New Molecular Clues Explain Aggressive Neuroblastoma and Point to Targeted Treatments

An international team led by researchers from the Institute of Biomedicine of Seville has identified new molecular clues that help explain why some cases of neuroblastoma, one of the most common childhood cancers, evolve in a particularly aggressive way while others exhibit a much more favorable behavior.

Neuroblastoma is the most common extracranial solid tumor in children and is responsible for approximately 15% of childhood cancer deaths. Its most perplexing feature is its enormous clinical variability: in some patients it may even remit spontaneously, while in others it progresses rapidly, with metastasis and relapses, despite intensive treatment.

The study, led by Francisco M. Vega and Ricardo Pardal from the Neural Stem Cell Pathophysiology group, with María A. Gómez-Muñoz as first author, focused on systematically analyzing the Rho GTPases signaling network, a family of key proteins involved in cellular processes such as morphology, migration, proliferation, and especially differentiation. It was published in the journal Cell Commun Signal.

Cell Differentiation

Cell differentiation—that is, the degree of maturation of a cell—is a determining factor in the behavior of neuroblastoma. Tumors with a higher proportion of immature or undifferentiated cells tend to be more aggressive and resistant to treatment. However, until now, a comprehensive evaluation of the role of the different Rho GTPases subfamilies and their regulators in this pediatric tumor had not been performed.

To address this question, researchers analyzed gene expression profiles in multiple cohorts of neuroblastoma patients. They studied not only Rho GTPases, but also their regulators (such as GAP and GEF proteins) and their effectors, correlating expression levels with clinical parameters such as stage, presence of metastases, relapse, survival, and high-risk genetic alterations.

The results revealed widespread dysregulation of Rho GTPase signaling in tumors. Some proteins, such as RHOA and RHOV, were increased in advanced stages of the disease and were associated with greater malignancy. In contrast, others, such as RHOB, RHOU, and, particularly significantly, Cdc42, showed reduced levels in the most aggressive tumors and were linked to a worse prognosis.

The key role of CDC42

One of the most significant findings of the study is precisely the role of Cdc42. Analyses demonstrated that its low expression is strongly correlated with adverse parameters and reduced survival. Furthermore, the team experimentally confirmed, both in cell lines and in vivo models, that decreased Cdc42 expression is necessary to maintain the malignant and undifferentiated phenotype of neuroblastoma cells.

Conversely, when Cdc42 levels increase , tumor cells tend to differentiate. Researchers observed that its overexpression drives neuritogenesis—the formation of neuronal processes—and promotes microtubule stability, processes associated with cell maturation. In fact, increasing Cdc42 was sufficient to promote the differentiation of cells derived from undifferentiated tumoriforms, while reducing it reinforced a more primitive and proliferative state.

These data suggest that Cdc42 may act as a functional tumor suppressor in neuroblastoma, regulating the balance between differentiation and pluripotency. In practical terms, its molecular activity could be considered a kind of “biological brake” that limits tumor aggressiveness by encouraging cells to leave the immature state.

The study also identifies a possible mechanism responsible for the decrease in Cdc42 in the most aggressive tumors. Researchers detected elevated levels of ARHGAP31 —also known as CdGAP— in undifferentiated neuroblastoma progenitor cells . This protein acts as a negative regulator of Cdc42. In gene silencing experiments, reducing ARHGAP31 led to a significant increase in Cdc42 and reproduced the effects observed with its overexpression: decreased proliferation and increased differentiation.

This CdGAP/Cdc42 molecular axis could play a key role in the most treatment-resistant cell populations , characterized by their high plasticity and ability to regenerate tumors. Identifying this mechanism opens the door to therapeutic strategies aimed not only at destroying cancer cells, but also at forcing their maturation, thereby reducing their malignant potential.

Relevant clinical implications of the new molecular clues

Beyond the cellular mechanisms, the work also has relevant clinical implications. Based on a global analysis of the Rho GTPases network, the team developed a minimal genetic signature with strong prognostic value. This signature, based on the expression of a small set of genes related to this pathway, demonstrated the ability to predict patient survival in different independent cohorts.

Identifying molecular biomarkers with predictive value is especially important in a tumor as heterogeneous as neuroblastoma. Currently, one of the major clinical challenges is adjusting treatment intensity to each patient’s actual risk: avoiding overly aggressive therapies in low-risk cases and, at the same time, intensifying or innovating in those with high-risk disease to improve outcomes.

The authors note that, although Rho GTPases are emerging as important mediators of tumor progression, they have historically been difficult to target pharmacologically. Therefore, they suggest that a more promising strategy could involve directing therapies against their regulators —such as the GAP and GEF proteins—or against specific components of the signaling network associated with aggressive phenotypes.

Taken together, these findings reinforce the idea that cell identity and plasticity are central to neuroblastoma biology. Understanding how the balance between differentiation and pluripotency is regulated not only helps explain the clinical variability of the disease but also offers new opportunities for designing more precise therapies.

This work lays the groundwork for future research aimed at validating therapeutic targets within the Rho GTPases network and translating these observations to clinical practice. In pediatric cancer, where aggressiveness can mean the difference between cure and relapse, deciphering these molecular mechanisms represents a crucial step toward more effective and personalized treatments.

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(Featured image by 3D illustrations via Unsplash)

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First published in GACETA MEDICA. A third-party contributor translated and adapted the article from the original. In case of discrepancy, the original will prevail.

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