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Identification of dormant cells using a novel fluorescent reporter of RNA-polymerase II activity

ABSTRACT: Dormancy is a reversible cellular state in which the cell cycle and metabolic activity of a cell is dramatically decreased, leading to protection from genetic damage and prolonged survival. One example of dormant cells is the somatic stem cell, which is crucial for tissue homeostasis and response to injury or transplantation. However, while dormant cells have been well characterized in some tissues, the ability to identify them irrespective of tissue of origin remains elusive. Moreover, in some tissues (e.g. the intestinal epithelium) dormant stem cells showed heterogeneity in the marker’s profile that makes their identification and isolation challenging. Here, we developed a live cell reporter of dormancy based on our observation that phosphorylation of RNA Polymerase II (RNApII), a hallmark of active mRNA transcription elongation, is largely absent in dormant stem cells from multiple lineages. We show that insertion of a short RNApII kinase target peptide directly into the yellow fluorescent protein Venus generates a live cell Optical Stem Cell Activity Reporter (OSCAR) for detection of dormant cells. We found, using small intestinal crypt cultures, that OSCAR is able to show the dynamics of dormancy induction and cellular differentiation in real time. Generation and analysis of mice ubiquitously expressing OSCAR showed several populations of OSCARhigh and OSCARlow cells. Microscopy, RNA-Seq and single-cell culture confirmed that OSCAR enables direct identification and isolation of cell populations bearing different transcriptional states and provides a useful tool for understanding dormant cell biology.

ORGANISM(S): Mus musculus

PROVIDER: GSE147030 | GEO | 2021/04/16

REPOSITORIES: GEO

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Hematopoietic stem cells (HSCs)

Project description:G0 marker-separation of dormant and active hematopoietic stem cells reveals dormancy regulation by basal cytoplasmic calcium

2019-12-19 | PXD012093 | JPOST Repository

Single Cell Analysis Unveils the Role of the Tumor Immune Microenvironment and Notch Signaling in Dormant Minimal Residual Disease

Project description:Understanding the complex ecosystem that promotes dormant cell survival and elucidating those factors that eventually overcome growth constraints and result in proliferation may provide new insights and help identify novel strategies to prolong dormancy and prevent recurrence. To dissect the molecular pathways and the microenvironments involved in regulation of tumor dormancy, we utilized a novel immunocompetent transgenic model to study residual disease, dormancy, and relapse. We discovered a significant reorganization of cancer cell structures, stroma, and immune cells with cancer cells showing dormant cell signatures. Single-cell RNA sequencing uncovered remodeling of myeloid and lymphoid compartments. Additionally, the Jagged-1/Notch signaling pathway was shown to regulate many aspects of tumorigenesis including stem cell development, epithelial-mesenchymal transition, and immune cell homeostasis during dormancy. An anti-Jagged-1 inhibitory antibody prolonged dormancy and delayed tumor recurrence due to the pleotropic effects of inhibiting the Jagged-1/Notch signaling pathway both in the tumor cells and the microenvironment.

2021-12-18 | GSE171464 | GEO

Identifying dormant Nfatc1-marked stem/progenitor cells as an important contributor for mammary lobuloalveoli formation

Project description:The Mammary gland undergoes complicated epithelial remodeling to form lobuloalveoli during pregnancy, in which basal epithelial cells remarkably increase to form a basket-like architecture. However, it remains largely unknown how dormant mammary basal stem/progenitor cells involve in lobuloalveolar development. Here, we show that Nfatc1 expression marks a rare population of mammary epithelial cells with the majority being basal epithelial cells. Nfatc1 reporter-marked basal epithelial cells are relatively dormant mammary stem/progenitor cells. Although Nfatc1 reporter-marked basal epithelial cells show limited contribution to the homeostasis of mammary epithelium, they divide rapidly during pregnancy and contribute to lobuloalveolar development. Furthermore, Nfatc1 reporter-marked basal epithelial cells are preferentially used for multiple pregnancies. Using single-cell RNA-seq analysis, we identify multiple functionally distinct clusters within the Nfatc1 reporter-marked cell-derived progeny cells during pregnancy. Taken together, our findings underscore Nfatc1 reporter-marked basal cells as dormant stem/progenitor cells that contribute to mammary lobuloalveolar development during pregnancy.

