RESUMEN
The role of the nervous system in the regulation of cancer is increasingly appreciated. In gliomas, neuronal activity drives tumour progression through paracrine signalling factors such as neuroligin-3 and brain-derived neurotrophic factor1-3 (BDNF), and also through electrophysiologically functional neuron-to-glioma synapses mediated by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors4,5. The consequent glioma cell membrane depolarization drives tumour proliferation4,6. In the healthy brain, activity-regulated secretion of BDNF promotes adaptive plasticity of synaptic connectivity7,8 and strength9-15. Here we show that malignant synapses exhibit similar plasticity regulated by BDNF. Signalling through the receptor tropomyosin-related kinase B16 (TrkB) to CAMKII, BDNF promotes AMPA receptor trafficking to the glioma cell membrane, resulting in increased amplitude of glutamate-evoked currents in the malignant cells. Linking plasticity of glioma synaptic strength to tumour growth, graded optogenetic control of glioma membrane potential demonstrates that greater depolarizing current amplitude promotes increased glioma proliferation. This potentiation of malignant synaptic strength shares mechanistic features with synaptic plasticity17-22 that contributes to memory and learning in the healthy brain23-26. BDNF-TrkB signalling also regulates the number of neuron-to-glioma synapses. Abrogation of activity-regulated BDNF secretion from the brain microenvironment or loss of glioma TrkB expression robustly inhibits tumour progression. Blocking TrkB genetically or pharmacologically abrogates these effects of BDNF on glioma synapses and substantially prolongs survival in xenograft models of paediatric glioblastoma and diffuse intrinsic pontine glioma. Together, these findings indicate that BDNF-TrkB signalling promotes malignant synaptic plasticity and augments tumour progression.
Asunto(s)
Adaptación Fisiológica , Glioma , Plasticidad Neuronal , Sinapsis , Animales , Niño , Humanos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Proliferación Celular , Progresión de la Enfermedad , Glioma/metabolismo , Glioma/patología , Ácido Glutámico/metabolismo , Neuronas/citología , Neuronas/metabolismo , Receptor trkB/genética , Receptor trkB/metabolismo , Receptores AMPA/metabolismo , Transducción de Señal , Sinapsis/metabolismo , Microambiente Tumoral , OptogenéticaRESUMEN
Development of effective targeted cancer therapies is fundamentally limited by our molecular understanding of disease pathogenesis. Diffuse intrinsic pontine glioma (DIPG) is a fatal malignancy of the childhood pons characterized by a unique substitution to methionine in histone H3 at lysine 27 (H3K27M) that results in globally altered epigenetic marks and oncogenic transcription. Through primary DIPG tumor characterization and isogenic oncohistone expression, we show that the same H3K27M mutation displays distinct modes of oncogenic reprogramming and establishes distinct enhancer architecture depending upon both the variant of histone H3 and the cell context in which the mutation occurs. Compared with non-malignant pediatric pontine tissue, we identify and functionally validate both shared and variant-specific pathophysiology. Altogether, we provide a powerful resource of epigenomic data in 25 primary DIPG samples and 5 rare normal pediatric pontine tissue samples, revealing clinically relevant functional distinctions previously unidentified in DIPG.
Asunto(s)
Glioma Pontino Intrínseco Difuso/genética , Histonas/genética , Encéfalo/patología , Neoplasias Encefálicas/genética , Reprogramación Celular/genética , Glioma Pontino Intrínseco Difuso/metabolismo , Elementos de Facilitación Genéticos/genética , Epigénesis Genética/genética , Epigenómica , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/genética , Glioma/genética , Glioma/metabolismo , Humanos , Lisina/genética , Mutación/genética , Puente/metabolismo , Transducción de Señal , Transcriptoma/fisiologíaRESUMEN
High-grade gliomas are lethal brain cancers whose progression is robustly regulated by neuronal activity. Activity-regulated release of growth factors promotes glioma growth, but this alone is insufficient to explain the effect that neuronal activity exerts on glioma progression. Here we show that neuron and glioma interactions include electrochemical communication through bona fide AMPA receptor-dependent neuron-glioma synapses. Neuronal activity also evokes non-synaptic activity-dependent potassium currents that are amplified by gap junction-mediated tumour interconnections, forming an electrically coupled network. Depolarization of glioma membranes assessed by in vivo optogenetics promotes proliferation, whereas pharmacologically or genetically blocking electrochemical signalling inhibits the growth of glioma xenografts and extends mouse survival. Emphasizing the positive feedback mechanisms by which gliomas increase neuronal excitability and thus activity-regulated glioma growth, human intraoperative electrocorticography demonstrates increased cortical excitability in the glioma-infiltrated brain. Together, these findings indicate that synaptic and electrical integration into neural circuits promotes glioma progression.
