Osteosarcoma cells-derived secretome induce pre-metastatic changes in the lung microenvironment that support lung metastasis formation
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ABSTRACT:
PROVIDER: PRJNA895082 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22070309.fastq.gz | Fastqsanger.gz | |||
| SRR22070310.fastq.gz | Fastqsanger.gz | |||
| SRR22070311.fastq.gz | Fastqsanger.gz | |||
| SRR22070312.fastq.gz | Fastqsanger.gz | |||
| SRR22070313.fastq.gz | Fastqsanger.gz |
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Project description:To investigate the molecular and cellular alterations occurring in the lung tissue during the pre-metastatic niche formation in osteosarcoma, we used two different approaches in which mice were implanted subcutaneously with the 143B OS cells for a primary tumour (PT) formation or treated with the 143B cell-derived secretome (SCR) to mimic the release of secreted factors by a locally primary tumour.
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Project description:Purpose: Lung metastasis is responsible for nearly all deaths caused by osteosarcoma, the most common pediatric bone tumor. How malignant bone cells coerce the lung microenvironment to support metastatic growth is unclear. This study delineates how osteosarcoma cells educate the lung microenvironment during metastatic progression. Experimental design: Using single-cell transcriptomics (scRNA-seq), we characterized genome- and tissue-wide molecular changes induced within lung tissues by disseminated osteosarcoma cells in both immunocompetent murine models of metastasis and patient samples. We confirmed transcriptomic findings at the protein level and determined spatial relationships with multi-parameter immunofluorescence. We evaluated the ability of nintedanib to impair metastatic colonization and prevent osteosarcoma-induced education of the lung microenvironment in both immunocompetent murine osteosarcoma and immunodeficient human xenograft models. Results: Osteosarcoma cells induced acute alveolar epithelial injury upon lung dissemination. scRNA-seq demonstrated that the surrounding lung stroma adopts a chronic, non-resolving wound-healing phenotype similar to that seen in other models of lung injury. Accordingly, metastasis-associated lung demonstrated marked fibrosis, likely due to the accumulation of pathogenic, pro-fibrotic, partially-differentiated epithelial intermediates. Inhibitionintermediates. Inhibition of fibrotic pathways with nintedanib prevented metastatic progression in multiple murine and human xenograft models. Conclusions: Our work demonstrates that osteosarcoma cells co-opt fibrosis to promote metastatic outgrowth. When harmonized with data from adult epithelial cancers, our results support a generalized model wherein aberrant mesenchymal-epithelial interactions are critical for promoting lung metastasis. Adult epithelial carcinomas induce fibrotic pathways in normal lung fibroblasts, whereas osteosarcoma, a pediatric mesenchymal tumor, exhibits fibrotic reprogramming in response to the aberrant wound-healing behaviors of an otherwise normal lung epithelium, which are induced by tumor cell interactions.
2024-06-19 | GSE270231 | GEO
Project description:Purpose: Lung metastasis is responsible for nearly all deaths caused by osteosarcoma, the most common pediatric bone tumor. How malignant bone cells coerce the lung microenvironment to support metastatic growth is unclear. This study delineates how osteosarcoma cells educate the lung microenvironment during metastatic progression. Experimental design: Using single-cell transcriptomics (scRNA-seq), we characterized genome- and tissue-wide molecular changes induced within lung tissues by disseminated osteosarcoma cells in both immunocompetent murine models of metastasis and patient samples. We confirmed transcriptomic findings at the protein level and determined spatial relationships with multi-parameter immunofluorescence. We evaluated the ability of nintedanib to impair metastatic colonization and prevent osteosarcoma-induced education of the lung microenvironment in both immunocompetent murine osteosarcoma and immunodeficient human xenograft models. Results: Osteosarcoma cells induced acute alveolar epithelial injury upon lung dissemination. scRNA-seq demonstrated that the surrounding lung stroma adopts a chronic, non-resolving wound-healing phenotype similar to that seen in other models of lung injury. Accordingly, metastasis-associated lung demonstrated marked fibrosis, likely due to the accumulation of pathogenic, pro-fibrotic, partially-differentiated epithelial intermediates. Inhibitionintermediates. Inhibition of fibrotic pathways with nintedanib prevented metastatic progression in multiple murine and human xenograft models. Conclusions: Our work demonstrates that osteosarcoma cells co-opt fibrosis to promote metastatic outgrowth. When harmonized with data from adult epithelial cancers, our results support a generalized model wherein aberrant mesenchymal-epithelial interactions are critical for promoting lung metastasis. Adult epithelial carcinomas induce fibrotic pathways in normal lung fibroblasts, whereas osteosarcoma, a pediatric mesenchymal tumor, exhibits fibrotic reprogramming in response to the aberrant wound-healing behaviors of an otherwise normal lung epithelium, which are induced by tumor cell interactions.
