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

By Christine L. Chaffer, Ines Brueckmann, C. Scheel, A. Kaestli, Paul A. Wiggins, L. Rodrigues, M. Brooks, Ferenc Reinhardt, Ying Su, K. Polyak and 4 more. Proceedings of the National Academy of Sciences of the United States of America, 2011

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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.

Subfields: Biotechnology, Cell Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/6b57a356a9ac6202cb6fd1cfde0250c6ab12cdf3

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Citations in the corpus

Epithelial-Mesenchymal Plasticity: A central regulator of cancer progression (2015, background): “Moreover, intrinsic epithelial-mesenchymal plasticity enables cancer cells to switch between the mesenchymal CSC state and a more differentiated, more rapidly proliferating epithelial state, thereby creating one important dimension of intra-tumoral heterogeneity (Chaffer et al., 2011; Chaffer et al.”
Cancer stem cells: current status and evolving complexities. (2012, background): “Blocking antibodies against CD47, which serves as a ‘‘don’t eat me’’ signal to tumor macrophages, may also be effective in eliminating LSCs in ALL that express higher levels of this antigen than their normal counterpart (Chao et al., 2011).”
Cancer stem cells: impact, heterogeneity, and uncertainty. (2012, background): “Recent studies have suggested that the differentiation of cancer stem cells into nontumorigenic cells may be reversible (Chaffer et al., 2011; Gupta et al., 2011).”
The ins and outs of the epithelial to mesenchymal transition in health and disease. (2011, background): “In terms of plasticity, EMT, and CSCs, a limitation that may arise in therapies directed to kill CSCs comes from the recent finding that normal and transformed mammary epithelial cells can be converted to stem cells and CSCs, respectively (Chaffer et al. 2011).”
Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. (2011, positive): “The prediction of a return to phenotypic equilibrium is consistent with the finding that CSCs give rise to tumors that recapitulate the differentiation-state heterogeneity present in the parental tumors from which they were derived.”
Slug and Sox9 Cooperatively Determine the Mammary Stem Cell State (2012, background): “Recent studies using immortalized or cancer cell lines have shown that nonstem cells can dedifferentiate to stem-like cells either spontaneously or under specific culture conditions (Chaffer et al., 2011; Gupta et al., 2011; Scheel et al., 2011).”
Epithelial–mesenchymal plasticity in carcinoma metastasis (2013, background): “…that basal breast cancer non-CSCs are populations that can generate CSCs de novo, and the CSC plasticity is controlled by the chromatin state of the Zeb1 promoter (Chaffer et al. 2011), further highlighting the critical role of EMT regulators in regulating CSC plasticity during tumor progression.”
Cancer epigenetics: Tumor Heterogeneity, Plasticity of Stem-like States, and Drug Resistance (2014, background): “For the chromatin regulation, gene silencing may be particularly important as controlled by the PcG proteins and the attendant H3K27me3mark and particularly in the setting of promoter bivalency (Chaffer et al., 2011; Marjanovic et al., 2013).”