A collective route to metastasis: Seeding by tumor cell clusters

Abstract

Despite decades of study, there are still many unanswered questions about metastasis, the process by which a localized cancer becomes a systemic disease. One of these questions is the nature of the tumor cells that give rise to metastases. Although conventional models suggest that metastases are seeded by single cells from the primary tumor, there is growing evidence that seeding requires the collective action of tumor cells traveling together in clusters. Here, we review this evidence, which comes from analysis of both experimental models and patient samples. We present a model of metastatic dissemination that highlights the activities of clusters of tumor cells that retain and require their epithelial properties.

Fig. 1.. Lineage analysis to identify the metastatic seeds in mouse models.

(A) A primary tumor composed of cancer cells of two different colors can generate single cells, single-colored clusters, and multicolored clusters. Single cells and single-colored clusters will generate single-colored metastases. In contrast, multicolored clusters generate multicolored metastases. The number of different colors observed in a metastasis can therefore be used to infer the cellular properties of its seed. (B) Representative example of a multicolored lung metastasis in a mouse model of breast cancer [adapted from (14)].

Fig. 2.. A model for metastatic spread that is based on collective dissemination of epithelial tumor cell clusters.

This model posits that primary tumor cells invade, circulate, and seed tumor growth at distant sites as collective units and that these activities require their expression of epithelial genes, such as K14. After arriving in the secondary organ (the lung), the predominantly K14⁺ seed (blue) from a primary breast cancer expands to form predominantly K14⁻ macrometastases (red). Further details are available in (14, 16).