ABSTRACT
SIGNIFICANCE: Dll1+ breast cancer cells activate Notch signaling in cancer-associated fibroblasts that increases Wnt ligand secretion and leads to ß-catenin-driven radioresistance and metastasis, opening new therapeutic avenues for breast cancer.
Subject(s)
Breast Neoplasms , Cancer-Associated Fibroblasts , Breast Neoplasms/pathology , Breast Neoplasms/radiotherapy , Cancer-Associated Fibroblasts/pathology , Female , Humans , Intercellular Signaling Peptides and Proteins , Ligands , Receptors, Notch , beta CateninABSTRACT
The original version of this Article contained an error in the spelling of the author Daniel D. Liu, which was incorrectly given as Daniel Liu. This has now been corrected in both the PDF and HTML versions of the Article.
ABSTRACT
Epithelial-mesenchymal transition (EMT) have been extensively characterized in development and cancer, and its dynamics have been modeled as a non-linear process. However, less is known about how such dynamics may affect its biological impact. Here, we use mathematical modeling and experimental analysis of the TGF-ß-induced EMT to reveal a non-linear hysteretic response of E-cadherin repression tightly controlled by the strength of the miR-200s/ZEBs negative feedback loop. Hysteretic EMT conveys memory state, ensures rapid and robust cellular response and enables EMT to persist long after withdrawal of stimuli. Importantly, while both hysteretic and non-hysteretic EMT confer similar morphological changes and invasive potential of cancer cells, only hysteretic EMT enhances lung metastatic colonization efficiency. Cells that undergo hysteretic EMT differentially express subsets of stem cell and extracellular matrix related genes with significant clinical prognosis value. These findings illustrate distinct biological impact of EMT depending on the dynamics of the transition.
