Identification of SAMD9 as an adaptive response gene to environmental changes and its association with overall survival and immunotherapeutic response in glioblastoma

TL;DR

This study identifies SAMD9 as a gene that responds to environmental changes in glioblastoma and shows it is linked to survival and immunotherapy response.

Contribution

The study reveals SAMD9 as a novel adaptive response gene in glioblastoma with therapeutic implications.

Findings

SAMD9 is expressed in immune-suppressive tumor cells and correlates with poor anti-PD-1 treatment outcomes.

SAMD9 is upregulated in hypoxic and TAM-rich environments, contributing to Bevacizumab resistance.

Dasatinib is identified as a potential therapeutic agent for SAMD9-high glioblastoma.

Abstract

Hypoxia and immune-suppressive microenvironments in glioblastoma drive transcriptional plasticity and phenotypic transition. Understanding these processes is crucial for overcoming therapy resistance and tumor relapse. This study investigates the expression pattern of sterile alpha motif domain-containing 9 (SAMD9) under these conditions, evaluates its prognostic value and spatial distribution, and explores its therapeutic implications.

We analyzed SAMD9 expression and its prognostic value across three independent IDH-wildtype glioblastoma cohorts and validated findings via immunohistochemistry in human glioma tissues. We mapped its spatial distribution using the IvyGAP database and leveraged integrated single-cell and spatial transcriptomic data to delineate local cellular interactions. Drug sensitivities were predicted using the oncoPredict package, and molecular docking was performed with Autodock for drug screening. Key findings regarding SAMD9 expression and its inducers were experimentally validated.

SAMD9 was prominently expressed in an immune-suppressive subset of glioma tumor cells and was strongly associated with an interferon (IFN) signature. Elevated levels of SAMD9 correlated with reduced efficacy of anti-PD-1 treatment. Spatial mapping revealed that SAMD9 was predominantly distributed in regions of microvessel proliferation and peri-necrotic niches, where SAMD9-positive tumor cells actively interacted with vascular cells and tumor-associated macrophages (TAMs). Hypoxia and TAM co-culture significantly upregulated SAMD9, suggesting a mechanism for Bevacizumab resistance. SAMD9-high tumors exhibited TAM-dominated immune infiltration, confirmed by immune signatures profiling and histological staining. Drug prediction and molecular docking identified the multi-kinase inhibitor Dasatinib as a promising therapeutic agent for SAMD9-high IDH-wildtype glioblastoma.

SAMD9 emerges as an adaptive response gene to environmental changes, exhibiting a significant immunomodulatory function, which highlights its promise as a therapeutic target for IDH-wildtype glioblastoma.

The online version contains supplementary material available at 10.1186/s12935-025-04068-3.

Figures