Single cell RNA sequencing of dormant and proliferating prostate cancer cells from murine bone metastases
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ABSTRACT:
PROVIDER: PRJNA613204 | ENA |
REPOSITORIES: ENA
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Project description:Using the immunocompetent bone-metastatic RM1 murine model of prostate cancer, the transriptomes of proliferating (PKH26-) eCFP+/luc2+ RM1 single cells (referred to as RM1536) were compared to dormant (PKH26+) RM1536 single cells dervied from bioluminescence imaging-verified bone metastases in mice at ~d16 post-intracardiac injection of PKH26 labelled RM1536 cells
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Project description:For many breast cancer (BCa) patients, symptomatic bone metastases appear after years or even decades of latency. How metastatic cells disseminate, and how micrometastatic lesions remain dormant and undetectable, are major questions in cancer research. Here we identify and functionally analyse a molecular mechanism involved in the bone metastatic latency of estrogen receptor (ER)+ BCa.
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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.
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Project description:Using the immunocompetent bone-metastatic murine model of prostate cancer, the transcriptomes of proliferating (PKH26-) eCFP+/luc2+ RM1 cells (referred to as RM1536) were compared to FACS-isolated, proliferating (PKH26-) RM1536 cells derived from matched bone and lung metastases for preliminary assessment of gene alterations that may specifically occur in bone.
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Project description:Analysis of bone metastases tissue from castration-resistant prostate cancer patients at the RNA level in relation to expression of constitutively active androgen receptor variants termed AR-V7 and AR-V567es. Total RNA obtained from frozen bone metastases samples were analyzed using a gene expression array and further to reveal differences in-between sample groups according to expression of AR-V7 and AR-V567es mRNA levels. Samples were defined to have high (AR-V high) or low (others) expression of those variants, respectively, for definition and more information please see Hörnberg et al PLoS One April 2011 Vol 6 Issue 4 , link and PMID below.
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Project description:Our goal was to determine whether previously identified and novel proteins are associated with the osteoblastic or osteolytic response in clinical specimens of PCa bone metastases. Custom Agilent 44K whole human genome expression oligonucleotide microarrays were used to profile 14 PCa metastases from 11 patients with highly osteoblastic and highly osteolytic bone reactions. Total RNA was isolated and amplified prior to hybridization against a common reference pool of prostate tumor cell lines.
2013-05-03 | E-GEOD-41619 | biostudies-arrayexpress
Project description:Analysis of bone metastases tissue from castration-resistant prostate cancer patients at the RNA level in relation to expression of constitutively active androgen receptor variants termed AR-V7 and AR-V567es.
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Project description:TGF-beta is a known driver of epithelial-mesenchymal transition (EMT) which is associated with tumor aggressiveness and metastasis. However, EMT has not been fully explored in clinical specimens of castration-resistant prostate cancer (CRPC) metastases. To assess EMT in CRPC, gene expression analysis was performed on 149 visceral and bone metastases from 62 CRPC patients and immunohistochemical analysis was performed on 185 CRPC bone and visceral metastases from 42 CRPC patients. In addition, to assess the potential of metastases to seed further metastases the mitochondrial genome was sequenced at different metastatic sites in one patient. TGF-beta was increased in bone versus visceral metastases. While primarily cytoplasmic; nuclear and cytoplasmic Twist were significantly higher in bone than in visceral metastases. Slug and Zeb1 were unchanged, with the exception of nuclear Zeb1 being significantly higher in visceral metastases. Importantly, nuclear Twist, Slug, and Zeb1 were only present in a subset of epithelial cells that had an EMT-like phenotype. Underscoring the relevance of EMT-like cells, mitochondrial sequencing revealed that metastases could seed additional metastases in the same patient. In conclusion, while TGF-beta expression and EMT-associated protein expression is present in a considerable number of CRPC visceral and bone metastases, nuclear Twist, Slug, and Zeb1 localization and an EMT-like phenotype (elongated nuclei and cytoplasmic compartment) was only present in a small subset of CRPC bone metastases. Mitochondrial sequencing from different metastases in a CRPC patient provided evidence for the seeding of metastases from previously established metastases, highlighting the biological relevance of EMT-like behavior in CRPC metastases.
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