Cancer stem cell generation during epithelial-mesenchymal transition is temporally gated by intrinsic circadian clocks

Aug 21, 2020Clinical & experimental metastasis

Cancer stem cell formation during cell state changes is controlled by internal daily clocks

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Abstract

Circadian rhythms are associated with changes in the size of cancer stem cell populations after epithelial-mesenchymal transition in two cancer cell lines.

Epithelial-mesenchymal transition (EMT) increases cell invasiveness and cancer stem cell (CSC) populations.
A previously unconfirmed circadian clock was observed in MCF-7 tumorspheres through bioluminescence imaging of Per2 gene expression.
Circadian oscillations in the size of the post-EMT CSC population were identified in both C6 and MCF-7 cultures.
Distinct cellular changes and the expression of specific stem cell and EMT-related proteins confirmed EMT occurrence.
Time-lapse imaging indicated that the post-EMT population size is largely influenced by circadian rhythms in epithelial-like cancer cells.
A specific phase of circadian rhythm in Per2 gene activation may serve as a target for therapies aimed at suppressing EMT and limiting metastasis.

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Epithelial-mesenchymal transition (EMT) is a key event preceding tumor cell metastasis that increases cell invasiveness and cancer stem cell (CSC) populations. Studies suggest that genes used in generating circadian rhythms also serve in regulating EMT. To test the role of circadian clocks in cellular EMT events two cancer cell lines were compared, one that has a well-established circadian clock, C6 from rat glioma, and one that does not, MCF-7 from human breast tumor. MCF-7 tumorsphere cultures were tested for evidence of circadian rhythms because of previously reported circadian rhythm enhancement in C6 tumorspheres shown by elevated rhythm amplitude and increased expression of circadian clock gene Per2. Bioluminescence imaging of Per2 gene expression in MCF-7 tumorspheres revealed a previously unconfirmed circadian clock in this important cancer research model. Inducing CSC generation through EMT in C6 and MCF-7 monolayer cultures revealed circadian oscillations in the size of the post-EMT CSC population, confirming that circadian rhythms are additional processes controlling this stage of cancer progression. EMT was verified by distinct cellular morphological changes and expression of stem cell proteins OCT4, nestin, MSI1, and CD133 along with EMT-related proteins ZEB1, vimentin, and TWIST. Quantifying single-cell events and behaviors through time-lapse imaging indicated the post-EMT population size was determined largely by circadian rhythms in epithelial-like cancer cells undergoing EMT. We then identified a specific phase of the circadian rhythm in Per2 gene activation as a potential target for therapeutic treatments that may suppress EMT, minimize CSCs, and limit metastasis.

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Cancer stem cell generation during epithelial-mesenchymal transition is temporally gated by intrinsic circadian clocks

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