bims-cabrim 2022-09-25 papers

Nat Commun. 2022 Sep 19. 13(1): 5494

Angiocrine extracellular vesicles impose mesenchymal reprogramming upon proneural glioma stem cells.

Lata Adnani, Jordan Kassouf, Brian Meehan, Cristiana Spinelli, Nadim Tawil, Ichiro Nakano, Janusz Rak.

Glioblastoma (GBM) is an incurable form of primary astrocytic brain tumor driven by glioma stem cell (GSC) compartment closely associated with the vascular niche. GSC phenotypes are heterogeneous and range from proneural to mesenchymal-like, the latter characterised by greater invasiveness. Here we document the secretory (angiocrine) role of endothelial cells and their derived extracellular vesicles (EVs) as drivers of proneural-to-mesenchymal reprogramming of GSCs. These changes involve activation of matrix metalloproteinases (MMPs) and NFκB, and inactivation of NOTCH, while altering responsiveness to chemotherapy and driving infiltrative growth in the brain. Our findings suggest that EV-mediated angiocrine interactions impact the nature of cellular stemness in GBM with implications for disease biology and therapy.

DOI: https://doi.org/10.1038/s41467-022-33235-7

Brain. 2022 Sep 21. pii: awac180. [Epub ahead of print]

Regional healthy brain activity, glioma occurrence and symptomatology.

Tianne Numan, Lucas C Breedt, Bernardo de A P C Maciel, Shanna D Kulik, Jolanda Derks, Menno M Schoonheim, Martin Klein, Philip C de Witt Hamer, Julie J Miller, Elizabeth R Gerstner, Steven M Stufflebeam, Arjan Hillebrand, Cornelis J Stam, Jeroen J G Geurts, Jaap C Reijneveld, Linda Douw.

It is unclear why exactly gliomas show preferential occurrence in certain brain areas. Increased spiking activity around gliomas leads to faster tumour growth in animal models, while higher non-invasively measured brain activity is related to shorter survival in patients. However, it is unknown how regional intrinsic brain activity, as measured in healthy controls, relates to glioma occurrence. We first investigated whether gliomas occur more frequently in regions with intrinsically higher brain activity. Second, we explored whether intrinsic cortical activity at individual patients' tumour locations relates to tumour and patient characteristics. Across three cross-sectional cohorts, 413 patients were included. Individual tumour masks were created. Intrinsic regional brain activity was assessed through resting-state magnetoencephalography acquired in healthy controls and source-localized to 210 cortical brain regions. Brain activity was operationalized as: (i) broadband power; and (ii) offset of the aperiodic component of the power spectrum, which both reflect neuronal spiking of the underlying neuronal population. We additionally assessed (iii) the slope of the aperiodic component of the power spectrum, which is thought to reflect the neuronal excitation/inhibition ratio. First, correlation coefficients were calculated between group-level regional glioma occurrence, as obtained by concatenating tumour masks across patients, and group-averaged regional intrinsic brain activity. Second, intrinsic brain activity at specific tumour locations was calculated by overlaying patients' individual tumour masks with regional intrinsic brain activity of the controls and was associated with tumour and patient characteristics. As proposed, glioma preferentially occurred in brain regions characterized by higher intrinsic brain activity in controls as reflected by higher offset. Second, intrinsic brain activity at patients' individual tumour locations differed according to glioma subtype and performance status: the most malignant isocitrate dehydrogenase-wild-type glioblastoma patients had the lowest excitation/inhibition ratio at their individual tumour locations as compared to isocitrate dehydrogenase-mutant, 1p/19q-codeleted glioma patients, while a lower excitation/inhibition ratio related to poorer Karnofsky Performance Status, particularly in codeleted glioma patients. In conclusion, gliomas more frequently occur in cortical brain regions with intrinsically higher activity levels, suggesting that more active regions are more vulnerable to glioma development. Moreover, indices of healthy, intrinsic excitation/inhibition ratio at patients' individual tumour locations may capture both tumour biology and patients' performance status. These findings contribute to our understanding of the complex and bidirectional relationship between normal brain functioning and glioma growth, which is at the core of the relatively new field of 'cancer neuroscience'.

Keywords: cancer neuroscience; magnetoencephalography; network neuroscience; neuro-oncology; primary brain tumours

DOI: https://doi.org/10.1093/brain/awac180

Nervenarzt. 2022 Sep 21.

[Cancer Neuroscience].

Varun Venkataramani, Frank Winkler.

The nervous system integrates and processes information to act as master regulator of various vital, biological processes. However, increasing data suggest that the nervous system is also a key player in the initiation of cancer and cancer progression. Following the tenet that oncology follows ontogeny, it has been shown that brain tumors follow neural developmental processes. Incurable gliomas form neurite-like membrane tubes called tumor microtubes and are controlled by neurodevelopmental pathways. Tumor microtubes are used for invasion, proliferation and interconnection with other tumor cells, forming a tumor network that is therapeutically resistant. Additionally, neurons can activate tumor cells via glutamatergic synapses to drive tumor invasion and growth. The most recent knowledge of brain cancer neuroscience presented here with a focus on brain tumours has already led to new approaches for antitumour treatment.

Keywords: Antitumor treatment; Brain tumors; Nervous system; Treatment resistance; Tumor network

DOI: https://doi.org/10.1007/s00115-022-01380-5