A recent study of the Childhood Cancer and Blood Disorders group at Vall d'Hebron Research Institute (VHIR) has identified a new therapeutic strategy that could, by epigenetic reprogramming tumor cells, block the metastasis process in patients with neuroblastoma, a highly aggressive pediatric cancer.

Tumors of embryonic origin usually appear at an early age and there is increasing evidence that epigenome alterations play an important role in their development and progression. These alterations in chromatin structure, which directly affects the correct expression of genes in the different cell lineages, allow the survival, invasiveness, and metastatic capacity of many embryonal tumors. Among them is neuroblastoma, which represents between 8% and 10% of all childhood cancers and 15% of all cancer deaths in children. This is why new therapeutic strategies are urgently needed for these patients, and epigenetic therapies that reverse these important alterations in the epigenome are an increasingly promising option.

In this study, recently published in the journal Molecular Cancer, in collaboration with groups from the Institute for Research in Biomedicine of Barcelona (IRB) and the Bellvitge Biomedical Research Institute (IDIBELL), researchers from the Neural Tumors laboratory at VHIR have identified the key role in the evolution of neuroblastoma of a highly altered epigenetic regulator, the BAF chromatin remodeling complex. The results demonstrate the relevant role of BAF in the maintenance of a gene expression program that allows neuroblastoma cells to invade and grow in the target organs of the metastatic process.

The role of BAF in neuroblastoma expansion

The researchers have carried out a comprehensive study of the BAF complex in neuroblastoma cells, integrating proteomic, transcriptomic and chromatin accessibility data. "Until now, the role of this epigenetic regulator in neuroblastoma was very enigmatic, but our results shed light on its functions as a regulator of the epigenome of these tumor cells, and have allowed us to discover that it is required for the expression of a broad set of genes essential for the process of metastasis," states Dr. Carlos Jiménez, a postdoctoral researcher in the Neural Tumors laboratory and first author of this study. The inhibition of two structural subunits of this multiprotein complex results in its structural disintegration, which allows an epigenetic inactivation of a gene expression program, simultaneously repressing multiple key effectors involved in the metastatic invasion. "We have identified something like an epigenetic switch which allows us to inactivate multiple integrins and cadherins, membrane proteins that allow cells to interact with their environment and invade new organs", adds. The effects of this epigenetic reprogramming were tested in mice models*, resulting in a significant disruption of the target organ invasion by neuroblastoma cells and the subsequent metastatic growth, and allowing the animals' survival to be expanded in nearly all cases.

This interdisciplinary work highlights the importance of creating synergies between the different biomedical research centers in Barcelona, as collaboration with basic and translational research groups has been crucial. On one hand, the participation of the researchers Mariona Nadal, Pablo La Torre and Carme Solé from the Cell Signaling group at IRB and Universitat Pompeu Fabra, led by Eulàlia de Nadal and Francesc Posas, has allowed the detection of chromatin remodeling events after blocking the BAF complex using the cutting-edge ATAC-Seq technology, which is key to the conclusions of the study. On the other hand, the participation of the researchers Laura Devis and David Llobet, from the Oncobell program (Molecular Mechanisms and Experimental Therapy in Oncology) of IDIBELL, allowed associating a high activity of the BAF complex with a worse prognosis of neuroblastoma patients, through the biostatistical analysis of gene expression data, bringing these findings closer to the clinical reality.

An important step in developing new therapies

"This research in addition to answering major questions about the function of the BAF complex in neuroblastoma and contributing to our understanding of the epigenome of these tumors, represents an important step in the development of new epigenetic therapies for the treatment of a highly metastatic and aggressive disease," says Dr. Miguel Segura, head of the Neural Tumors laboratory. In fact, this study has highlighted the need to design and develop new drugs that reproduce the structural disruption of this chromatin remodeling complex and that allow the clinical implementation of these findings, and from which patients with neuroblastoma and other oncological diseases could benefit. "These results represent the starting point for new research projects focused on the generation of an epigenetic therapy for metastatic neuroblastoma with the BAF chromatin remodeling complex as a target," concludes Dr. Segura.

This interdisciplinary work highlights the importance of creating synergies between the different biomedical research centers in Barcelona, as collaboration with basic and translational research groups has been crucial. On one hand, the participation of the researchers Mariona Nadal, Pablo La Torre and Carme Solé from the Cell Signaling group at IRB and Universitat Pompeu Fabra, led by Eulàlia de Nadal and Francesc Posas, has allowed the detection of chromatin remodeling events after blocking the BAF complex using the cutting-edge ATAC-Seq technology, which is key to the conclusions of the study. On the other hand, the participation of the researchers Laura Devis and David Llobet, from the Oncobell program (Molecular Mechanisms and Experimental Therapy in Oncology) of IDIBELL, allowed associating a high activity of the BAF complex with a worse prognosis of neuroblastoma patients, through the biostatistical analysis of gene expression data, bringing these findings closer to the clinical reality.

The study was made possible thanks to funding from the Acción Estratégica en Salud of the Instituto de Salud Carlos III, as well as the Ayudas para la contratación de personal investigador predoctoral en formación (FI) of the Generalitat de Catalunya and the European Social Fund. The research team also highlights the support of patient family associations such as the NEN Association, the Joan Petit Foundation, the Candela Bracelets Association, and the Rotary Foundation.

*Institutional Declaration on the Use of Animals in Research