An epigenetically distinct breast cancer cell subpopulation promotes collective invasion
Jill M. Westcott, Amanda M. Prechtl, Erin A. Maine, Tuyen T. Dang, Matthew A. Esparza, Han Sun, Yunyun Zhou, Yang Xie, Gray W. Pearson
Jill M. Westcott, Amanda M. Prechtl, Erin A. Maine, Tuyen T. Dang, Matthew A. Esparza, Han Sun, Yunyun Zhou, Yang Xie, Gray W. Pearson
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Research Article Oncology

An epigenetically distinct breast cancer cell subpopulation promotes collective invasion

Abstract

Tumor cells can engage in a process called collective invasion, in which cohesive groups of cells invade through interstitial tissue. Here, we identified an epigenetically distinct subpopulation of breast tumor cells that have an enhanced capacity to collectively invade. Analysis of spheroid invasion in an organotypic culture system revealed that these “trailblazer” cells are capable of initiating collective invasion and promote non-trailblazer cell invasion, indicating a commensal relationship among subpopulations within heterogenous tumors. Canonical mesenchymal markers were not sufficient to distinguish trailblazer cells from non-trailblazer cells, suggesting that defining the molecular underpinnings of the trailblazer phenotype could reveal collective invasion-specific mechanisms. Functional analysis determined that DOCK10, ITGA11, DAB2, PDFGRA, VASN, PPAP2B, and LPAR1 are highly expressed in trailblazer cells and required to initiate collective invasion, with DOCK10 essential for metastasis. In patients with triple-negative breast cancer, expression of these 7 genes correlated with poor outcome. Together, our results indicate that spontaneous conversion of the epigenetic state in a subpopulation of cells can promote a transition from in situ to invasive growth through induction of a cooperative form of collective invasion and suggest that therapeutic inhibition of trailblazer cell invasion may help prevent metastasis.

Authors

Jill M. Westcott, Amanda M. Prechtl, Erin A. Maine, Tuyen T. Dang, Matthew A. Esparza, Han Sun, Yunyun Zhou, Yang Xie, Gray W. Pearson

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Figure 7

The trailblazer signature gene DOCK10 is required for metastasis.

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The trailblazer signature gene DOCK10 is required for metastasis. (A) Re...
(A) Representative bioluminescence imaging of control and DOCK10 shRNA–expressing SUM159 trailblazer-Luc-GFP primary tumors. Graph shows the relative photon flux of the primary tumors (mean ± SD, control = 7 mice, DOCK10 shRNA = 8 mice). NS, unpaired Student’s t test. (B) Representative bioluminescence imaging (BLI) and fluorescent imaging of the lungs from mice bearing control and DOCK10 shRNA–expressing SUM159 trailblazer-Luc-GFP primary tumors. Images show bioluminescence imaging of lungs immediately after mice were sacrificed and GFP expression of SUM159 trailblazer cells in the lungs immediately after mice were sacrificed (control = 7 mice, DOCK10 shRNA = 8 mice; scale bar: 100 μm) as well as lungs immunostained with anti-GFP antibody and counterstained with phalloidin. (control = 7 mice, DOCK10 shRNA = 8 mice; scale bar: 50 μm). Graphs show the relative photon flux and number of micrometastases in the lungs normalized to the photon flux of the corresponding primary tumor (mean ± SD, control = 7 mice, DOCK10 shRNA = 8 mice). ***P < 0.001, Mann Whitney U test.