Biology subjects

Roque, R.

Publications and source records attributed to Roque, R..

3 recordsLinked to original sources

bioRxiv2026

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

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.

cancer biology↗

bioRxiv2022

UBE2C promotes leptomeningeal dissemination and is a therapeutic target in brain metastatic disease

Despite current improvements in systemic cancer treatment, brain metastases (BM) remain incurable, and there is an unmet clinical need for effective targeted therapies. Here, we sought common molecular events in brain metastatic disease. RNA sequencing of thirty human BM identified the upregulation of UBE2C, a gene that ensures the correct transition from metaphase to anaphase, across different primary tumor origins. Tissue microarray analysis of an independent BM patient cohort revealed that high expression of UBE2C was associated with decreased survival. UBE2C-driven orthotopic mouse models developed extensive leptomeningeal dissemination, likely due to increased migration and invasion. Early cancer treatment with dactolisib (dual PI3K/mTOR inhibitor) prevented the development of UBE2C-induced leptomeningeal metastases. Our findings reveal UBE2C as a key player in the development of metastatic brain disease and highlight PI3K/mTOR inhibition as a promising anticancer therapy to prevent late-stage metastatic brain cancer.

cancer biology↗

bioRxiv2020

Patient-derived models of brain metastases recapitulate the histopathology and biology of human metastatic cancers

PurposeDissemination of cancer cells from primary tumors to the brain is observed in the great majority of cancer patients, contributing to increased morbidity and being the main cause of death. Most mechanistic and preclinical studies have relied on aggressive cancer cell lines, which fail to represent tumor heterogeneity and are unsuitable to validate therapies due to fast cancer progression in vivo. Experimental designWe established a unique library of subcutaneous and intracardiac patient-derived xenografts (PDXs) of brain metastases (BMs) from eight distinct primary tumor origins. Cancer progression in mice was compared to the matched patient clinical outcome, metastatic dissemination pattern and histopathological features. Preclinical studies with FDA approved drugs were performed. ResultsIn vivo tumor formation of flank-implanted BMs correlated with patients poor survival and serial passaging increased tumor aggressiveness. Subcutaneous xenografts originated spontaneous metastases in 61% of the cases, including in the leptomeningeal space (21%). The intracardiac model increased the tropism to the brain and leptomeninges (46%). Strikingly, 62% of intracardiac PDXs shared metastatic sites with the donor patients, including the primary cancer organ and the central nervous system (CNS). Of therapeutic relevance, PDX-derived cultures and corresponding mouse xenografts can be effectively treated with targeted anticancer drugs. ConclusionsPatient-derived models of BMs recapitulate the biology of human metastatic disease and can be a valuable translational platform for precision medicine. TRANSLATIONAL RELEVANCESubcutaneous and intracardiac mouse xenografts of human brain metastases exhibit a spontaneous dissemination pattern that resembles patients metastatic disease. The preclinical testing of targeted anticancer drugs using patient-derived cultures and patient-derived xenografts of brain metastasis showed an effective therapeutic response. These translational models represent an outstanding tool to advance the understanding of the biology of brain metastases and to foster the rapid discovery of novel therapeutics.

cancer biology↗