Immune-Induced Epithelial to Mesenchymal Transition <i>In vivo</i> Generates Breast Cancer Stem Cells

TLDR

The breast cancer stem cell hypothesis posits that tumors arise from a single stem‑like cell, yet the origin of these cells is unclear, and prior work has shown that an immune response can trigger epithelial‑to‑mesenchymal transition in vivo. CD8‑T‑cell–induced EMT produces mesenchymal tumor cells with a CD24^low/CD44^+ phenotype that are highly tumorigenic, can revert to epithelial tumors, and exhibit increased resistance to chemotherapy and radiation, demonstrating that EMT can generate breast cancer stem cells and underscoring implications for disease progression and relapse.

Abstract

The breast cancer stem cell (BCSC) hypotheses suggest that breast cancer is derived from a single tumor-initiating cell with stem-like properties, but the source of these cells is unclear. We previously observed that induction of an immune response against an epithelial breast cancer led in vivo to the T-cell-dependent outgrowth of a tumor, the cells of which had undergone epithelial to mesenchymal transition (EMT). The resulting mesenchymal tumor cells had a CD24(-/lo)CD44(+) phenotype, consistent with BCSCs. In the present study, we found that EMT was induced by CD8 T cells and the resulting tumors had characteristics of BCSCs, including potent tumorigenicity, ability to reestablish an epithelial tumor, and enhanced resistance to drugs and radiation. In contrast to the hierarchal cancer stem cell hypothesis, which suggests that breast cancer arises from the transformation of a resident tissue stem cell, our results show that EMT can produce the BCSC phenotype. These findings have several important implications related to disease progression and relapse.