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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE172882 | GEO | 2021/09/19

REPOSITORIES: GEO

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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

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

Long-term multi-modal recording reveals epigenetic adaptation routes in dormant breast cancer cells [scRNA-Seq]

Project description:Patients diagnosed with hormone dependent breast cancer (HDBC) receive five or more years of adjuvant endocrine therapies (ETs). Adjuvant ETs delay relapse by targeting clinically undetectable micro-metastatic deposits, yet up to 50% of patients receiving ET relapse at a constant rate over the course of decades after surgery. The mechanisms driving these clinical dynamics are largely unknown but likely involve dormancy. We developed two approaches to study the fate of dormant cells in long-term experiments. Firstly, we profiled samples from late relapse (10-35 yrs.) and patients treated with 16-44 months of neoadjuvant ETs until progression to dissect the contribution of genetic and transcriptional changes to tumour awakening. Next, we developed a first of its kind in vitro evolutionary study to systematically record adaptive strategies of individual lineages in unperturbed parallel experiments through several months. Collectively our data demonstrate that ETs induce a heritable cell state transition into dormancy via epigenetic reprogramming. Single lineages with divergent phenotypes awaken unpredictably via epigenetic erosion. Targeting the dormant epigenome shows promising activity against adapting cancer cells. Overall, this study uncovers the contribution of epigenetic adaptation to the evolution of resistance to ETs with profound implications for breast cancer.

2024-04-16 | GSE234181 | GEO

Long-term multi-modal recording reveals epigenetic adaptation routes in dormant breast cancer cells [RNA-Seq]

2024-04-16 | GSE234171 | GEO

Comparative transcriptome of proliferative cells, dormant cells and awaken cells throught a DDR1 depletion

Project description:The goal of this study is to compare the trancriptome of proliferative THEP3 cells to their dormant counterpart DHEP3 and an awaken version through DDR1 receptor depletion (shRNA control verus shRNA DDR1) to identify target genes involved in the dormancy state and the awakening process from where metatsiss will arise.

2021-10-20 | GSE182890 | GEO

Valproic acid achieves its anticancer activity by re-expression of cyclin D2

Project description:In this study we could show that the treatment of primary murine prostate cancer(PCa) cells derived from the well-established TRAMP (transgenic adenocarcinoma ofmouse prostate) model with the histone deacetylase inhibitor (HDI) valproic acid (VPA) has an anti-proliferative, anti-migrative and anti-invasive effect on the cells.To our knowledge this is the first study that identified that treatment of PCa cells with VPA leads to the re-expression of cyclin D2, which is known to be frequently inactive in patients with PCa. Additionally, we could demonstrate that VPA specifically induces re-expression of cyclin D2 as a family member of the highly conserved Dtype cyclins in human colorectal and mammary gland adenocarcinoma cell lines, whereas VPA treatment has no effect in NIH/3T3 fibroblasts. The observed cyclin D2 re-expression in cancer cells is activated by an increase of histone acetylation in the promoter region of the cyclin D2 gene and might be the underlying molecular mechanism of the inhibition of proliferation of cancer cells after VPA treatment. Taken together, our results confirm VPA as an anticancer therapeutic option in tumors with epigenetically repressed cyclin D2 expression. For the comparison of vpa treatment in murine protate cancer cells we hybridized 3 replicates per condition

2013-03-01 | E-GEOD-34072 | biostudies-arrayexpress

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

Valproic acid achieves its anticancer activity by re-expression of cyclin D2

2013-03-01 | GSE34072 | 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

RGS2-mediated translational control drives cellular dormancy and resistance to ER-stress-induced apoptosis by inducing proteasome-mediated ATF4 degradation

Project description:Slow-cycling/dormant cancer cells (SCCs) are thought to cause cancer relapse, but the underlying biology remains obscure. A subpopulation of SCCs has been found even in rapidly growing tumors and cancer cell lines. To investigate the mechanism underlying cellular dormancy, we obtained SCCs from three NSCLC cell lines (H460, H1299, and SK-MES-1) and PDX tumor by using a cell proliferation-dependent fluorescent dye (CSFE).

2020-08-31 | GSE141218 | GEO

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