Leading malignant cells initiate collective epithelial cell invasion in a three-dimensional heterotypic tumor spheroid model
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Solid tumors consist of genetically and phenotypically diverse subpopulations of cancer cells with unique capacities for growth, differentiation, and invasion. While the molecular and microenvironmental bases for heterogeneity are increasingly appreciated, the outcomes of such intratumor heterogeneity, particularly in the context of tumor invasion and metastasis, remain poorly understood. To study heterotypic cell–cell interactions and elucidate the biological consequences of intratumor heterogeneity, we developed a tissue-engineered multicellular spheroid (MCS) co-culture model that recapitulates the cellular diversity and fully three-dimensional cell–cell and cell–matrix interactions that characterize human carcinomas. We found that “invasion-competent” malignant cells induced the collective invasion of otherwise “invasion-incompetent” epithelial cells, and that these two cell types consistently exhibited distinct leader and follower roles during invasion. Analysis of extracellular matrix (ECM) microarchitecture revealed that malignant cell invasion was accompanied by extensive ECM remodeling including matrix alignment and proteolytic track-making. Inhibition of cell contractility- and proteolysis-mediated matrix reorganization prevented leader-follower behavior and malignant cell-induced epithelial cell invasion. These results indicate that heterogeneous subpopulations within a tumor may possess specialized roles during tumor progression and suggest that complex interactions among the various subpopulations of cancer cells within a tumor may regulate critical aspects of tumor biology and affect clinical outcome.
KeywordsIntratumor heterogeneity Invasion Migration 3D co-culture Extracellular matrix
This work was supported in part by the Cornell Center on the Microenvironment & Metastasis through Award Number U54CA143876 from the National Cancer Institute (NCI) and award number CMMI-1233827 from the NSF to CAR and a National Science Foundation Graduate Research Fellowship to SPC.
Conflict of interest
The authors declare that they have no conflict of interest.
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