Blazing the trail for metastasis
Metastasis of cancer cells from the primary tumor site is associated with advanced stage disease and poor clinical outcomes. Collective invasion is a process by which tumor cells migrate through a shared path through the epithelial extracellular matrix (ECM), leading to tumor cell dissemination throughout the body. This process is extremely aggressive and very little is known about how it is mediated. Jill Westcott, Amanda Prechtl, and colleagues at the University of Texas Southwestern Medical Center examined breast cancer cell spheroids in organotypic culture and identified cell populations that promote collective invasion by forming long cellular protrusions (LCPs) through the ECM, allowing migration from the spheroid. These trailblazer cells were epigenetically distinct from other migratory cells within the clonal population. Paths created by trailblazers allowed less invasive opportunist cells to migrate into the ECM. Moreover, coinjection of trailblazer cells promoted collective invasion of a typically noninvasive breast cancer in a murine xenograft model. Microarray analysis and siRNA-mediated genetic depletion identified a 7 gene signature that is upregulated in trailblazer cells and required for trailblazer-induced collective invasion. Importantly, increased expression of this gene signature correlated with shorter recurrence free and overall survival in patients with triple negative breast cancer. Several of the genes identified were required for trailblazer-induced LCP formation. In an orthotopic xenograft murine model of breast cancer, knockdown of the trailblazer-associated gene DOCK10 inhibited metastatic spread to the lung. The results of this study suggest that inhibition of trailblazer cell invasion may serve as a therapeutic approach to prevent breast cancer metastasis. The accompanying movie shows the invasion dynamics of breast cancer spheroids in organotypic culture. Spheroids are composed of trailblazer cells, opportunist cells, or a combination of the 2 cell types.
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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
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
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)