Abnormal signal pathways and tumor heterogeneity in osteosarcoma

Abstract

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.

GANT-61 induces cell cycle resting and autophagy by down-regulating RNAP III signal pathway and tRNA-Gly-CCC synthesis to combate chondrosarcoma

“…Analyses were carried out with software package R (version 4.1.2) as previously described [ 40 ]. Significance analysis was performed by using the “limma” package.…”

Amicis Omnia Sunt Communia: NF-κB Inhibition as an Alternative to Overcome Osteosarcoma Heterogeneity

“…However, unlike other sarcomas, OS lacks recurrent genetic alterations; instead, it is highly heterogeneous with varied ploidy abnormalities, chromosomal losses and gains, and somatic DNA copy number alterations [ 85 , 86 ]. Inactivation of classical tumor suppressor genes such as TP53, RB1, and hyperactivation oncogenes, including MYC and MDM2, are also common [ 87 , 88 ]. Additionally, epigenomic, transcriptomic, proteomic, metabolomic, and functional genomic approaches have constantly expanded the number of altered signaling pathways in OS.…”

Inflammasome‐related gene signatures as prognostic biomarkers in osteosarcoma

“…The heterogeneity of osteosarcoma at the molecular level presents both a challenge and an opportunity for researchers 20,21 . The advent of high‐throughput genomic and proteomic technologies has paved the way for the in‐depth characterisation of this heterogeneity, allowing for the subdivision of osteosarcomas into molecularly distinct subtypes 22,23 .…”

“…The heterogeneity of osteosarcoma at the molecular level presents both a challenge and an opportunity for researchers. 20 , 21 The advent of high‐throughput genomic and proteomic technologies has paved the way for the in‐depth characterisation of this heterogeneity, allowing for the subdivision of osteosarcomas into molecularly distinct subtypes. 22 , 23 This stratification is not merely academic; it bears direct implications for prognosis and therapeutic strategies, guiding the course of precision medicine—a tailored approach that aligns treatment with individual tumour profiles.…”