Biology subjects

Ruivo, P.

Publications and source records attributed to Ruivo, P..

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↗

bioRxiv2026

Systemic hypoxia suppresses solid tumor growth

Local hypoxia is a hallmark of solid tumors and a negative prognostic factor in the progression and treatment of cancer. Here, we showed that systemic hypoxia, in contrast to localized tumor hypoxia, decreases tumor growth in vivo across multiple cancer types and preclinical models. The reduced tumor growth in systemic hypoxia was not explained by hypoglycemia, hypoinsulinemia, or HIF activation. Instead, metabolite profiling in tumors and tumor interstitial fluid revealed extensive perturbations in purine-related metabolites. Stable isotope tracing demonstrated that systemic hypoxia caused tumors to suppress de novo purine synthesis. Furthermore, tumors did not develop resistance to systemic hypoxia therapy, and when used in combination with chemotherapy or immunotherapy, systemic hypoxia dramatically suppressed tumor growth. Finally, we showed that systemic hypoxia can be achieved pharmacologically with the small molecule HypoxyStat. These findings challenge the long-held paradigm of hypoxia as a negative prognostic factor in cancer progression, and they suggest a potential therapeutic role for systemic hypoxia in suppressing solid tumor growth.

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↗