CCR2 is a potential biomarker and therapeutic target in Group 3 medulloblastoma

Abstract

Background: Medulloblastoma (MB) is the most common malignant pediatric brain tumor, classified into four molecular subgroups: WNT, SHH, Group 3, and Group 4. Among these, Group 3 MB displays the worst prognosis with highest rates of dissemination and the worst survival outcomes. While current therapies control the primary tumor, metastatic disease remains largely incurable underscoring the need for novel therapeutic options. The CCL2/CCR2 axis is a well establish metastases driver in systemic tumors through the promotion of angiogenesis and cell migration. Recently, this axis has been implicated in MB pathogenesis and dissemination, particularly in Group 3 tumors. Therefore, we hypothesize that CCR2 represents a therapeutically actionable driver in aggressive MB. Methods: The clinical relevance of CCR2 in MB was assessed using publicly available gene expression data from two independent datasets. CCR2 expression was further evaluated by immunohistochemistry on paired primary and recurrent/metastatic tumor samples to validate these findings. Functional studies using ONS76 and UW228 MB cells with CCR2 overexpression evaluated proliferation, migration and CCR2 downstream signaling. Orthotopic xenograft mouse models assessed CCR2 effect on tumor invasion, dissemination, and survival. An in-silico drug screening identified potential CCR2 antagonists that were tested in vitro and in vivo. Results: Gene expression data analysis across 1094 MB primary samples correlated high CCR2 expression with dissemination and reduced survival in Group 3 MB patients. In an independent MB patient cohort, CCR2 protein levels were increased in recurrent/metastatic tumors compared with paired primary tumors. CCR2 overexpression in vitro promoted cancer cell proliferation and migration. CCR2-driven MB mouse xenografts, exhibited an aggressive disease phenotype and decreased survival, resembling Group 3 tumors. CCR2 targeting with Cenicriviroc suppressed CCR2-mediated signaling and showed therapeutic efficacy against established MB tumors in vivo. Conclusions: CCR2 identifies aggressive Group 3 MB and represents a promising actionable target for therapy.