NELL-1 regulates the matrisome to alter osteosarcoma disease progression
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ABSTRACT:
PROVIDER: PRJNA757449 | ENA |
REPOSITORIES: ENA
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Project description:Sarcomas produce abnormal extracellular matrix (ECM) which in turn provides instructive cues for cell growth and invasion. Neural EGF Like-Like molecule 1 (NELL-1) is a secreted glycoprotein characterized by its non-neoplastic osteoinductive effects, yet highly expressed in skeletal sarcomas. Here, NELL1 gene deletion markedly reduced invasive behavior across human osteosarcoma (OS) cell lines. This resulted in reduced OS disease progression, inhibited metastatic potential and improved survival in a xenograft model. These observations were recapitulated with Nell1 conditional knockout in mouse models of p53/Rb driven sarcomagenesis, including reduced tumor frequency, and extended tumor free survival. Transcriptomic and phospho-proteomic analysis demonstrated NELL1 loss skews the expression of matricellular proteins associated with reduced FAK signaling. Culture on OS enriched matricellular proteins reversed phenotypic and signaling changes among NELL1 knockout sarcoma cells. These findings in mouse and human models suggest that NELL-1 expression alters the sarcoma matrix, thereby modulating cellular invasive potential and prognosis. Disruption of NELL-1 signaling may represent a novel therapeutic approach to short circuit sarcoma disease progression.
2022-08-10 | GSE182703 | GEO
Project description:CNTNAP4 signaling regulates osteosarcoma disease progression
| PRJNA865383 | ENA
Project description:Improved treatment strategies for sarcoma rely on clarification of the molecular mediators of disease progression. Recently, we identified the secreted glycoprotein NELL1 modulates osteosarcoma (OS) disease progression in part via altering the sarcomatous extracellular matrix and cell-ECM interactions. Of known NELL1 interactor proteins, Contactin-associated protein-like 4 (Cntnap4) encodes a member of the neurexin superfamily of transmembrane molecules best known for its presynaptic functions in the central nervous system. Here, CRISPR/Cas9 gene deletion of CNTNAP4 reduced OS tumor growth, sarcoma-associated angiogenesis, and pulmonary metastases. CNTNAP4 knockout (KO) in OS tumor cells largely phenocopied the effects of NELL1 KO, including reductions in sarcoma cell attachment, migration, and invasion. Moreover, CNTNAP4 KO cells were unresponsive to the effects of NELL1 treatment. Transcriptomic analysis combined with protein phosphoarrray demonstrated notable reductions in MAPK signaling with CNTNAP4 deletion, the ERK agonist isoproterenol restored OS cell functions among CNTNAP4 KO tumor cells. Finally, human primary cells and tissues in combination with publicly available sequencing data confirmed the significance of CNTNAP4 signaling in human sarcomas. In summary, our findings demonstrate the biological importance of NELL-1/CNTNAP4 signaling in disease progression of human sarcomas and suggest that targeting NELL-1/CNTNAP4 signaling represents a strategy with therapeutic benefit in sarcoma patients.
2023-01-11 | GSE210373 | GEO
Project description:Purpose: The goal of this study was to identify BET-dependent pathways in the PDAC stroma and the epithelial compartment. Methods: Monocultures and Cocultures of a low passage PDAC cell line (MGH1319) and a cancer-associated fibroblast cell line (CAF-1) were treated with either BETi (CPI203) or CTRL for 24 hours. Each condition was done as a single experiment and all cells were subjected to FACS, RNA was isolated using the RNeasy Micro Kit (CAT No.74004) and sequenced at 75 bp Pair End on the NextSeq sequencer (Illumina). qRT–PCR validation was performed using TaqMan assays. Results: In vitro co-cultures of PDAC and CAF cells demonstrated that matrisome expression was regulated by BET-dependent PDAC-CAF crosstalk. Conclusions: PDAC matrisome expression is dependent on tumor-stroma crosstalk and regulated in parts by BET proteins.
