An epigenetically distinct breast cancer cell subpopulation promotes collective invasion
Jill M. Westcott, … , Yang Xie, Gray W. Pearson
Jill M. Westcott, … , Yang Xie, Gray W. Pearson
Published May 1, 2015; First published April 6, 2015
Citation Information: J Clin Invest. 2015;125(5):1927-1943. https://doi.org/10.1172/JCI77767.
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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 1

Breast cancer cell lines contain subpopulations of invasive trailblazer and noninvasive opportunist cells.

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Breast cancer cell lines contain subpopulations of invasive trailblazer ...
(A) Representative images of breast cancer spheroids in organotypic culture stained as indicated (n = 3). Masks show the outline of the spheroids. Inset regions are indicated by dashed boxes. Solid arrows identify representative invasive trailblazer spheroids. Arrows with dashed tails identify representative noninvasive opportunist spheroids. Scale bar: 50 μm. PR, progesterone receptor. (B) The percentage of invasive trailblazer spheroids in each cell line. Error bars indicate SD, n = 3. *P < 0.05, ***P < 0.001, unpaired Student’s t test, compared with T47D. (C) Representative H&E-stained primary breast tumors. Arrows indicate patterns of tumor organization that are consistent with collective invasion. Scale bar: 50 μm. (D) Representative images of SUM159 spheroids (day 5) stained as indicated (n = 3). Inset regions are indicated by dashed boxes. Solid arrows indicate where collagen I is being reorganized into parallel tracks by trailblazer cells. Arrows with dashed tails indicate where collagen I is arranged perpendicular to the edge of the noninvasive opportunist spheroid. Scale bar: 50 μm. (E) Time-lapse phase images of the SUM159 spheroids and cell displacement over 18 hours (mean ± SD, n = 3, 15 spheroids total per condition). Solid arrows indicate a leading cell. The arrow with a dotted tail indicates a following cell. Scale bar: 50 μm. **P < 0.01, unpaired Student’s t test.