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Spatial transcriptomic atlas of aggressive osteosarcomas reveals shared gene surface expression and immune landscape.

ABSTRACT: Osteosarcoma remains a highly aggressive malignancy with limited advancements in treatment efficacy and survival rates over the past four decades. Current therapeutic strategies fail in a significant proportion of patients, leading to metastatic relapse and poor prognosis. The substantial genomic instability and cellular plasticity of osteosarcoma contribute to its complex biology, necessitating innovative approaches for improved diagnosis and treatment. In this study, we applied spatial transcriptomics (ST) to 26 osteosarcoma samples, primary tumors and metastatic or local relapse samples. We described diverse differentiation phenotypes, ranging from mostly undifferentiated to metaphyseal-like organized highly differentiated phenotypes. Despite the phenotypic variability within and across samples, a comprehensive surfaceome analysis identified 306 cancer-specific membrane protein genes, among which nine formed a robust osteosarcoma-specific theranostic signature validated in multiple bulk RNAseq datasets. Additionally, spatial analysis of immune cell dynamics confirmed the systemic lymphoid cell exclusion and distinguished between cancer-excluded and -infiltrating myeloid populations. This identified three distinct populations along the osteoclastic lineage, with a systematic cancer-infiltration capacity. Cancer-infiltrating potential was also associated with type I interferon response and specific integrin-mediated adhesion mechanisms. This study provides a valuable resource to improve the understanding of osteosarcoma biology. We also suggest new clinically relevant targets in osteosarcoma, enabling the development of adapted and targeted treatment strategies for patients with the hope of improving clinical outcomes in the future.

ORGANISM(S): Homo sapiens

PROVIDER: GSE293065 | GEO | 2026/04/10

REPOSITORIES: GEO

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Project description:Background Identification of the molecular determinants of invasion and metastatic potential may guide the development of a rational strategy for devising specific therapies that target the pathways leading to osteosarcoma. Methods In this study, we used pathway-focused GEarrays to screen for candidate genes related to tumor progression. Expression patterns of the selected genes were validated by real time PCR on 61 osteosarcoma patient tumor samples and correlated with clinical and pathological data. Results THBS3, SPARC and SPP1 were identified with pathway-focused GEarrays as genes differentially expressed in osteosarcoma. In particular, THBS3 was expressed at significantly high levels (p=0.0001) in biopsies from patients with metastasis at diagnosis, which is a predictor of worse overall survival, event-free survival and relapse free survival at diagnosis. After chemotherapy, patients with tumors over-expressing THBS3 have worse relapse free survival. High SPARC expression was found in 51 of 55 (96.3%) osteosarcoma samples and correlated with the worst event-free survival (p=0.03) and relapse free survival (p=0.07). Overexpression of SPP1 was found in 47 of 53 (89%) osteosarcomas correlating with better overall survival, event-free survival and relapse free survival at diagnosis. Conclusion With pathway-focused Gearrays, we identified three genes, which interestingly all encode for proteins involved in extracellular remodeling suggesting potential roles in osteosarcoma progression. This is the first report on the THBS3 gene working as a stimulator of tumor progression. Higher levels of THBS3 maintain the capacity of angiogenesis. High levels of SPARC are not required for tumor progression but are necessary for tumor growth and maintenance. SPP1 is not necessary for tumor progression in osteosarcoma and may be associated with inflammatory response and bone remodeling, functioning as a good biomarker. Keywords: disease state analysis using Superarray Pathway focused arrays

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Spatial transcriptomic atlas of aggressive osteosarcomas reveals shared gene surface expression and immune landscape.

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