Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state

TLDR

Stem cell biology models posit that normal and neoplastic stem cells occupy the apex of hierarchies and differentiate unidirectionally into nonstem progeny. We discovered that basal‑like human mammary epithelial cells can spontaneously dedifferentiate into stem‑like cells, a process amplified by oncogenic transformation so that nonstem cancer cells generate CSC‑like cells in vitro and in vivo, and that the differentiation state of the original cells strongly influences post‑transformation behavior, indicating that normal and cancer stem cells can arise de novo from differentiated cells and that mammary stem cell hierarchies must allow bidirectional conversion, with implications for deriving patient‑specific stem cells and cancer therapies.

Abstract

Current models of stem cell biology assume that normal and neoplastic stem cells reside at the apices of hierarchies and differentiate into nonstem progeny in a unidirectional manner. Here we identify a subpopulation of basal-like human mammary epithelial cells that departs from that assumption, spontaneously dedifferentiating into stem-like cells. Moreover, oncogenic transformation enhances the spontaneous conversion, so that nonstem cancer cells give rise to cancer stem cell (CSC)-like cells in vitro and in vivo. We further show that the differentiation state of normal cells-of-origin is a strong determinant of posttransformation behavior. These findings demonstrate that normal and CSC-like cells can arise de novo from more differentiated cell types and that hierarchical models of mammary stem cell biology should encompass bidirectional interconversions between stem and nonstem compartments. The observed plasticity may allow derivation of patient-specific adult stem cells without genetic manipulation and holds important implications for therapeutic strategies to eradicate cancer.