Webinar on Cancer Neuroscience

The mechanisms and impact of tumor-brain cross-talk

Speakers: Dorien Maas, Varun Venkataramani and Shawn Hervey-Jumper,

Recorded: June 21, 2023

Neuron-glia interactions in health and disease

Dorien Maas, Assistant Professor, Anatomy and Neurosciences at Amsterdam UMC

Short Abstract

Neurons and glial cells form an intricate network of cell-cell interactions that are essential for healthy brain functioning. Oligodendrocytes (as well as astrocytes and microglial cells) can have direct effects on neuronal signaling through these cell-cell interactions and harbour much of the brain’s plasticity. In the adult brain, new oligodendrocytes can be obtained from a pool of precursor cells. These precursor cells have the ability to proliferate and differentiate into mature cell types upon demand. Mature oligodendrocytes myelinate neuronal axons and increase their conduction velocity, as such optimizing neuronal network functioning. On the one hand, the production of new oligodendrocytes and the production or retraction of myelin sheaths are therefore essential for plastic processes such as learning complex skills and cognitive functioning. On the other hand, the plasticity of oligodendrocytes renders them vulnerable to intrinsic and extrinsic insults that can result in neurological disease. Glioma is a disease that forms an example of negative effects of adult brain plasticity, as a brain tumor arises from over-proliferating oligodendrocyte precursor cells in the adult brain. During my talk, I will provide you with the biological basis of neuron-oligodendrocyte interactions in health and during the devastating brain disease glioma.

The cancer neuroscience of brain tumor networks

Varun Venkataramani, MD, PhD, Department of Neurology, Heidelberg University Clinic

Short Abstract

Cancer cells can organize and communicate within functional networks, playing a crucial role in growth and resilience, much like other networks in biological and sociological contexts. Glioblastomas, along with other incurable brain tumors, demonstrate the formation of versatile multicellular tumor networks consisting of neuron-tumor and tumor-tumor networks. These networks contribute to tumor growth and resistance to standard therapies, raising the question of how to disconnect brain tumor networks to halt tumor growth and improve the effectiveness of existing treatments. Within glioblastomas, a subpopulation of cells forms a functional and therapy-resistant tumor cell network interconnected by TMs, while other subpopulations appear unconnected, leaving their biological role unclear. Whole-brain colonization is fueled by glioblastoma cells that lack connections with other tumor cells and astrocytes but receive synaptic input from neurons. These cells correspond to neuronal and neural-progenitor-like tumor cell states, as defined by single-cell transcriptomics in both mouse models and human disease. By superimposing molecular and functional single-cell data, it becomes evident that neuronal mechanisms govern glioblastoma cell invasion on multiple levels, explaining how glioblastoma’s dissemination and cellular heterogeneity are closely interlinked.
The emerging principles of tumor networks, their potential relevance for tumor types outside the brain, and translational implications, including clinical trials based on these discoveries, are also discussed in this context.

Therapeutic implication of diffuse gliomas remodeling of neural circuits in the human brain

Shawn Hervey-Jumper, Associate Professor, Neurosurgeon Researcher, University of California San Fransisco

Short Abstract

Short abstract
Gliomas synaptically integrate into neural circuits. Previous research has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth and gliomas increasing neuronal excitability. In this study we sought to determine how glioma-induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. Using intracranial brain recordings during cognitive task performance in awake humans together with site-specific tumour tissue biopsies and molecular analysis, we find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumour-infiltrated cortex well beyond the cortical regions that are normally recruited in the healthy brain. Site-directed biopsies from regions within the tumour that exhibit high functional connectivity between the tumour and the rest of the brain are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumour cells from functionally connected regions secrete several synaptogenic factors including thrombospondin-1, which contributes to the differential neuron–glioma interactions observed in functionally connected tumour regions compared with tumour regions with less functional connectivity. TSP-1 signaling through NTNG1 presented novel therapeutic opportunities to treat activity dependent glioma proliferation. Pharmacological inhibition and gene editing of thrombospondin-1 using the FDA-approved drug gabapentin decreases glioblastoma proliferation. The degree of functional connectivity between glioblastoma and the normal brain negatively affects both patient survival and performance in language tasks. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumour progression and impairs cognition.