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Project description:The high concentration of Well5 cells was resuspended into 20μl PBS, the needle along the tibia direction, before reaching in a breakthrough sense, direct injection cells. At 7 days after injection, proximal tibia was able to reach mass production. At 20 days after injection, the proximal tibia mass increased.If prolonging exposure by BLI,this stage displayedthat tumor cell signalsbegan to lung metastasis. Osteosarcoma orthotopic lung metastasis model was successfully constructed. Total RNA was extracted from sorted osteosarcoma cells of the primary site and lung metastases using Trizol (Invitrogen). We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated genes during osteosarcoma lung metastasis. In support of the notion that fibrosis marks the lung metastasis, the expression of numerous fibrosis-related genes such as FN1, COLs, and MMPs were upregulated from the primary site to lung metastasis in Well5-luc orthotopic inoculation model.
2016-08-13 | GSE85537 | GEO
Project description:The high concentration of Well5 cells was resuspended into 20μl PBS, the needle along the tibia direction, before reaching in a breakthrough sense, direct injection cells. At 7 days after injection, proximal tibia was able to reach mass production. At 20 days after injection, the proximal tibia mass increased.If prolonging exposure by BLI,this stage displayedthat tumor cell signalsbegan to lung metastasis. Osteosarcoma orthotopic lung metastasis model was successfully constructed. Total RNA was extracted from sorted osteosarcoma cells of the primary site and lung metastases using Trizol (Invitrogen). We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated genes during osteosarcoma lung metastasis. In support of the notion that fibrosis marks the lung metastasis, the expression of numerous fibrosis-related genes such as FN1, COLs, and MMPs were upregulated from the primary site to lung metastasis in Well5-luc orthotopic inoculation model. Total RNA was extracted from sorted osteosarcoma cells using Trizol (Invitrogen). Gene expression profiling was conducted by Shanghai Biotechnology Corporation using Affymetrix U133 plus 2.0 arrays (Affymetrix, Santa Clara, CA). All data were analyzed according to the manufacturerâ??s protocol. Raw data generated from Affymetrix CEL files were normalized by RMA background correction; values were log2 transformed. For the enrichment of P values of each GO term, we used Fisherâ??s exact test to calculate P values and R package stats to calculate FDR (q value) by BH method (www.r-project.org).
2016-08-13 | E-GEOD-85537 | biostudies-arrayexpress
Project description:Osteosarcoma is an aggressive and deadly bone tumor, primarily afflicting children, adolescents, and young adults. Poor outcomes for osteosarcoma patients are intricately linked with the development of lung metastasis. While lung metastasis is responsible for nearly all deaths caused by osteosarcoma, identification of biologically defined, metastasis-targeting therapies remains elusive because the underlying cellular and molecular mechanisms that govern metastatic colonization of circulating tumor cells to the lung remains poorly understood. While thousands of tumor cells are released into circulation each day, very few can colonize the lung. Herein, using a combination of a novel organotypic metastasis in vitro model, single-cell RNA sequencing, human xenograft, and murine immunocompetent osteosarcoma models, we find that metastasis is initiated by a subpopulation of hypo-proliferative cells with the unique capacity to sustain production of metastasis promoting cytokines such as IL6 and CXCL8 in response to lung-epithelial derived IL1α. Critically, genomic and pharmacologic disruption of IL1 signaling in osteosarcoma cells significantly reduces metastatic progression. Collectively, our study supports that tumor-stromal interactions are important for metastasis, and suggests that metastatic competency is driven, in part, by the tumor cell’s ability to respond to the metastatic niche. Our findings support that disruption of tumor-stromal signaling is a promising therapeutic approach to disrupt metastasis progression.
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