A groundbreaking study from St. Jude Children’s Research Hospital is shedding new light on the elusive molecular mechanisms behind ependymoma, a pediatric brain tumor that ranks third in prevalence among childhood malignancies. By delving into the biophysical behavior of an abnormal fusion protein, ZFTA–RELA, which is implicated in approximately 95% of ependymoma cases in the brain cortex, researchers have unveiled a critical role played by biomolecular condensates in tumor development. These condensates, described as membraneless organelles, are emerging as vital organizational hubs within cells that concentrate specific molecules to carry out diverse biological functions. The study’s publication in the prestigious journal Nature Cell Biology marks an important milestone in understanding how fusion proteins orchestrate cancer progression at a biophysical level.
While conventional therapeutic strategies for ependymoma have remained relatively stagnant for the past three decades, this research offers a transformative perspective by characterizing the ZFTA–RELA fusion protein’s unique molecular properties. The team, co-led by Dr. Stephen Mack and Dr. Richard Kriwacki at St. Jude, demonstrated that the intrinsically disordered regions within the RELA component of the fusion protein mediate the condensation into droplets within the nucleus of cells. These condensates serve as critical assemblies that not only concentrate proteins and nucleic acids but also modulate gene expression programs central to oncogenesis. This discovery provides a fresh conceptual framework for how fusion oncoproteins leverage phase separation and condensate formation to drive malignancy.
The fusion protein ZFTA–RELA is composed of two distinct domains with complementary functional contributions. The ZFTA portion directly binds to DNA, anchoring the condensates to chromatin and targeting specific gene loci, while the RELA region, characterized by a lack of defined tertiary structure, facilitates the dynamic assembly of condensates through multivalent weak interactions. This property, known as intrinsic disorder, enables flexible conformations and transient interactions that are essential for droplet nucleation. These findings align with emerging paradigms in molecular cell biology where phase separation and dynamic condensate formation modulate critical cellular processes, including transcriptional regulation.
Intriguingly, experimental deletion of the disordered RELA segment abrogated condensate formation entirely and prevented ependymoma formation in murine models. This causal link illustrates that the condensate assembly driven by intrinsic disorder is necessary for the oncogenic program. Furthermore, by replacing the RELA domain with other unrelated disordered protein regions, the authors demonstrated that the condensate formation mechanism is robust and transferrable, underscoring the fundamental role of disordered regions in mediating oncogenic condensates. Such modularity hints at a universal principle by which diverse fusion proteins could hijack phase separation pathways to perturb chromatin biology and promote cancer.
The implications of these discoveries are profound. Traditional drug development targeting fusion proteins has been notoriously challenging due to their structural complexity and lack of obvious enzymatic activity. By shifting focus to the condensates themselves and their constituent interacting partners, researchers now envision novel therapeutic strategies that could disrupt the formation or stability of oncogenic condensates, thereby dampening aberrant gene expression. This indirect targeting approach exploits the biophysical dependencies of tumor cells, potentially opening a new frontier in precision oncology for ependymoma and other fusion-driven cancers.
Within the formed condensates, the ZFTA domain guides localization to DNA elements encoding oncogenes, orchestrating a localized and aberrant transcriptional activation. These membraneless organelles function as specialized transcriptional microenvironments, concentrated hubs where molecular machinery is spatially organized to drive oncogene expression. The biophysical nature of condensates—fluid yet structured assemblies governed by weak multivalent interactions—allows dynamic regulation and responsiveness, characteristics that pathological fusion proteins co-opt for tumorigenesis.
Given the critical dependency of ependymoma tumor cells on these condensates, dismantling their architecture could yield therapeutic benefit. The study’s insights suggest that targeting scaffold proteins or co-factors essential for condensate maintenance may represent viable drug targets. Identifying such interacting partners within condensates is the next logical step and could provide the basis for developing small molecules or biologics that selectively impair tumor-specific phase-separated compartments without affecting normal cellular functions.
Moreover, these findings resonate beyond ependymoma. Numerous other cancers involve fusion oncoproteins with intrinsically disordered regions, implying that condensate formation may be a widespread oncogenic mechanism. This emerging concept elevates biomolecular condensates as a unifying principle in cancer biology and highlights the importance of biophysical investigations in understanding the spatial-temporal regulation of gene expression by pathological proteins.
The researchers emphasize that their discovery of aberrant condensate assembly mechanisms challenges conventional paradigms in cancer research that focus predominantly on genetic mutations or signaling pathways. Instead, it draws attention to the physical chemistry of intracellular environments as a critical determinant of malignancy. Such interdisciplinary approaches integrating structural biology, cell biology, and oncology are vital to unraveling complex diseases like ependymoma and developing innovative interventions.
Funded by multiple prominent agencies including the National Cancer Institute, the Department of Defense, the National Institutes of Health, and foundations dedicated to pediatric cancer research, this study represents a significant collaborative effort aimed at deciphering the molecular underpinnings of childhood brain tumors. The multidisciplinary team of co-first authors and collaborators from institutions worldwide exemplifies the global commitment to tackling this devastating disease through cutting-edge science.
In summary, St. Jude Children’s Research Hospital scientists have unveiled a novel biophysical mechanism wherein the oncogenic ZFTA–RELA fusion protein drives ependymoma by assembling biomolecular condensates essential for aberrant gene expression. This breakthrough not only redefines our understanding of fusion protein-driven cancers but also suggests exciting new avenues for therapeutic development targeting the condensate machinery. As the field of biomolecular phase separation continues to expand, this work situates ependymoma at the forefront of cancer biology’s new frontier.
Subject of Research: Mechanisms of condensate formation by the ZFTA–RELA fusion protein driving childhood ependymoma brain tumors.
Article Title: Research implicates biomolecular condensates in a type of childhood brain cancer
News Publication Date: August 27, 2025
Web References:
- St. Jude Media Contact Stephen Mack
- St. Jude Department of Structural Biology
- St. Jude Department of Developmental Neurobiology
- Original Article DOI
Image Credits: St. Jude Children’s Research Hospital
Keywords: Structural biology, Developmental neuroscience, Biomolecular condensates, Phase separation, Fusion oncoproteins, Ependymoma, Childhood brain cancer, Intrinsically disordered proteins, Transcriptional regulation, Cancer biology
