Multi-omics analysis identifies osteosarcoma subtypes with distinct prognosis indicating stratified treatment

Jiang, Yafei; Wang, Jinzeng; Sun, Mengxiong; Zuo, Dongqing; Wang, Hongsheng; Shen, Junhao; Jiang, Wenyan; Mu, Haoran; Ma, Xiao‐Jun; Yin, Fei; Lin, Jun; Wang, Chongren; Yu, Shuting; Jiang, Lu; Lv, Gang; Liu, Feng; Xue, Liyan; Tian, Kai; Wang, Gangyang; Zhou, Zifei; Lv, Yu; Wang, Zhuoying; Zhang, Tao; Xu, Jing; Liu, Yang; Zhao, Ke-Wen; Sun, Wei; Tang, Yujie; Cai, Zhengdong; Wang, Shengyue; Hua, Yingqi

doi:10.1038/s41467-022-34689-5

Cited by 40 publications

(35 citation statements)

References 98 publications

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“…Moreover, our study validate that the BM-MSCs with co-deletion of WWOX and p53 are tumorigenic compared to p53 deletion alone although with a later latency as compared with BM-MSCs harboring p53 and Rb co-deletion 34 . Furthermore, our DKO yBM model exhibited early molecular pathway enrichment, which is consistent with a recent multi-omics analysis performed on human OS clinical samples 35 . Interestingly, Myc amplification and overexpression of Myc targets were detected and correlated with a worse prognosis, indicating the crucial role of Myc in osteosarcomagenesis.…”

Section: Discussionsupporting

confidence: 89%

WWOX promotes osteosarcoma development via upregulation of Myc

Akkawi¹,

Monin²,

Diment³

et al. 2023

Preprint

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Osteosarcoma (OS) is an aggressive bone tumor that primarily affects children and adolescents. This malignant tumor is highly aggressive, associated with poor clinical outcomes, and metastasizes mainly to the lungs. Due to its rarity and biological heterogeneity, limited studies of its molecular basis exist, thus hindering the development of effective therapies. WW domain-containing oxidoreductase (WWOX) spans one of the most active and common fragile sites that is frequently altered in human OS. The combined deletion of Wwox and Trp53 using Osterix1-Cre transgenic mice has been shown to accelerate OS development. In this study, we generated a traceable OS mouse model, SKO-Trp53 or DKO-Wwox/Trp53, expressing a tdTomato reporter. By tracking tomato expression at different time points, we detected the early presence of tdTomato-positive cells in the bone marrow (BM) mesenchymal stem cells (MSCs) of non-OS bearing mice, young BM (yBM). We found that DKO yBM cells, but not SKO yBM cells, exhibited tumorigenic traits both in vitro and in vivo. Molecular and cellular characterization of these DKO yBM cells revealed their resemblance to OS tumor cells. Interestingly, one of the early observed transcriptomic changes in DKO yBM was the upregulation of Myc and its target genes compared to SKO yBM cells. As a prototype target, we further demonstrated the upregulation of MCM7, a known Myc target, in DKO yBM relative to SKO yBM. Therapeutic targeting of MCM7 using simvastatin (SVA) resulted in attenuation of OS tumor growth. Our findings reveal BM-MSCs as a platform to study OS, and reveal Myc and its targets as early molecular events during osteosarcomagenesis.

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Section: Discussionsupporting

confidence: 89%

WWOX promotes osteosarcoma development via upregulation of Myc

Akkawi¹,

Monin²,

Diment³

et al. 2023

Preprint

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“…We used different methods to identify the heterogeneity of OS, but partially with similar molecular features and clinical prognosis, such as Immune activated (S-IA) and our immunogenic subtype both have immunological traits and better clinical prognosis. Their Immune suppressed (S-IS) subtype has activated adipogenesis and fatty acid metabolism-related pathways and encodes the fatty acid scavenger receptor CD36 which is in line with our adipocyte-like subtype [64]. We explored the heterogeneity and the underlying mechanism of OS that could help to provide better, customized therapy.…”