2022-02-18 | GSE175432 | GEO

RNA-sequencing of D2A1 and D2.OR cell lines in both 2D and 3D cultures

Project description:Reactivation of dormant cancer cells can lead to cancer relapse, metastasis and patient death. Dormancy is a non-proliferative state and is linked to late relapse and death. No targeted therapy is currently available to eliminate dormant cells, highlighting the need for a deeper understanding and reliable models. Here, we thoroughly characterize the dormant D2.OR and proliferative D2A1 breast cancer cell line models in vivo and in vitro, and assess if there is overlap between a dormant and a senescent phenotype. We show that D2.OR but not D2A1 cells become dormant in the liver of an immunocompetent model. In vitro, we show that D2.OR cells are polyploid ER+/Her2+ cells, and in response to a 3D environment are growth arrested in G1, of which a subpopulation resides in a 4NG1 state. The dormancy state is reversible, and not associated with a senescence phenotype. This will aid future research on breast cancer dormancy.

2021-09-19 | GSE172882 | GEO

Modeling androgen deprivation therapy-induced prostate cancer dormancy and its clinical implications

Project description:Purpose: Treatment-induced tumor dormancy is a state in cancer progression where residual disease is present but remains asymptomatic. Dormant cancer cells are treatment-resistant and responsible for cancer recurrence and metastasis. Prostate cancer (PCa) treated with androgen-deprivation therapy (ADT) often enters a dormant state. ADT-induced PCa dormancy remains poorly understood due to the challenge in acquiring clinical dormant PCa cells and the lack of representative models. We, therefore, aimed to develop clinically relevant models that can be used for studying ADT-induced PCa dormancy. Experimental design: Dormant PCa models were established by castrating mice bearing PCa patient-derived xenografts (PDXs) of hormonal naïve or sensitive PCa. Dormancy status and tumor relapse were monitored and evaluated. Paired pre- and post-castration (dormant) PDX tissues were subjected to morphological and transcriptome profiling analyses. Results: We established eleven ADT-induced dormant PCa models that closely mimicked the clinical courses of ADT-treated PCa. We identified two ADT-induced dormancy subtypes that differed in morphology, gene expression, and relapse rates. We discovered transcriptomic differences in pre-castration PDXs that predisposed the dormancy response to ADT. We further developed a dormancy subtype-based, predisposed gene signature that was significantly associated with ADT response in hormonal naïve PCa and clinical outcome in castration-resistant PCa treated with ADT or androgen-receptor pathway inhibitors.

2022-01-11 | GSE193500 | GEO

Comparative label-free lipidomic analysis of Mycobacterium tuberculosis during dormancy and reactivation

Project description:Mycobacterium tuberculosis employs several strategies to combat and adapt to adverse conditions encountered inside the host. The non-replicative dormant state of the bacterium is linked to drug resistance and slower response to anti-tubercular therapy. It is known that alterations in lipid content allow dormant bacteria to acclimatize to cellular stress. Employing comparative lipidomic analysis we profiled the changes in lipid metabolism in M. tuberculosis using a modified Wayne's model of hypoxia-induced dormancy. Further we subjected the dormant bacteria to resuscitation, and analyzed their lipidomes until the lipid profile was similar to that of normoxially grown bacteria. An enhanced degradation of cell wall-associated and cytoplasmic lipids during dormancy, and their gradual restoration during reactivation, were clearly evident. This study throws light on distinct lipid metabolic patterns that M. tuberculosis undergoes to maintain its cellular energetics during dormancy and reactivation.

