Platelets favor the outgrowth of established metastases
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB73382 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR12712683_1.fastq.gz | Fastqsanger.gz | |||
| ERR12712683_2.fastq.gz | Fastqsanger.gz | |||
| ERR12712684_1.fastq.gz | Fastqsanger.gz | |||
| ERR12712684_2.fastq.gz | Fastqsanger.gz | |||
| ERR12712685_1.fastq.gz | Fastqsanger.gz |
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Project description:The survival of women with brain metastases (BM) from breast cancer remains very poor, and more than 80% will die within a year of their diagnosis. Here we define the function of IL13Rα2 in outgrowth of breast cancer brain metastases (BCBM) in vitro and in vivo, and postulate IL13Rα2 as a suitable therapeutic target for BM. Experimental design: We performed IHC staining of IL13Rα2 in BCBM to define its prognostic value. Using inducible-shRNAs in TNBC and HER2+ breast-brain metastatic models we assessed IL13Rα2 function in vitro and in vivo. We performed RNAseq and functional studies to define the molecular mechanisms underlying IL13Rα2 function in BCBM. Results: High IL13Rα2 expression in BCBM predicted worse survival after BM diagnoses. IL13Rα2 was essential for cancer-cell survival, promoting proliferation while repressing invasion. IL13Rα2 KD resulted in repression of cell cycle and proliferation mediator Cyclin D2 and upregulation of Ephrin B1 signaling. Ephrin-B1 (i) promoted invasion of BC cells in vitro, (ii) marked micrometastasis and invasive fronts in BCBM, (iii) predicted shorter disease-free survival (DFS) and BM-free survival (BMFS) in breast primary tumors known to metastasize to the brain. In experimental metastases models, which bypass early tumor invasion, downregulation of IL13Rα2 prior or after tumor seeding and brain intravasation decreased BMs, suggesting that IL13Rα2 and a switch to a more proliferative phenotype is critical to BM outgrowth.
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Project description:IL13Rα2 promotes the proliferative switch required for outgrowth of breast cancer brain metastases
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Project description:Metastasis formation is the major cause for cancer-related deaths and the underlying mechanisms remain poorly understood. In this study we describe spontaneous metastasis xenograft mouse models of human neuroblastoma used for unbiased identification of metastasis-related proteins by applying an infrared laser (IR) for sampling primary tumor and metastatic tissues, followed by mass spectrometric proteome analysis. IR aerosol samples were obtained from ovarian and liver metastases, which were indicated by bioluminescence imaging (BLI), and matched subcutaneous primary tumors. Corresponding histology proved the human origin of metastatic lesions. Ovarian metastases were commonly larger than liver metastases indicating differential outgrowth capacities. Among ~1,700 proteins identified at each of the three sites, 89 proteins were differentially regulated in ovarian metastases while 290 proteins were regulated in liver metastases. There was an overlap of 26 and 10 proteins up- and down-regulated at both metastatic sites, respectively, most of which were so far not related to metastasis such as LYPLA2, ACTL8, EIF4B, LGALS7, GFAP, and ELAVL4. Moreover, we established in vitro sublines from primary tumor and metastases and demonstrate differences in cellular protrusions, migratory/invasive potential and glycosylation. Summarized, this work identified several novel putative drivers of metastasis formation that are tempting candidates for future functional studies.
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Project description:Cancer stem cells (CSCs) are a minority population of cancer cells that display stem cell-like multipotent and self-renewal properties. They give rise to the bulk of cancer cells with limited replicative potential. In colorectal cancer (CRC), CSCs are marked by expression of the leucine-rich repeat-containing G-protein receptor 5 (Lgr5). Since CSCs display multipotent and self-renewal properties, this population is thought to seed metastases. Here, we used a mouse model and human xenografts to investigate the cell-of-origin of metastases. Surprisingly, we found that most CRC cells that disseminated and entered the blood circulation were Lgr5-. Lgr5- cancer cells arriving at the metastatic site formed lesions in which Lgr5+ CSCs appeared. This plasticity could occur independently of stemness-inducing factors, and was an indispensable event for the outgrowth of metastases, since neutralization of this plasticity prevented metastatic outgrowth. Combined, our study shows that most metastases are seeded by Lgr5- cancer cells, and that these cells have a niche-independent and intrinsic capacity to become CSCs and restore epithelial hierarchy.
