Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

RNAseq on PYMT cells treated with TGFB2 and/or BMP4 in 3D matrigel

ABSTRACT: Dormancy of disseminated tumor cells in secondary organs leads to late breast cancer-related deaths after relapse. The bone marrow is one of the primary breast cancer metastatic sites and is associated with poor prognosis. Here, we investigated the role of major factors of the bone marrow, BMP4 and TGF?2, in regulating cancer cell dormancy. Unexpectedly, we observed that TGF?2 and BMP4 have a synergistic effect that induces dormancy in both normal and transformed mammary stem cells. Several assays (3D matrigel, FUCCI Cell Cycle Indicator) showed that co-exposure to TGF?2 and BMP4 had a stronger anti-proliferative effect than each ligand alone. In addition, transformed cells fully retained this synergistic effect while they became less sensitive to individual cytokines. Surprisingly, single-cell RNAseq analysis revealed the heterogeneity of the G0 compartment at the transcriptomic level. We identified a unique deep dormant cluster under TGF?2 and BMP4 co-exposure characterized by a blended signature from treatments by TGF?2 or BMP4 alone. These findings reveal that disseminated breast cancer cells in the bone marrow are placed in a deep dormant stage by the synergistic effect of TGF?2 and BMP4 that neither factor can achieve alone. Lastly, our data suggest that the local BMP4 levels decrease with tissue aging and can therefore contribute to dormant cell awakening. By providing a better understanding of BMP4/TGF?2 signaling, our results open opportunities to prevent cancer relapse.

ORGANISM(S): Mus musculus

PROVIDER: GSE232164 | GEO | 2024/05/10

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Tumor Cell Heterogeneity and Dormancy in Single Disseminated Prostate Cancer Cells

2014-09-16 | GSE48995 | GEO

Cellular adhesion promotes prostate cancer cells escape from dormancy

Project description:Dissemination of prostate cancer (PCa) cells to the bone marrow is an early event in the disease process. In some patients, following initial treatment, disseminated tumor cells (DTC) proliferate to form active metastases after a prolonged period of undetectable disease known as tumor dormancy. Identifying mechanisms of PCa dormancy and reactivation remain a challenge due to the lack of in vitro models. Here, we characterized in vitro PCa dormancy-reactivation by inducing three apparently dormant patient-derived xenograft (PDX) lines to proliferate through tumor cell contact with each other and with bone marrow stroma. Proliferating PCa cells demonstrated tumor cell-cell contact and integrin clustering on immunofluorescence. Global gene expression analyses on proliferating cells cultured on bone marrow stroma revealed a downregulation of TGFB2 in all of the three proliferating PCa PDX lines when compared to their non-proliferating counterparts. Furthermore, constitutive activation of myosin light chain kinase (MLCK), a downstream effector of integrin-beta1 and TGF-beta2, in non-proliferating cells resumed cell proliferation. This cell proliferation was associated with an upregulation of CDK6 and a downregulation of E2F4. Taken together, our data provide evidence to support cellular adhesion and downregulation of TGFB2 as a potential mechanism by which PCa cells escape from dormancy. Targeting TGF-beta 2-associated mechanism could provide novel opportunities to prevent lethal PCa metastasis. Custom Agilent-016162 44K whole human genome expression oligonucleotide microarrays were used to profile dormant and proliferating cells isolated from three separate LuCaP xenograft lines grown in co-culture with bone marrow stromal cells isolated from a patient with PCa bone metastases. RNA from 10 cells was amplified prior to hybridization against a common reference pool of prostate tumor cell lines.

2015-10-26 | E-GEOD-64262 | biostudies-arrayexpress

Co-culture of human prostate cancer cells and mouse osteoblasts as a model for tumor dormancy in bone metastasis

Project description:Prostate cancer (PCa) cells, when disseminated to the bone, may stay quiescent or dormant for years before proliferation into overt metastases. Previous studies suggest that osteoblasts, the bone forming cells, may be responsible for induction of dormancy of bone-disseminated prostate cancer cells.

