A human organotypic microfluidic tumor model permits investigation of the interplay between patient-derived fibroblasts and breast cancer cells

Danh D. Truong, Alexander Kratz, Jin G. Park, Eric S. Barrientos, Harpinder Saini, Toan Nguyen, Barbara Pockaj, Ghassan Mouneimne, Joshua LaBaer, Mehdi Nikkhah

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Tumor-stroma interactions significantly influence cancer cell metastasis and disease progression. These interactions are partly comprised of the cross-talk between tumor and stromal fibroblasts, but the key molecular mechanisms within the cross-talk that govern cancer invasion are still unclear. Here, we adapted our previously developed microfluidic device as a 3Din vitro organotypic model to mechanistically study tumor- stroma interactions by mimicking the spatial organization of the tumor microenvironment on a chip. We cocultured breast cancer and patient-derived fibroblast cells in 3D tumor and stroma regions, respectively, and combined functional assessments, including cancer cell migration, with transcriptome profiling to unveil the molecular influence of tumor-stroma cross-talk on invasion. This led to the observation that cancerassociated fibroblasts (CAF) enhanced invasion in 3D by inducing expression of a novel gene of interest, glycoprotein nonmetastatic B (GPNMB), in breast cancer cells, resulting in increased migration speed. Importantly, knockdown of GPNMB blunted the influence of CAF on enhanced cancer invasion. Overall, these results demonstrate the ability of our model to recapitulate patient-specific tumor microenvironments to investigate the cellular and molecular consequences of tumor-stroma interactions. Significance: An organotypic model of tumor-stroma interactions on a microfluidic chip reveals that CAFs promote invasion by enhancing expression of GPNMB in breast cancer cells.

Original languageEnglish (US)
Pages (from-to)3139-3151
Number of pages13
JournalCancer Research
Volume79
Issue number12
DOIs
StatePublished - Jun 15 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Truong, D. D., Kratz, A., Park, J. G., Barrientos, E. S., Saini, H., Nguyen, T., Pockaj, B., Mouneimne, G., LaBaer, J., & Nikkhah, M. (2019). A human organotypic microfluidic tumor model permits investigation of the interplay between patient-derived fibroblasts and breast cancer cells. Cancer Research, 79(12), 3139-3151. https://doi.org/10.1158/0008-5472.CAN-18-2293