Targeting autocrine CCL2 signaling reveals oncogenic networks and prognostic biomarkers in medulloblastoma
Abstract
BackgroundCCL2 is a well-established mediator of immune cell recruitment to the tumor microenvironment (TME), however, its autocrine role in medulloblastoma remains poorly understood. This study investigated the molecular and prognostic consequences of CCL2 ablation in medulloblastoma cells.MethodsCCL2 expression was characterized in HTB-186 medulloblastoma cells, and CRISPR/Cas9 was used to generate CCL2 knockout (KO) cells. Transcriptomic alterations were assessed by RNA sequencing followed by differential gene expression, KEGG pathway, and Gene Ontology analyses. Select signaling pathways were validated by cytokine and protein analyses. The prognostic significance of differentially expressed genes was evaluated using Kaplan-Meier and multivariable Cox proportional hazards analyses in the Cavalli medulloblastoma cohort (n = 488).ResultsHTB-186 cells expressed high levels of CCL2, and approximately 40% of cells expressed the CCL2 receptor CCR2, supporting the existence of autocrine signaling. CCL2 ablation resulted in 2, 284 differentially expressed genes and significantly altered pathways involved in PI3K/Akt, NF-κB, JAK/STAT, cAMP, and Hippo signaling. These transcriptomic findings were confirmed by reduced IL-6 production and altered activation of Akt, NF-κB, CREB, and YAP. Survival analyses identified four genes upregulated following CCL2 knockout (KSR2, DLG4, DGKA, and PLD2) that were associated with improved overall survival, whereas four downregulated genes (HSPA8, MYC, CCND1, and ETS2) were associated with poorer survival. These associations remained significant after adjustment for age, sex, metastatic status, histology, and molecular subgroup.ConclusionsOur findings demonstrate that autocrine CCL2 signaling regulates multiple oncogenic pathways in medulloblastoma and promotes transcriptional programs associated with tumor growth, survival, and poor clinical outcome. These results identify CCL2 as a potential therapeutic target and highlight CCL2-regulated gene signatures as candidate prognostic biomarkers in medulloblastoma.
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BibTeX
@article{donninger2026targeting,
title = {{Targeting autocrine CCL2 signaling reveals oncogenic networks and prognostic biomarkers in medulloblastoma}},
author = {Howard Donninger and Elizabeth B. Amona and Raphael Jigo and Lewis C. Chew and Preethi Sundararaj and Omar S. Sarkar and Megan Jacobs and Ryley Ortega and Maiying Kong and Kavitha Yaddanapudi},
journal = {Frontiers in Oncology},
year = {2026},
month = nov,
doi = {10.3389/fonc.2026.1968412},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1968412},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Targeting autocrine CCL2 signaling reveals oncogenic networks and prognostic biomarkers in medulloblastoma
AU - Howard Donninger
AU - Elizabeth B. Amona
AU - Raphael Jigo
AU - Lewis C. Chew
AU - Preethi Sundararaj
AU - Omar S. Sarkar
AU - Megan Jacobs
AU - Ryley Ortega
AU - Maiying Kong
AU - Kavitha Yaddanapudi
PY - 2026
DA - 2026/11/06
JO - Frontiers in Oncology
DO - 10.3389/fonc.2026.1968412
UR - https://www.frontiersin.org/articles/10.3389/fonc.2026.1968412
AB - BackgroundCCL2 is a well-established mediator of immune cell recruitment to the tumor microenvironment (TME), however, its autocrine role in medulloblastoma remains poorly understood. This study investigated the molecular and prognostic consequences of CCL2 ablation in medulloblastoma cells.MethodsCCL2 expression was characterized in HTB-186 medulloblastoma cells, and CRISPR/Cas9 was used to generate CCL2 knockout (KO) cells. Transcriptomic alterations were assessed by RNA sequencing followed by differential gene expression, KEGG pathway, and Gene Ontology analyses. Select signaling pathways were validated by cytokine and protein analyses. The prognostic significance of differentially expressed genes was evaluated using Kaplan-Meier and multivariable Cox proportional hazards analyses in the Cavalli medulloblastoma cohort (n = 488).ResultsHTB-186 cells expressed high levels of CCL2, and approximately 40% of cells expressed the CCL2 receptor CCR2, supporting the existence of autocrine signaling. CCL2 ablation resulted in 2, 284 differentially expressed genes and significantly altered pathways involved in PI3K/Akt, NF-κB, JAK/STAT, cAMP, and Hippo signaling. These transcriptomic findings were confirmed by reduced IL-6 production and altered activation of Akt, NF-κB, CREB, and YAP. Survival analyses identified four genes upregulated following CCL2 knockout (KSR2, DLG4, DGKA, and PLD2) that were associated with improved overall survival, whereas four downregulated genes (HSPA8, MYC, CCND1, and ETS2) were associated with poorer survival. These associations remained significant after adjustment for age, sex, metastatic status, histology, and molecular subgroup.ConclusionsOur findings demonstrate that autocrine CCL2 signaling regulates multiple oncogenic pathways in medulloblastoma and promotes transcriptional programs associated with tumor growth, survival, and poor clinical outcome. These results identify CCL2 as a potential therapeutic target and highlight CCL2-regulated gene signatures as candidate prognostic biomarkers in medulloblastoma.
SN - 2234-943X
ER -