In:
Frontiers in Cell and Developmental Biology, Frontiers Media SA, Vol. 9 ( 2021-6-15)
Abstract:
Breast cancer stem cells (BCSCs) represent a subpopulation of tumor cells that can self-renew and generate tumor heterogeneity. Targeting BCSCs may ameliorate therapy resistance, tumor growth, and metastatic progression. However, the origin and molecular mechanisms underlying their cellular properties are poorly understood. The transcriptional coactivator with PDZ-binding motif (TAZ) promotes mammary stem/progenitor cell (MaSC) expansion and maintenance but also confers stem-like traits to differentiated tumor cells. Here, we describe the rapid generation of experimentally induced BCSCs by TAZ-mediated reprogramming of human mammary epithelial cells, hence allowing for the direct analysis of BCSC phenotypes. Specifically, we establish genetically well-defined TAZ-dependent (TAZ DEP ) and -independent (TAZ IND ) cell lines with cancer stem cell (CSC) traits, such as self-renewal, variable resistance to chemotherapeutic agents, and tumor seeding potential. TAZ DEP cells were associated with the epithelial to mesenchymal transition, embryonic, and MaSC signature genes. In contrast, TAZ IND cells were characterized by a neuroendocrine transdifferentiation transcriptional program associated with Polycomb repressive complex 2 (PRC2). Mechanistically, we identify Cyclin D1 (CCND1) as a critical downstream effector for TAZ-driven tumorigenesis. Overall, our results reveal a critical TAZ-CCND1-CDK4/CDK6 signaling axis, suggesting novel therapeutic approaches to eliminate both BCSCs and therapy-resistant cancer cells.
Type of Medium:
Online Resource
ISSN:
2296-634X
DOI:
10.3389/fcell.2021.673374
DOI:
10.3389/fcell.2021.673374.s001
DOI:
10.3389/fcell.2021.673374.s002
DOI:
10.3389/fcell.2021.673374.s003
DOI:
10.3389/fcell.2021.673374.s004
DOI:
10.3389/fcell.2021.673374.s005
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2021
detail.hit.zdb_id:
2737824-X
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