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Project description:Platelets are blood cells who play critical roles in numerous biological and disease processes. This study was designed to identify lncRNAs that may play a role in platelet reactivity. In this study, by using large-scale deep sequencing, we determined the expression profiles of lncRNAs in both hyperreactive and hyporeactive human platelets. To determine the potential link between the expression of lncRNAs and the function of platelets, the expression profiles of hyperreactive and hyporeactive platelets were compared. Compared with hyperreactive platelets, deep sequencing analysis demonstrated that differential lncRNA expression was a remarkable characteristic in hyporeactive platelets.
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Project description:Beyond a function in hemostasis and thrombosis, platelets can regulate innate and adaptive immune responses. Hyperactive platelets are frequently associated with multiple human autoimmune diseases, yet their pathogenic functions in these diseases have not been fully established. Emerging studies show an essential function of the phosphatase and tensin homolog (PTEN) in maintenance of immune homeostasis. Here, we show that mice with platelet-specific deletion of Pten, develop age-related lymphoproliferative diseases and humoral autoimmunity not seen in wildtype animals. Platelet-specific Pten-deficient mice have aberrant T cell activation, excessive T follicular helper (Tfh) cell responses and accumulation of platelet aggregates in lymph nodes. Transferred Pten-deficient platelets are able to infiltrate into the peripheral lymphoid tissues and form more aggregates. Moreover, Pten-deficient platelets are hyperactive and overproduce multiple Tfh-promoting cytokines via activation of the PDK1/mTORC2-AKT-SNAP23 pathway. Pten-deficient platelets show enhanced interaction with CD4+ T cells and promote conversion of CD4+ T cells into Tfh cells. Our results implicate PTEN in platelet-mediated immune homeostasis, and provide evidence that hyperactive platelets function as an important mediator in autoimmune diseases using mouse models.
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Project description:Platelets are active players in hemostasis, coagulation, and tumorigenesis. The cross-talk between platelets and circulating tumor cells (CTCs) has been suggested to have a myriad of pro-cancerous effects including promoting tumor growth, epithelial-mesenchymal transition (EMT) induction, aiding metastatic cells for survival, adhesion, arrest, setting up the pre-metastatic niche and metastasis. These interactions might cause alterations on the transcriptome of the platelets. However, as CTCs are rare events, the cross-talk between CTCs and platelets is poorly understood. Taking advantage of established colon CTC lines, we aim to explore the reciprocal interaction of colon CTCs and platelets in vitro.
2023-08-03 | GSE230557 | GEO
Project description:Early diagnosis of acute myeloid leukemia (AML) in the pre-leukemic stage remains a clinical challenge, as pre-leukemic patients show no symptoms, lacking any known morphological or numerical abnormalities in blood cells. Here, we demonstrate that platelets with structurally abnormal mitochondria emerge at the pre-leukemic phase of AML, preceding detectable changes in blood cell counts or detection of leukemic blasts in blood. We visualized frozen-hydrated platelets from mice at different time points during AML development in situ using electron cryo-tomography (cryo-ET) and identified intracellular organelles through an unbiased semi-automatic process followed by quantitative measurement. A large proportion of platelets exhibited changes in the overall shape and depletion of organelles in AML. Notably, 23% of platelets in pre-leukemic cells exhibit abnormal, round mitochondria with unfolded cristae, accompanied by a significant drop in ATP levels and altered expression of metabolism-related gene signatures. Our study demonstrates that detectable structural changes in pre-leukemic platelets may serve as a biomarker for the early diagnosis of AML.
2022-02-08 | GSE189844 | GEO