Section: Discussionmentioning

confidence: 90%

Abnormal signal pathways and tumor heterogeneity in osteosarcoma

et al. 2023

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Background Osteosarcoma (OS) is the most frequent and aggressive primary malignant sarcoma among adolescents and chemotherapy has not substantially progressed for decades. New insights into OS development and therapeutic strategies are urgently needed. Methods We analyzed integrated single-cell transcriptomes, bulk RNA-seq, and microarray data from Gene Expression Omnibus (GEO) datasets. We also used Weighted Gene Co-expression Network Analysis (WGCNA), Gene set enrichment analysis (GSEA), and Gene set variation analysis (GSVA), along with Simple ClinVar and Enrichr web servers. Results The findings of integrated single-cell analysis showed that OS arises from imperfect osteogenesis during development. Novel abnormalities comprised deficient TGFβ and P53 signal pathways, and cell cycle pathway activation, and a potentially new driver mutation in the interferon induced transmembrane protein 5 (IFITM5) that might function as a pathogenic factor in OS. Osteosarcoma is characterized by oncocyte heterogeneity, especially in immunogenic and adipocyte-like subtypes that respectively promote and hamper OS treatment. Etoposide is a promising chemotherapeutic that provides palliation by affecting the subtype of OS and correcting the abnormal pathways. Conclusion Various abnormal signal pathways play indispensable roles in OS development. We explored the heterogeneity and underlying mechanisms of OS and generated findings that will assist with OS assessment and selecting optimal therapies.

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“…Future research will seek to identify and validate novel functional neoantigens that may aid in the killing of OS tumor cells in vivo , as we demonstrated that vitamin D 3 disproportionately induced the upregulation of NMD-target genes in OS cells. In addition, it appears that calcipotriol may function similarly to 1,25(OH) 2 D, with enhanced effects on cell migration and gene expression across multiple pathways, such as EMT and NMD, within subtypes of OS cells 113 .…”

Section: Discussionmentioning

confidence: 99%

Vitamin D inhibits osteosarcoma by reprogramming nonsense-mediated RNA decay and SNAI2-mediated epithelial-to-mesenchymal transition

Capobianco

McGaughey

Seraphin

et al. 2023

Preprint

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Osteosarcomas are immune-resistant and metastatic in part due to an increase in nonsense-mediated RNA decay (NMD), reactive oxygen species (ROS), and epithelial-to-mesenchymal transition (EMT) induction. In this study, we examined the impact of vitamin D3 and its receptor (VDR) on the NMD-ROS-EMT signaling axis in osteosarcoma cells and spheroids, as well as wound-induced cell migration and osteosarcoma metastasis in vivo models. Activated VDR signaling enriched the EMT pathway in gene set enrichment analysis, whereas the active vitamin D3 metabolite, 1,25(OH)2D, inhibited EMT in osteosarcoma subtypes. Because EMT processes in cancer and tissue wounds are similar, experimentally induced EMT of mouse hair follicle stem cells revealed that Vdr signaling restricts cell migration during cutaneous wound healing. In osteosarcoma cells, ligand bound VDR inhibited EMT by interacting directly with and downregulating the EMT inducer SNAI2. Differential epigenetic regulation of SNAI2 and VDR distinguished highly metastatic from low metastatic osteosarcoma subtypes and responsiveness to 1,25(OH)2D. Furthermore, epigenome-wide motif and putative target gene analysis revealed the integration of the VDR with the NMD tumor immunogenic pathway. In an autoregulatory manner, 1,25(OH)2D inhibited NMD machinery genes, while simultaneously inducing the overexpression of known NMD target genes involved in tumor immune recognition and cell-to-cell adhesion. Dicer substrate siRNA knockdown of SNAI2 revealed superoxide dismutase 2 (SOD2)-mediated antioxidative responses and 1,25(OH)2D sensitization, which involves the non-canonical SOD2 nuclear-to-mitochondrial translocalization and inhibition of ROS. Calcipotriol, a clinically relevant non-calcemic vitamin D3 derivative, inhibited osteosarcoma metastasis in a mouse xenograft model. Our research reveals novel vitamin D3 and calcipotriol osteosarcoma-inhibiting processes.

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Multi-omics analysis identifies osteosarcoma subtypes with distinct prognosis indicating stratified treatment

Cited by 40 publications

References 98 publications

WWOX promotes osteosarcoma development via upregulation of Myc

WWOX promotes osteosarcoma development via upregulation of Myc

Abnormal signal pathways and tumor heterogeneity in osteosarcoma

Vitamin D inhibits osteosarcoma by reprogramming nonsense-mediated RNA decay and SNAI2-mediated epithelial-to-mesenchymal transition

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