Asunto(s)
Encéfalo/fisiopatología , Sinapsis Eléctricas/patología , Fenómenos Electrofisiológicos , Glioma/fisiopatología , Animales , Encéfalo/citología , Membrana Celular/patología , Proliferación Celular , Uniones Comunicantes/patología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Xenoinjertos , Humanos , Ratones , Ratones Endogámicos NOD , Neuronas/patología , Optogenética , Potasio/metabolismo , Transmisión Sináptica , Células Tumorales CultivadasRESUMEN
In the vibrissal area of rodent somatosensory cortex, information on whisker stimulation is processed by neuronal networks in a corresponding cortical column. To understand how sensory stimuli are represented in a column, it is essential to identify cell types constituting these networks. Layer 6 (L6) comprises 25% of all neurons in a column. In rats, 430 of these are inhibitory interneurons (INs). Little is known about the axon projection of L6 INs with reference to columnar and laminar organization. We quantified axonal projections of L6 INs (n = 68) with reference to columns and layers in somatosensory cortex of rats. We found distinct projection types differentially targeting layers of a cortical column. The majority of L6 INs did not show a column-specific innervation, densely projecting to neighboring columns as well as the home column. However, a small fraction targeted granular and supragranular layers, where axon projections were confined to the home column. We also quantified putative innervation of pyramidal cells as a functional correlate of axonal distribution. Electrophysiological properties were not correlated to axon projection. The quantitative data on axonal projections and electrophysiological properties of L6 INs can guide future studies investigating cortical processing of sensory information at the single cell level.
Asunto(s)
Neuronas GABAérgicas/fisiología , Inhibición Neural/fisiología , Vías Nerviosas/fisiología , Corteza Somatosensorial/citología , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/efectos de la radiación , Animales , Animales Recién Nacidos , Dendritas , Femenino , Neuronas GABAérgicas/citología , Glutamato Descarboxilasa/metabolismo , Lisina/análogos & derivados , Lisina/metabolismo , Masculino , Parvalbúminas/metabolismo , Técnicas de Placa-Clamp , Ratas , Ratas Wistar , VibrisasRESUMEN
PURPOSE: Because treatment options at progression are limited for patients with glioma, accuracy in definition of progression is pivotal. Clinically asymptomatic, newly detected, nonmeasurable, speckled contrast-enhancing lesions (SCEs) without immediate relation to prior immune therapy or radiation therapy appear relatively frequently during the course of disease in patients with glioma and challenge the definition of progression based on Response Assessment in Neuro-oncology criteria. Therefore, data characterizing these SCEs are needed for recommendations of subsequent clinical management. MATERIALS AND METHODS: Magnetic resonance imaging of 746 patients with glioma included in this study were retrospectively revised for appearance of newly detected SCEs during the course of disease. Associations with molecular and clinical baseline parameters and their prognostic impact were statistically analyzed, and frequency, natural course, and location of SCEs were described. RESULTS: SCEs occurred more frequently in World Health Organization grade 2 and 3 astrocytoma and oligodendroglial tumors and were significantly associated with isocitrate dehydrogenase mutation in World Health Organization grade 3 astrocytoma and glioblastoma. SCEs mostly remained stable or dissolved in follow-up magnetic resonance imaging, even if no new treatment was initiated. SCEs were frequently located within the tumor or tumor-associated fluid-attenuated inversion recovery abnormalities, but distant appearance also occurred. In patients with glioblastoma, SCEs were associated with a favorable prognosis, which was also observed in the subgroup of patients with glioblastoma with isocitrate dehydrogenase wildtype status. CONCLUSIONS: The data demonstrate a predominantly benign course of SCEs after their appearance and emphasize cautious definitions of progression and regular clinical and radiographic follow-up rather than premature initiation of new antitumor therapies until progression is confirmed.