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.
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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.
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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.
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