Dr. Carlos Jiménez Jiménez, Childhood Cancer and Blood Disorders group.

Epigenetic programming during development is essential for the determination of cell lineages, and its alteration contributes to the initiation of embryonal tumors. In neuroblastoma, neural crest progenitors block their natural differentiation course into sympathoadrenergic cells, leading to an aggressive and metastatic pediatric cancer. The study of the epigenetic regulators responsible for oncogenic epigenomic networks is crucial to develop new epigenetic-based therapies against these tumors.

mSWI/SNF ATP-dependent chromatin remodeling complexes act genome-wide translating epigenetic signals into opened chromatin states. With the aim of understanding the role of mSWI/SNF complexes in the control of the oncogenic epigenomes of neuroblastoma, we carried out a functional characterization of these remodelers in neuroblastoma cells by proteomic, transcriptomic and chromatin accessibility approaches, discovering that only the structural disruption of BAF subtype complexes impairs proliferation by promoting cell cycle blockade. Genome-wide chromatin remodeling analysis coupled with whole transcriptome data revealed that BAF disruption results in the epigenetic repression of an extensive invasiveness-related expression program, involving integrins, cadherins and key mesenchymal regulators, thereby reducing extracellular matrix adhesion and invasion in vitro, together with a drastic inhibition of neuroblastoma metastasis initiation and growth in vivo.

We defined a novel ATPase-independent role for BAF complex in the maintenance of an epigenomic program that allows neuroblastoma invasiveness and metastasis, urging the development of new BAF pharmacological structural disruptors for its therapeutic exploitation in metastatic neuroblastoma.

Host: Dr. Miguel Segura, Childhood Cancer and Blood Disorders group.