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 6

Multiple trailblazer genes are necessary for LCP formation.

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Multiple trailblazer genes are necessary for LCP formation. (A) SUM159 t...
(A) SUM159 trailblazer cells transfected with the indicated siRNAs were plated onto a layer of ECM for 24 hours and stained. Scale bar: 50 μm. Graph shows the relative length of LCPs (mean + SD of ≥20 cells, n = 3). (B) Invasion of SUM159 trailblazer cells transfected with the indicated siRNAs. Scale bar: 50 μm. Graph shows relative invasion (mean + SD, n = 3). (C) Collective invasion of SUM159 opportunist CDC42Q61L cells, as shown in B. Graph shows relative invasion compared with control SUM159 trailblazer cells (mean + SD, n = 3). (D) Relative invasion of SUM159 trailblazer and SUM159 trailblazer CDC42Q61L cells transfected with the indicated siRNAs (mean + SD, n = 3). (E) SUM159 trailblazer cells transfected with the indicated siRNAs were plated onto a layer of ECM for 24 hours and stained. Scale bar: 50 μm. Graph shows the relative length of LCPs (mean ± SD of ≥20 cells, n = 3). Horizontal bars indicate the medians, boxes indicate 25th to 75th percentiles, and whiskers indicate minimum and maximum. (F) Representative images of the movement of SUM159 trailblazer cells transfected with the indicated siRNAs over a 14-hour time period in monolayer culture. The color indicates the time period within the 14 hours of imaging. Scale bar: 50 μm. Graph shows the displacement of cells over time (mean ± SD, n = 3). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001, unpaired Student’s t test.