2023-10-23 | GSE210751 | GEO

Cellular adhesion promotes prostate cancer cells escape from dormancy

2015-10-26 | GSE64262 | GEO

STING suppresses the reactivation of dormant metastasis

Project description:Metastatic relapse frequently develops from disseminated cancer cells that remain dormant in distant organs after the apparently successful treatment of a primary tumor. Disseminated cancer cells fluctuate between immune evasive quiescent and cell cycle reentry states, which exposes them to elimination by the immune system. Little is known about the molecules that determine immune-mediated clearing of awakened metastatic cells and how this process could be therapeutically activated to eliminate residual disseminated disease in patients. Here, we use models of indolent metastasis to identify cancer cell-intrinsic determinants of immune reactivity during cancer cell exit from dormancy. Through in vivo genetic screens of tumor-intrinsic immune regulators, we identified the STING (stimulator of interferon genes) pathway as a suppressor of metastatic outbreak in dormant models of human and mouse lung adenocarcinoma metastasis. STING levels and signaling activity rise in metastatic progenitors that reenter the cell cycle and are dampened by STING enhancer hypermethylation in breakthrough metastases or enhancer chromatin repression in cells reentering dormancy in response to TGF-β. STING expression in cancer cells from spontaneous metastases suppresses their outgrowth in a NK cell- and CD8+ T cell-dependent manner. Systemic treatment of mice with pharmacologic STING agonists eliminates indolent metastatic cells and prevents spontaneous metastasis, both effects requiring cancer cell STING function. Thus, STING signaling represents a checkpoint against the progression of dormant metastasis and suggests a therapeutically actionable strategy for the prevention of disease relapse. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for histone modification markers H3K4me1, H3K4me3, H3K27ac in human lung cancer cells at different stages of metastasis and in cells treated with TGF-β or not.

2023-01-30 | GSE210946 | GEO

Tumor Cell Heterogeneity and Dormancy in Single Disseminated Prostate Cancer Cells

Project description:Prostate cancer (PCa) disseminated tumor cells (DTC) in the bone marrow (BM) can remain dormant for prolonged periods before recurrence. Our aim was to characterize individual prostate DTC, analyze tumor cell heterogeneity, and identify markers of tumor dormancy. Custom Agilent 44K whole human genome expression oligonucleotide microarrays were used to profile single disseminated tumor cells isolated from bone marrow (BM) samples of four patients with no evidence of disease (NED) upon follow-up and six advanced disease (ADV) prostate cancer patients. Essentially, a two-step selection process was employed, in which anti-CD45 and anti-CD61 conjugated to immunomagnetic beads were used for negative selection, and anti-HEA was used for positive selection. Cells were then fluorescently stained for BerEP4, counter stained with RPE anti-CD45, and individually selected (10 single cells each per patient) under fluorescent light using a micropipette system for further analysis. RNA was amplified using the WT-Oviation one-direct system and hybridized against a common reference pool of prostate tumor cell lines.

2014-09-16 | E-GEOD-48995 | biostudies-arrayexpress

The Marrow Niche Controls The Cancer Stem Cell Phenotype Of Disseminated Prostate Cancer

Project description:Dissemination of cancer stem cells (CSCs) serves as the basis of metastasis. Recently, we demonstrated that circulating prostate cancer (PCa) targets the hematopoietic stem cell (HSCs) ‘niche’ in marrow during dissemination. Once in the niche, disseminated tumor cells (DTCs) may remain dormant for extended periods. As the major function of the HSC niche is to maintain stem cell functions, we hypothesized that the niche regulates CSC activities of DTCs. We show that DTCs recovered from marrow were significantly enriched for a CSC phenotype. Critically, the conversion of DTCs to CSCs is regulated by niche. The data demonstrate that the niche plays a significant role in maintaining tumor-initiating PCa in marrow and suggests a functional relationship between CSCs and dormancy. Understanding how the marrow niche regulates the conversion of DTCs to CSCs is critical for the development of therapeutics specifically targeting skeletal bone metastasis and dormancy. We used microarrays to determine the global changes in gene expression underlying the significant roles of the marrow niche in activating cancer stem-like cell programs of prostate caner.

2016-01-30 | GSE77379 | GEO

Stromal Changes in The Aged Lung Induce an Emergence From Melanoma Dormancy

Project description:Disseminated cancer cells (DCCs) that escape the primary site can seed in distal tissues, but may take several years, or even decades to grow out into overt metastases, a phenomenon termed tumor dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully model or characterize dormancy within melanoma. Here, we show that age-related changes in the lung microenvironment facilitate a permissive niche for efficient outgrowth of disseminated dormant tumor cells, in contrast to the aged skin, where age-related changes suppress melanoma growth but drive dissemination. A model of melanoma progression that addresses these microenvironmental complexities is the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state1-3. We have previously shown that dermal fibroblasts are key orchestrators of promoting phenotype switching in primary melanoma tumors via changes in the secretion of soluble factors during aging4-8. Our new data identifies Wnt5A as a master regulator of activating melanoma DCC dormancy within the lung, which initially enables efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of the soluble Wnt antagonist sFRP1, which inhibits Wnt5A, enabling efficient metastatic outgrowth. Further, we have identified the tyrosine kinase receptors AXL and MER as promoting a dormancy-toreactivation axis respectively. Overall, we find that age-induced changes in distal metastatic microenvironments promotes efficient reactivation of dormant melanoma cells in the lung.

2022-03-03 | MSV000088977 | MassIVE

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

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

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data