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Aggressive tumours are defined by microenvironmental stress adaptation and metabolic reprogramming. Within this niche, lipid droplet accumulation has emerged as a key strategy to buffer toxic lipids and suppress ferroptosis. Lipid droplet formation can occur via de novo lipogenesis or extracellular lipid-scavenging. However, how tumour cells coordinate these processes remains poorly understood. Here we identify a chondroitin sulfate (CS)-enriched glycocalyx as a hallmark of the acidic microenvironment in glioblastoma and central nervous system metastases. This CS-rich glycocalyx encapsulates tumour cells, limits lipid particle uptake and protects against lipid-induced ferroptosis. Mechanistically, we demonstrate that converging hypoxia-inducible factor and transforming growth factor beta signalling induces a glycan switch on syndecan-1—replacing heparan sulfate with CS—thereby impairing its lipid-scavenging function. Dual inhibition of CS biosynthesis and diacylglycerol O-acyltransferase-1, a critical enzyme in lipid droplet formation, triggers catastrophic lipid peroxidation and ferroptotic cell death. These findings define glycan remodelling as a core determinant of metabolic plasticity, positioning the dynamic glycocalyx as a master regulator of nutrient access, ferroptotic sensitivity and therapeutic vulnerability in cancer.

Neuron–glioma interactions are critical drivers of glioma progression, with neuronal activity promoting tumor growth and invasion through paracrine signaling and direct synaptic input. Beyond well-established glutamatergic synapses, recent discoveries revealed that GABAergic interactions also contribute to glioma proliferation. Here, we focus on how glioma cells decode neuronal cues via epigenetic mechanisms, including enhancer reprogramming, chromatin remodeling, and rewiring of 3D genome organization, with transcriptions factors such as SMAD3 and PITX1 orchestrating transcriptional programs that sustain neuron-to-glioma communication. Additionally, recent integration of multi-omics data highlights gene regulatory networks linked to GABAergic signaling as contributors to glioblastoma (GB) pathogenesis. We also underscore the distinct roles of GABAergic signaling across glioma subtypes, noting that, in GB, GABA-related metabolic and paracrine mechanisms, rather than synaptic input, may drive tumor progression. Understanding how epigenetic reprogramming facilitates glioma integration into neural circuits opens new avenues to disrupt these malignant neuron–glioma interactions by targeting the epigenetic machinery.

Wnt signaling plays a pivotal role during development and homeostasis. Upon pathway activation, CTNNB1 (also known as beta-catenin) drives the expression of target genes from regulatory regions bound by TCF/LEF transcription factors. Gene regulation, however, entails the interplay between sequence information and 3D genome structure, yet the impact of Wnt signaling on genome structure has been poorly explored. Here, we investigate how Wnt signaling influences CTCF and cohesin, key regulators of 3D genome organization. We identify a series of novel CTCF binding sites that emerge upon Wnt stimulation: CTCF Redistributions Under Wnt (RUW). RUW sites are characterized by CTCF, cohesin, and TCF/LEF occupancy, and are dependent on beta-catenin. Beta-catenin and CTCF colocalize upon pathway activation, and disruption of selected binding sites perturbs target gene regulation. Moreover, Wnt signaling reorganizes the 3D genome as evidenced by genome-wide alterations in CTCF-bound loops. This work reveals a previously unexplored role for CTCF in the regulation of Wnt signaling.

Chromatin organization controls transcription by modulating 3D-interactions between enhancers and promoters in the nucleus. Alterations in epigenetic states and 3D-chromatin organization result in gene expression changes contributing to cancer. Here, we map the promoter-enhancer interactome and regulatory landscape of glioblastoma, the most aggressive primary brain tumour. Our data reveals profound rewiring of promoter-enhancer interactions, chromatin accessibility and redistribution of histone marks in glioblastoma. This leads to loss of long-range regulatory interactions and overall activation of promoters, which orchestrate changes in the expression of genes associated to glutamatergic synapses, axon guidance, axonogenesis and chromatin remodelling. SMAD3 and PITX1 emerge as major transcription factors controlling genes related to synapse organization and axon guidance. Inhibition of SMAD3 and neuronal activity stimulation cooperate to promote proliferation of glioblastoma cells in co-culture with glutamatergic neurons, and in mice bearing patient-derived xenografts. Our findings provide mechanistic insight into the regulatory networks that mediate neurogliomal synaptic communication.