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Therapeutic induction of mesenchymal-epithelial transition via epigenetic reprogramming curtails metastatic progression and sensitizes breast cancers to treatment [RNA-seq]

ABSTRACT: The epithelial-mesenchymal transition (EMT) is a developmental program that is co-opted by tumor cells to aid in their embarking on the metastatic cascade. Tumor cells that undergo EMT are known to be endowed by, amongst other traits, heightened resistance to chemotherapy. Despite a clear understanding of the role played by the EMT program in conferring cells with these aggressive traits, there are currently no therapeutic avenues specifically targeting the program. Here we show that treatment of mesenchymal-like breast cancer cells with eribulin, an FDA-approved drug for the treatment of advanced breast cancers, leads to a mesenchymal-epithelial transition (MET), accompanied by a loss of metastatic propensity and sensitization of tumor cells to subsequent rounds of chemotherapy. We uncover a novel alternate mechanism of action that provides evidence for eribulin pretreatment as a viable clinical mechanism of MET induction that curtails metastatic progression and the evolution of therapy resistance.

ORGANISM(S): Mus musculus

PROVIDER: GSE207772 | GEO | 2023/08/02

REPOSITORIES: GEO

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Therapeutic induction of mesenchymal-epithelial transition via epigenetic reprogramming curtails metastatic progression and sensitizes breast cancers to treatment [ATAC-seq]

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Suppression of major attributes of tumor-initiating cells through epithelial-mesenchymal transition

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Regan2022 - Mechanosensitive EMT model with autocrine TGFbeta signaling

Project description:This model is an expansion of the Regan2022 - Mechanosensitive EMT model (MODEL2208050001); it includes a TGFβ signaling module and autocrine signaling in mesenchymal cells. The expanded 150-node (630 link) modular model undergoes EMT triggered by biomechanical and growth signaling crosstalk, or by TGFβ. As its predecessor, this model also reproduces the ability of the core EMT transcriptional network to maintain distinct epithelial, hybrid E/M and mesenchymal states, as well as EMT driven by mitogens such as EGF on stiff ECM. We also reproduce the observed lack of stepwise MET, in that our model's dynamics does not pass through the hybrid E/M state during MET. We show that in the absence of strong autocrine signals such as TGFβ (not included in this version), cells cannot maintain their mesenchymal state in the absence of mitogens, on softer matrices, or at high cell density. In contrast, potent autocrine signaling can stabilize the mesenchymal state in all but very dense monolayers on soft ECM. This expanded model also reproduces the inhibitory effects of TGFβ on proliferation and anoikis resistance in mesenchymal cells, as well as its ability to trigger apoptosis on soft ECM vs. EMT on stiff matrices. The model offers several experimentally testable predictions related to the effect of neighbors on partial vs. full EMT, the tug of war between mitosis and the maintenance of migratory hybrid E/M states, as well as cell cycle defects in dynamic, heterogeneous populations of epithelial, hybrid E/M and mesenchymal cells.

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Suppression of major attributes of tumor-initiating cells through epithelial-mesenchymal transition

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Regan2022 - Mechanosensitive EMT model

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