Intratumoral Heterogeneity in a Trp53-Null Mouse Model of Human Breast Cancer

Abstract Intratumoral heterogeneity correlates with clinical outcome and reflects the cellular complexity and dynamics within a tumor. Such heterogeneity is thought to contribute to radio- and chemoresistance because many treatments may target only certain tumor cell subpopulations. A better understanding of the functional interactions between various subpopulations of cells, therefore, may help in the development of effective cancer treatments. We identified a unique subpopulation of tumor cells expressing mesenchymal-like markers in a Trp53-null mouse model of basal-like breast cancer using fluorescence-activated cell sorting and microarray analysis. Both in vitro and in vivo experiments revealed the existence of cross-talk between these “mesenchymal-like” cells and tumor-initiating cells. Knockdown of genes encoding ligands upregulated in the mesenchymal cells and their corresponding receptors in the tumor-initiating cells resulted in reduced tumorigenicity and increased tumor latency. These studies illustrate the non–cell-autonomous properties and importance of cooperativity between tumor subpopulations. Significance: Intratumoral heterogeneity has been considered one important factor in assessing a patient's initial response to treatment and selecting drug regimens to effectively increase tumor response rate. Elucidating the functional interactions between various subpopulations of tumor cells will help provide important new insights in understanding treatment response and tumor progression. Cancer Discov; 5(5); 520–33. ©2015 AACR. See related commentary by Brooks and Wicha, p. 469 This article is highlighted in the In This Issue feature, p. 453