Abstract
The proliferation-quiescence decision is a dynamic process that remains incompletely understood. Live-cell imaging with fluorescent cell cycle sensors now allows us to visualize the dynamics of cell cycle transitions and has revealed that proliferation-quiescence decisions can be highly heterogeneous, even among clonal cell lines in culture. Under normal culture conditions, cells often spontaneously enter non-cycling G0 states of varying duration and depth. This also occurs in cancer cells and G0 entry in tumors may underlie tumor dormancy and issues with cancer recurrence. Here we show that a cell cycle indicator previously shown to indicate G0 upon serum starvation, mVenus-p27K-, can also be used to monitor spontaneous quiescence in untransformed and cancer cell lines. We find that the duration of spontaneous quiescence in untransformed and cancer cells is heterogeneous and that a portion of this heterogeneity results from asynchronous proliferation-quiescence decisions in pairs of daughters after mitosis, where one daughter cell enters or remains in temporary quiescence while the other does not. We find that cancer dormancy signals influence both entry into quiescence and asynchronous proliferation-quiescence decisions after mitosis. Finally, we show that spontaneously quiescent prostate cancer cells exhibit altered expression of components of the Hippo pathway and are enriched for the stem cell markers CD133 and CD44. This suggests a hypothesis that dormancy signals could promote cancer recurrence by increasing the proportion of quiescent tumor cells poised for cell cycle re-entry with stem cell characteristics in cancer.
Highlights
Cycling cells tend to enter quiescence, a reversible, non-cycling state in response to contact inhibition, reduced levels of mitogens, or under various stress conditions
This leads to heterogeneity in cell culture, with a subpopulation of cells entering and leaving temporary quiescent states (Overton et al, 2014). This proliferative heterogeneity may underlie states of dormancy in cancer and has been shown to be related to cancer therapeutic resistance (Recasens and Munoz, 2019; Risson et al, 2020; Nik Nabil et al, 2021). This is relevant in prostate cancer, where it is thought that early spreading of tumor cells to the bone marrow and other tissues may provide signals leading to quiescence and tumor dormancy (Chen et al, 2021)
We find that signals associated with promoting or releasing tumor dormancy can influence quiescence and asynchronous proliferation-quiescence decisions in prostate cancer cells
Summary
Cycling cells tend to enter quiescence, a reversible, non-cycling state in response to contact inhibition, reduced levels of mitogens, or under various stress conditions. Using the mVenus-p27K− G0 reporter, we isolate populations containing quiescent cancer cells and find they are enriched for a subpopulation expressing stem cell markers and express high levels of Hippo pathway signaling components, but with inactivated YAP, which may indicate a state poised for cell cycle re-entry.
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