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Age-Related Alterations in Immune Contexture Are Associated with Aggressiveness in Rhabdomyosarcoma
Patrizia Gasparini1, Orazio Fortunato2, Loris De Cecco3
1Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy. patrizia.gasparini@istitutotumori.mi.it.
Insights
Adolescents and young adults with rhabdomyosarcoma (RMS) show distinct microRNA and gene expression profiles compared to children. These molecular differences, particularly in immune cell signaling, may drive tumor aggressiveness and impact patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Adolescents and young adults (AYA) with rhabdomyosarcoma (RMS) have poorer survival rates than children.
- Understanding the molecular differences between pediatric and AYA-RMS is crucial for improving treatment outcomes.
Purpose of the Study:
- To investigate the molecular distinctions, including microRNA and gene expression, between AYA-RMS and pediatric RMS.
- To identify potential therapeutic targets and understand the biological basis for AYA-RMS aggressiveness.
Main Methods:
- MicroRNA and gene expression profiling (GEP) on 49 RMS tumors and 15 non-neoplastic tissues.
- Validation using Real-Time PCR, miRNA in situ hybridization (ISH), and immunohistochemistry (IHC).
Main Results:
- Over-expression of miR-223 and down-regulation of miR-431 were observed in AYA-RMS.
- Significant age-correlated gene expression changes were detected, including down-modulation of NOTCH2 and FGFR1/2.
- AYA-RMS tumors showed increased infiltration of CD4, CD8, and neutrophils, with altered gene expression related to immune cells.
Conclusions:
- Distinct molecular profiles, including microRNA and immune microenvironment alterations, characterize AYA-RMS.
- These differences in tumor biology and immune contexture may contribute to the aggressiveness of AYA-RMS.
- Targeting these molecular and immune differences could lead to improved therapeutic strategies for AYA-RMS.
Abstract:
Adolescents and young adults (AYA) with rhabdomyosarcoma (RMS) form a subgroup of patients whose optimal clinical management and access to care remain a challenge and whose survival lacks behind that of children diagnosed with histologically similar tumors. Understanding the tumor biology that differentiates children from AYA-RMS could provide critical information and drive new initiatives to improve the final outcome. MicroRNA (miRNA) and gene expression profiling (GEP) was evaluated in a RMS cohort of 49 tumor and 15 non-neoplastic tissues. miRNAs analysis identified miR-223 over-expression and miR-431 down-regulation in AYA, validated by Real-Time PCR and miRNA in situ hybridization (ISH). GEP analysis detected 793 age-correlated genes in tumors, of which 194 were anti-correlated. NOTCH2, FGFR1/2 were significantly down-modulated in AYA-RMS. miR-223 was associated with up-regulation of epithelial mesenchymal translation (EMT) and inflammatory pathways, whereas miR-431 was correlated to myogenic differentiation and muscle metabolism. GEP showed an increase in genes associated with CD4 memory resting cells and a decrease in genes associated with γδ T-cells in AYA-RMS. Immunohistochemistry (IHC) analysis demonstrated an increase of infiltrated CD4, CD8, and neutrophils in AYA-RMS tumors. Our results show that aggressiveness of AYA-RMS could be explained by differences in microenvironmental signal modulation mediated by tumor cells, suggesting a fundamental role of immune contexture in AYA-RMS development.
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