NELL-1 regulates the matrisome to alter osteosarcoma disease progression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA757449 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15600639_1.fastq.gz | Fastqsanger.gz | |||
| SRR15600639_2.fastq.gz | Fastqsanger.gz | |||
| SRR15600641_1.fastq.gz | Fastqsanger.gz | |||
| SRR15600641_2.fastq.gz | Fastqsanger.gz | |||
| SRR15600642_1.fastq.gz | Fastqsanger.gz |
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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:Sarcomas produce an abnormal extracellular matrix (ECM), which in turn provides instructive cues for cell growth and invasion. Neural EGF like-like molecule 1 (NELL1) is a secreted glycoprotein characterized by its nonneoplastic osteoinductive effects, yet it is highly expressed in skeletal sarcomas. Here, we show that genetic deletion of NELL1 markedly reduces invasive behavior across human osteosarcoma (OS) cell lines. NELL1 deletion resulted in reduced OS disease progression, inhibiting metastasis and improving survival in a xenograft mouse model. These observations were recapitulated with Nell1 conditional knockout in mouse models of p53/Rb-driven sarcomagenesis, which reduced tumor frequency and extended tumor-free survival. Transcriptomic and phosphoproteomic analyses demonstrated that NELL1 loss skews the expression of matricellular proteins associated with reduced FAK signaling. Culturing NELL1 knockout sarcoma cells on wild-type OS-enriched matricellular proteins reversed the phenotypic and signaling changes induced by NELL1 deficiency. In sarcoma patients, high expression of NELL1 correlated with decreased overall survival. These findings in mouse and human models suggest that NELL1 expression alters the sarcoma ECM, thereby modulating cellular invasive potential and prognosis. Disruption of NELL1 signaling may represent a novel therapeutic approach to short-circuit sarcoma disease progression.SignificanceNELL1 modulates the sarcoma matrisome to promote tumor growth, invasion, and metastasis, identifying the matrix-associated protein as an orchestrator of cell-ECM interactions in sarcomagenesis and disease progression.
| S-EPMC9357190 | biostudies-literature
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:Improved treatment strategies for sarcoma rely on clarification of the molecular mediators of disease progression. Recently, we reported that the secreted glycoprotein NELL-1 modulates osteosarcoma (OS) disease progression in part via altering the sarcomatous extracellular matrix (ECM) and cell-ECM interactions. Of known NELL-1 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 NELL-1 KO, including reductions in sarcoma cell attachment, migration, and invasion. Further, CNTNAP4 KO cells were found to be unresponsive to the effects of NELL-1 treatment. Transcriptomic analysis combined with protein phospho-array demonstrated notable reductions in the MAPK/ERK signaling cascade with CNTNAP4 deletion, and the ERK1/2 agonist isoproterenol restored cell functions among CNTNAP4 KO tumor cells. Finally, human primary cells and tissues in combination with sequencing datasets confirmed the significance of CNTNAP4 signaling in human sarcomas. In summary, our findings demonstrate the biological importance of NELL-1/CNTNAP4 signaling axis in disease progression of human sarcomas and suggest that targeting the NELL-1/CNTNAP4 signaling pathway represents a strategy with potential therapeutic benefit in sarcoma patients.
| S-EPMC9813000 | biostudies-literature
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:Background: Osteosarcoma, a primary malignant bone tumor predominantly affecting children and adolescents, exhibits a dismal prognosis for patients with metastatic or recurrent disease, characterized by low five-year survival rates. This poor outcome is largely attributed to the incomplete understanding of the molecular mechanisms governing osteosarcoma aggressiveness and metastasis, coupled with a paucity of effective early diagnostic biomarkers and targeted therapeutic strategies. Consequently, elucidating the critical molecular events driving osteosarcoma pathogenesis and identifying novel biomarkers are of paramount importance for improving patient outcomes. Prior research has demonstrated aberrant expression of Zinc Finger DHHC-Type Palmitoyltransferase 9 (ZDHHC9) in various malignancies, but its specific function and clinical significance in osteosarcoma remain poorly defined. Methods: This study employed a comprehensive approach integrating bioinformatic analyses and experimental validation to investigate the functional role and clinical relevance of ZDHHC9 in osteosarcoma. Bioinformatic analyses (TIMER, GEPIA, TCGA databases) were utilized to examine ZDHHC9 expression across a pan-cancer landscape and its association with survival in osteosarcoma patients. Immunohistochemistry (IHC) and Western blotting were employed to analyze ZDHHC9 expression in clinical osteosarcoma specimens and cell lines. In vitro assays (CCK-8, colony formation, wound healing, Transwell, flow cytometry, and Western blotting) were performed to evaluate the impact of ZDHHC9 on osteosarcoma cell proliferation, migration, and invasion. Proteomic sequencing, molecular docking, and co-immunoprecipitation (Co-IP) experiments were conducted to explore the interaction between ZDHHC9 and KRAS. Western blotting was used to analyze the regulation of Raf1, ERK1/2, and p-ERK1/2 expression by ZDHHC9 and KRAS. Finally, a xenograft model was employed to assess the effect of ZDHHC9 on in vivo tumor growth. Results: Bioinformatic analyses revealed that elevated ZDHHC9 expression correlates with poor prognosis in osteosarcoma. IHC and Western blotting confirmed significantly increased ZDHHC9 expression in osteosarcoma tissues compared to adjacent non-tumorous tissues. Upregulation of ZDHHC9 was significantly associated with elevated Ki67 levels and advanced Enneking stage, suggesting a link to tumor aggressiveness. In vitro studies demonstrated that downregulation of ZDHHC9 suppressed osteosarcoma cell proliferation, migration, and invasion, while promoting apoptosis. Conversely, upregulation of ZDHHC9 elicited opposite effects. Proteomic sequencing revealed that ZDHHC9 knockdown significantly downregulated the expression of proteins associated with the RAS/MAPK signaling pathway. Functional experiments showed that overexpression of KRAS partially abrogated the inhibitory effects of ZDHHC9 knockdown on cell proliferation, migration, and invasion. Molecular docking and Co-IP experiments confirmed a specific interaction between ZDHHC9 and KRAS, leading to activation of the RAS/MAPK signaling pathway. Conclusion: ZDHHC9 promotes osteosarcoma cell proliferation, migration, and invasion by enhancing KRAS-mediated activity of the RAS/MAPK signaling pathway, which promotes cell cycle progression while inhibiting apoptosis.
2025-10-27 | PXD066322 | Pride
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: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