2018-10-22 | MTBLS304 | MetaboLights

Coordinated miRNA activity mediates the cellular transition into dormancy during embryonic diapause

Project description:Dormancy is a key feature of stem cell function in adult tissues as well as embryonic cells in the context of diapause. The establishment of dormancy is an active process that involves extensive transcriptional, epigenetic, and metabolic rewiring. How these processes are coordinated to successfully transition cells to the resting dormant state is not known. Here we show that microRNA activity, which is normally dispensable for pre-implantation development, is essential for the adaptation of early mouse embryos to the dormant state of diapause. In particular, the pluripotent epiblast depends on miRNA activity, the absence of which results in loss of pluripotency and embryo collapse. Through tissue-specific small RNA profiling of single embryos and computational analyses of miRNA targets, we identified the miRNA-protein network of diapause. Individual miRNA function contributes to combinatorial regulation by the network of most notably RNA processing and chromatin modifier proteins. Without miRNAs, multiple nuclear and cytoplasmic bodies show aberrant expression and structure in normal ESCs and fail to reorganize in response to stress. We find extensive alternative splicing in wild-type, but not miRNA-deficient ESCs, of cell cycle and metabolic regulators. Our results reveal that miRNAs are critical for the transcriptional and structural rewiring of pluripotent cells in response to stress and to establish dormancy in the pluripotent state.

2024-03-26 | PXD044550 | Pride

Osteoclasts Control Re-activation of Dormant Myeloma Cells by Remodeling the Endosteal Niche

Project description:Multiple myeloma is largely incurable, despite development of therapies that target myeloma cell-intrinsic pathways. Disease relapse is thought to originate from dormant myeloma cells, localized in specialized niches, which resist therapy and re-populate the tumor. However, little is known about the niche, and how it exerts cell-extrinsic control over myeloma cell dormancy and re-activation. In this study we track individual myeloma cells by intravital imaging as they colonize the endosteal niche, enter a dormant state and subsequently become activated to form colonies. We demonstrate that dormancy is a reversible state which is switched ‘on’ by engagement with bone lining cells or osteoblasts, and switched ‘off’ by osteoclasts remodeling the endosteal niche. Dormant myeloma cells are resistant to chemotherapy targeting dividing cells. The demonstration that the endosteal niche is pivotal in controlling myeloma cell dormancy highlights the potential for targeting cell-extrinsic mechanisms to overcome cell-intrinsic drug resistance and prevent disease relapse.

2015-11-30 | GSE57695 | GEO

Discrimination of dormant and active hematopoietic stem cells by G0 markers reveals dormancy regulation by cytoplasmic calcium

Project description:Quiescent hematopoietic stem cells (HSCs) are typically dormant, and only a few quiescent HSCs are active. The relationship between “dormant” and “active” HSCs remains unresolved. Here we generated a G0 marker (G0M) mouse line that visualizes quiescent cells. G0M identifies a small population of active HSCs (G0Mlow), which are distinct from dormant HSCs (G0Mhigh), within the conventional quiescent HSC fraction. Single-cell RNA-Seq analyses showed that the gene expression profiles of these populations were nearly identical, yet differed in their Cdk4/6 activity. Furthermore high-throughput small molecule screening revealed that high concentrations of cytoplasmic calcium ([Ca2+]c) were linked to dormancy of HSCs. These findings indicate that G0M separates dormant and active adult HSCs, which are regulated by Cdk4/6 and [Ca2+]c. This G0M mouse line represents a useful resource for investigating physiologically important stem cell subpopulations.

2019-12-20 | GSE139013 | GEO

Identifying dormant cells in colorectal cancer spheroids

Project description:Cellular dormancy and heterogeneous cell cycle lengths provide important explanations for treatment failure following adjuvant therapy with S-phase cytotoxics in colorectal cancer (CRC) yet the molecular control of the dormant versus cycling state remains unknown. In CRCs dormant cells are found to be highly clonogenic and resistant to chemotherapies. We sought to understand the molecular features of dormant CRC cells to facilitate rationale identification of compounds to target both dormant and cycling tumour cells.

2018-05-21 | GSE114012 | GEO

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