To B (Bone Morphogenic Protein-2) or Not to B (Bone Morphogenic Protein-2): Mesenchymal Stem Cells May Explain the Protein’s Role in Osteosarcomagenesis

Xu, Chunfeng; Wang, Mingjie; Zandieh-Doulabi, Behrouz; Sun, Wei; Wei, Lingfei; Liu, Yuelian

doi:10.3389/fcell.2021.740783

Cited by 4 publications

(2 citation statements)

References 161 publications

(173 reference statements)

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“…First, based on bulk RNA results, we focused on osteogenic-related expression among tumor cells ( Figure 4B ). Osteosarcomagenesis has been reported to be closely associated with the osteoblastic lineage and shows osteogenic differentiation-related activity in proliferation, ECM secretion and ossification induction ( 25 , 26 ). We noticed that C11, C18 and C38 strongly upregulated proliferative expression, including DNA replication, chromosome organization and miotic expression.…”

Section: Resultsmentioning

confidence: 99%

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Development of a Chemoresistant Risk Scoring Model for Prechemotherapy Osteosarcoma Using Single-Cell Sequencing

Zeng

Zhang

et al. 2022

Front. Oncol.

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BackgroundChemoresistance is one of the leading causes that severely limits the success of osteosarcoma treatment. Evaluating chemoresistance before chemotherapy poses a new challenge for researchers. We established an effective chemoresistance risk scoring model for prechemotherapy osteosarcoma using single-cell sequencing.MethodsWe comprehensively analyzed osteosarcoma data from the bulk mRNA sequencing dataset TARGET-OS and the single-cell RNA sequencing (scRNA-seq) dataset GSE162454. Chemoresistant tumor clusters were identified using enrichment analysis and AUCell scoring. Its differentiated trajectory was achieved with inferCNV and pseudotime analysis. Ligand–receptor interactions were annotated with iTALK. Furthermore, we established a chemoresistance risk scoring model using LASSO regression based on scRNA-seq-based markers of chemoresistant tumor clusters. The TARGET-OS dataset was used as the training group, and the bulk mRNA array dataset GSE33382 was used as the validation group. Finally, the performance was verified for its discriminatory ability and calibration.ResultsUsing bulk RNA data, we found that osteogenic expression was upregulated in chemoresistant osteosarcoma as compared to chemosensitive osteosarcoma. Then, we transferred the bulk RNA findings to scRNA-seq and noticed osteosarcoma tumor clusters C14 and C25 showing osteogenic cancer stem cell expression patterns, which fit chemoresistant characteristics. C14 and C25 possessed bridge roles in interactions with other clusters. On the one hand, they received various growth factor stimulators and could potentially transform into a proliferative state. On the other hand, they promote local tumor angiogenesis, bone remodeling and immunosuppression. Next, we identified a ten-gene signature from the C14 and C25 markers and constructed a chemoresistant risk scoring model using LASSO regression model. Finally, we found that chemoresistant osteosarcoma had higher chemoresistance risk score and that the model showed good discriminatory ability and calibration in both the training and validation groups (AUCtrain = 0.82; AUCvalid = 0.84). Compared with that of the classic bulk RNA-based model, it showed more robust performance in validation environment (AUCvalid-scRNA = 0.84; AUCvalid-bulk DEGs = 0.54).ConclusionsOur work provides insights into understanding chemoresistant osteosarcoma tumor cells and using single-cell sequencing to establish a chemoresistance risk scoring model. The model showed good discriminatory ability and calibration and provided us with a feasible way to evaluate chemoresistance in prechemotherapy osteosarcoma.

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Section: Resultsmentioning

confidence: 99%

“…In addition, we noticed that the transmission came through upregulating osteoblastic differentiation-like expression. Studies have revealed that osteoblastic differentiation is closely associated with osteosarcoma tumorigenesis ( 25 , 26 ). This result supported the osteogenic CSC roles of C14 and C25.…”

Section: Discussionmentioning

confidence: 99%

Development of a Chemoresistant Risk Scoring Model for Prechemotherapy Osteosarcoma Using Single-Cell Sequencing

Zeng

Zhang

et al. 2022

Front. Oncol.

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Bone regeneration after marginal bone resection in two-stage treatment of chronic long bone infection - a combined histopathological and clinical pilot study

Wang

Alagboso

Walter

et al. 2022

Injury

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The contribution of the novel CLTC-VMP1 fusion gene to autophagy regulation and energy metabolism in cisplatin-resistant osteosarcoma

Zou,

Tao,

Yang

et al. 2025

American Journal of Physiology-Cell Physiology

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Osteosarcoma (OS) is a highly malignant tumor, and chemotherapy resistance is a major challenge in the treatment of this disease. This study aims to explore the role of the CLTC-VMP1 gene fusion in the mechanism of chemotherapy resistance in OS and investigate its molecular mechanisms in mediating energy metabolism reprogramming by regulating autophagy and apoptosis balance. Using single-cell transcriptome analysis, the heterogeneity of OS cells and their correlation with resistance to platinum drugs were revealed. Cisplatin-resistant cell lines were established in human OS cell lines for subsequent experiments. Based on transcriptomic analysis, the importance of VMP1 in chemotherapy resistance was confirmed. Lentiviral vectors overexpressing or interfering with VMP1 were used, and it was observed that inhibiting VMP1 could reverse cisplatin resistance, promote cell apoptosis, and inhibit autophagy, as well as mitochondrial respiration and glycolysis. Furthermore, the presence of CLTC-VMP1 gene fusion was validated, and its ability to regulate autophagy and apoptosis balance, promote mitochondrial respiration, and glycolysis was demonstrated. Mouse model experiments further confirmed the promoting effect of CLTC-VMP1 on tumor growth and chemotherapy resistance. In summary, the CLTC-VMP1 gene fusion mediates energy metabolism reprogramming by regulating autophagy and apoptosis balance, which promotes chemotherapy resistance in OS.

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To B (Bone Morphogenic Protein-2) or Not to B (Bone Morphogenic Protein-2): Mesenchymal Stem Cells May Explain the Protein’s Role in Osteosarcomagenesis

Cited by 4 publications

References 161 publications

Development of a Chemoresistant Risk Scoring Model for Prechemotherapy Osteosarcoma Using Single-Cell Sequencing

Development of a Chemoresistant Risk Scoring Model for Prechemotherapy Osteosarcoma Using Single-Cell Sequencing

Bone regeneration after marginal bone resection in two-stage treatment of chronic long bone infection - a combined histopathological and clinical pilot study

The contribution of the novel CLTC-VMP1 fusion gene to autophagy regulation and energy metabolism in cisplatin-resistant osteosarcoma

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