2020-09-30 | GSE155442 | GEO
Project description:Metastatic ovarian tissues represent a complex tumour microenviroment. We analysed the tumour matrisome and immune cell environment in 39 metastatic ovarian tissues. We developed a disease score system, which positively correlated with the tumour matrisome. A distinct matrisome signature was identfied with increasing disease. Immune abundance and phenotype positively correaletd with tumour matrisome components. We developed a decellularised tissue model using metastatic ovarian omental tissues that maintained ECM protein content and architecture and cultured human blood-derived macrophages derived from four different donors. Monocytes cultured on high diseased tissues differerntiated into a distinct macrophage population, different from uninvovled (low disease) samples. Tumour ECM cultured macrophages had pro-tumorgenic phenotype and function.
2023-03-24 | GSE186145 | GEO
Project description:It has been reported that GLI2 promotes proliferation, migration, and invasion of mesenchymal stem cell and osteosarcoma cells. To examine the molecular mechanisms of GLI2-mediated osteosarcoma metastasis, we performed a microarray analysis. The gene encoding ribosomal protein S3 (RPS3) was identified as a target of GLI2. Real-time PCR revealed that RPS3 was upregulated in osteosarcoma cell lines compared with normal osteoblast cells. Knockdown of GLI2 decreased RPS3 expression, whereas forced expression of a constitutively active form of GLI2 upregulated the expression of RPS3. RPS3 knockdown by siRNA decreased the migration and invasion of osteosarcoma cells. Although forced expression of constitutively active GLI2 increased the migration of human mesenchymal stem cells, knockdown of RPS3 reduced the up-regulated migration. In contrast, forced expression of RPS3 increased migration and invasion of osteosarcoma cells. Moreover, reduction of migration by GLI2 knockdown was rescued by forced expression of RPS3. Immunohistochemical analysis showed that RPS3 expression was increased in primary osteosarcoma lesions with lung metastases compared with those without. These findings indicate that GLI2–RPS3 signaling may be a marker of invasive osteosarcoma and a therapeutic target for patients with osteosarcoma.
2012-12-14 | GSE42903 | GEO
Project description:High Expression of SRSF1 Facilitates Osteosarcoma Progression and Unveilsits Potential Mechanisms
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Project description:In this study, through coupling of our ISDoT tissue decellularisation technology with quantitative mass spectrometry, we explored the changing tumour matrisome during mammary tumourigenesis in the PyMT breast cancer model compared to age-matched healthy control mammary gland
2022-03-30 | MSV000089167 | MassIVE
Project description:Pulmonary metastasis continues to be the most common cause of death in osteosarcoma. Indeed, the 5-year survival for newly diagnosed osteosarcoma patients has not significantly changed in over 20 years. Further understanding of the mechanisms of metastasis and resistance for this aggressive pediatric cancer is necessary. Pet dogs naturally develop osteosarcoma providing a novel opportunity to model metastasis development and progression. Given the accelerated biology of canine osteosarcoma, we hypothesized that a direct comparison of canine and pediatric osteosarcoma expression profiles may help identify novel metastasis-associated tumor targets that have been missed through the study of the human cancer alone. Collectively, these data support the strong similarities between human and canine osteosarcoma and underline the opportunities provided by a comparative oncology approach as a means to improve our understanding of cancer biology and therapy.
2009-11-04 | GSE16088 | GEO
Project description:Pulmonary metastasis continues to be the most common cause of death in osteosarcoma. Indeed, the 5-year survival for newly diagnosed osteosarcoma patients has not significantly changed in over 20 years. Further understanding of the mechanisms of metastasis and resistance for this aggressive pediatric cancer is necessary. Pet dogs naturally develop osteosarcoma providing a novel opportunity to model metastasis development and progression. Given the accelerated biology of canine osteosarcoma, we hypothesized that a direct comparison of canine and pediatric osteosarcoma expression profiles may help identify novel metastasis-associated tumor targets that have been missed through the study of the human cancer alone. Collectively, these data support the strong similarities between human and canine osteosarcoma and underline the opportunities provided by a comparative oncology approach as a means to improve our understanding of cancer biology and therapy.
2009-11-04 | GSE16087 | GEO