how modifications in model parameters influence changes in the simulated architecture. Three parameters have been considered in our study, which define cell sensitivity to proliferative, apoptotic and cell-ECM adhesive cues. By mapping experimental morphologies of four MCF10A-derived cell lines carrying different oncogenic mutations onto the model parameter space, we identified changes in cellular processes potentially underlying structural modifications of these mutants. As a case study, we focused on MCF10A cells expressing an oncogenic mutant HER2-YVMA to quantitatively assess changes in cell doubling time, cell apoptotic rate, and cell sensitivity to ECM accumulation when compared to the parental non-tumorigenic cell line. By mapping in vitro mutant morphologies onto in silico ones we have generated a means of linking the morphological and molecular scales via computational modeling. Thus, IBCell in combination with 3D acini cultures can form a computational/experimental platform for suggesting the relationship between the histopathology of neoplastic lesions and their underlying molecular defects.

Original languageEnglish (US)
Article numbere1000900
JournalPLoS Computational Biology
Volume6
Issue number8
DOIs
StatePublished - Aug 1 2010

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Modeling and Simulation
  • Ecology
  • Molecular Biology
  • Genetics
  • Cellular and Molecular Neuroscience
  • Computational Theory and Mathematics

Fingerprint Dive into the research topics of 'Linking changes in epithelial morphogenesis to cancer mutations using computational modeling'. Together they form a unique fingerprint.

  • Cite this

    Rejniak, K. A., Wang, S. E., Bryce, N. S., Chang, H., Parvin, B., Jourquin, J., Estrada, L., Gray, J. W., Arteaga, C. L., Weaver, A. M., Quaranta, V., & Anderson, A. R. A. (2010). Linking changes in epithelial morphogenesis to cancer mutations using computational modeling. PLoS Computational Biology, 6(8), [e1000900]. https://doi.org/10.1371/journal.pcbi.1000900