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 4

Trailblazer cells express higher levels of genes required for collective invasion.

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Trailblazer cells express higher levels of genes required for collective...
(A) Heat map showing the expression of the 26 genes that are specifically elevated in SUM159 and HCC1143 trailblazer cells. Expression is the mean of 2 biological replicates. (B) The relative invasion of SUM159 trailblazer cells ≥50 μm into the ECM. The number of invasive cells is normalized to the total cell number in the field of view for each condition. Relative invasion is the normalized invasive value of the test condition divided by the normalized invasion value of the control cells from the experimental replicate (median ± range, n = 3). The dashed red box indicates genes that were further investigated. Images are representative x-z views of SUM159 trailblazer invasion into ECM after transfection with the indicated siRNAs. For images of additional siRNA-transfected cells, see Supplemental Figure 5. Scale bar: 50 μm. (C) The relative invasion of SUM229 trailblazer cells ≥40 μm into the ECM normalized to the total cell number and compared with control cells (mean ± SD, n = 3). (D) Heat map showing that genes required for trailblazer cell invasion are highly expressed in 578T cells. Expression is the mean of 2 biological replicates. (E) The relative invasion of 578T cells ≥50 μm into the ECM normalized to the total cell number and compared with control cells (mean ± SD, n = 3).