Brain tumors (gliomas) are heterogeneous cellular ecosystems, where non-neoplastic monocytic cells have emerged as key regulators of tumor maintenance and progression. However, relative to macrophages/microglia, comparatively less is known about the roles of neurons and T cells in glioma pathobiology. Herein, we leverage genetically engineered mouse models and human biospecimens to define the axis in which neurons, T cells, and microglia interact to govern Neurofibromatosis-1 (NF1) low-grade glioma (LGG) growth. NF1-mutant human and mouse brain neurons elaborate midkine to activate naïve CD8⁺ T cells to produce Ccl4, which induces microglia to produce a key LGG growth factor (Ccl5) critical for LGG stem cell survival. Importantly, increased CCL5 expression is associated with reduced survival in patients with LGG. The elucidation of the critical intercellular dependencies that constitute the LGG neuroimmune axis provides insights into the role of neurons and immune cells in controlling glioma growth, relevant to future therapeutic targeting.

Cells experience mechanical forces throughout their lifetimes. Vinculin is critical for transmitting these forces, yet how it achieves its distinct functions at cell–cell and cell–matrix adhesions remains unanswered. Here, we show vinculin is phosphorylated at Y822 in cell–cell, but not cell–matrix, adhesions. Phosphorylation at Y822 was elevated when forces were applied to E-cadherin and was required for vinculin to integrate into the cadherin complex. The mutation Y822F ablated these activities and prevented cells from stiffening in response to forces on E-cadherin. In contrast, Y822 phosphorylation was not required for vinculin functions in cell–matrix adhesions, including integrin-induced cell stiffening. Finally, forces applied to E-cadherin activated Abelson (Abl) tyrosine kinase to phosphorylate vinculin; Abl inhibition mimicked the loss of vinculin phosphorylation. These data reveal an unexpected regulatory mechanism in which vinculin Y822 phosphorylation determines whether cadherins transmit force and provides a paradigm for how a shared component of adhesions can produce biologically distinct functions.

Background: One of the clinical hallmarks of low-grade gliomas (LGGs) arising in children with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome is significant clinical variability with respect to tumor growth, associated neurologic deficits, and response to therapy. Numerous factors could contribute to this clinical heterogeneity, including the tumor cell of origin, the specific germline NF1 gene mutation, and the coexistence of additional genomic alterations. Since human specimens are rarely acquired, and have proven difficult to maintain in vitro or as xenografts in vivo, we have developed a series of Nf1 mutant optic glioma mouse strains representing each of these contributing factors. Methods: Optic glioma stem cells (o-GSCs) were generated from this collection of Nf1 genetically engineered mice, and analyzed for their intrinsic growth properties, as well as the production of chemokines that could differentially attract T cells and microglia. Results: The observed differences in Nf1 optic glioma growth are not the result of cell autonomous growth properties of o-GSCs, but rather the unique patterns of o-GSC chemokine expression, which differentially attract T cells and microglia. This immune profile collectively dictates the levels of chemokine C-C ligand 5 (Ccl5) expression, the key stromal factor that drives murine Nf1 optic glioma growth. Conclusions: These findings reveal that genetic and genomic alterations create murine LGG biological heterogeneity through the differential recruitment of T cells and microglia by o-GSC–produced chemokines, which ultimately determine the expression of stromal factors that drive tumor growth.

The brilliant and often prescient hypotheses of Ramon y Cajal have proven foundational for modern neuroscience, but his statement that “In adult centers the nerve paths are something fixed, ended, immutable … ” is an exception that did not stand the test of empirical study. Mechanisms of cellular and circuit-level plasticity continue to shape and reshape many regions of the adult nervous system long after the neurodevelopmental period. Initially focused on neurons alone, the field has followed a meteoric trajectory in understanding of activity-regulated neurodevelopment and ongoing neuroplasticity with an arc toward appreciating neuron–glial interactions and the role that each neural cell type plays in shaping adaptable neural circuity. In this review, as part of a celebration of the 50th anniversary of Society for Neuroscience, we provide a historical perspective, following this arc of inquiry from neuronal to neuron–glial mechanisms by which activity and experience modulate circuit structure and function. The scope of this consideration is broad, and it will not be possible to cover the wealth of knowledge about all aspects of activity-dependent circuit development and plasticity in depth.

Neuronal activity is emerging as a driver of central and peripheral nervous system cancers. Here, we examined neuronal physiology in mouse models of the tumor predisposition syndrome Neurofibromatosis-1 (NF1), with different propensities to develop nervous system cancers. We show that central and peripheral nervous system neurons from mice with tumor-causing Nf1 gene mutations exhibit hyperexcitability and increased secretion of activity-dependent tumor-promoting paracrine factors. We discovered a neurofibroma mitogen (COL1A2) produced by peripheral neurons in an activity-regulated manner, which increases NF1-deficient Schwann cell proliferation, establishing that neurofibromas are regulated by neuronal activity. In contrast, mice with the Arg1809Cys Nf1 mutation, found in NF1 patients lacking neurofibromas or optic gliomas, do not exhibit neuronal hyperexcitability or develop these NF1-associated tumors. The hyperexcitability of tumor-prone Nf1-mutant neurons results from reduced NF1-regulated hyperpolarization-activated cyclic nucleotide-gated (HCN) channel function, such that neuronal excitability, activity-regulated paracrine factor production, and tumor progression are attenuated by HCN channel activation. Collectively, these findings reveal that NF1 mutations act at the level of neurons to modify tumor predisposition by increasing neuronal excitability and activity-regulated paracrine factor production.