Eighty percent of malignant tumors that develop in the central nervous system are malignant gliomas, which are essentially incurable. Here, we discuss how recent sequencing studies are identifying ...unexpected drivers of gliomagenesis, including mutations in isocitrate dehydrogenase 1 and the NF-κB pathway, and how genome-wide analyses are reshaping the classification schemes for tumors and enhancing prognostic value of molecular markers. We discuss the controversies surrounding glioma stem cells and explore how the integration of new molecular data allows for the generation of more informative animal models to advance our knowledge of glioma's origin, progression, and treatment.
The cellular origin of gliomas remains a topic of controversy in cancer research. Advances in neurobiology, molecular genetics, and functional genomics have ushered new insights through exploiting ...the development of more sophisticated tools to address this question. Diverse distinct cell populations in the adult brain have been reported to give rise to gliomas, although how these studies relate physiologically to mechanisms of spontaneous tumour formation via accumulation of tumour-initiating mutations within a single cell are less well developed. Recent studies in animal models indicate that the lineage of the tumour-initiating cell may contribute to the biological and genomic phenotype of glioblastoma. These results suggest that the cell of origin may not only serve as a source of diversity for these tumours, but may also provide new avenues for improved diagnostics and therapeutic targeting that may prolong the lives of patients.
Glioblastoma multiforme is the most common primary malignant brain tumour, with a median survival of about one year. This poor prognosis is due to therapeutic resistance and tumour recurrence after ...surgical removal. Precisely how recurrence occurs is unknown. Using a genetically engineered mouse model of glioma, here we identify a subset of endogenous tumour cells that are the source of new tumour cells after the drug temozolomide (TMZ) is administered to transiently arrest tumour growth. A nestin-ΔTK-IRES-GFP (Nes-ΔTK-GFP) transgene that labels quiescent subventricular zone adult neural stem cells also labels a subset of endogenous glioma tumour cells. On arrest of tumour cell proliferation with TMZ, pulse-chase experiments demonstrate a tumour re-growth cell hierarchy originating with the Nes-ΔTK-GFP transgene subpopulation. Ablation of the GFP+ cells with chronic ganciclovir administration significantly arrested tumour growth, and combined TMZ and ganciclovir treatment impeded tumour development. Thus, a relatively quiescent subset of endogenous glioma cells, with properties similar to those proposed for cancer stem cells, is responsible for sustaining long-term tumour growth through the production of transient populations of highly proliferative cells.
Highlights ► PTEN is a negative regulator of the PI3K/AKT pathway, and Pten germline mutations are found in a small subset of autism patients. ► Loss of PTEN function in the brain has profound and ...multiple effects on neuronal cells. ► The TSC/mTORC1 signaling pathway is a major PI3K/PTEN/AKT downstream pathway that mediates cellular and behavioral effects in the nervous system. ► The PTEN pathway can synergize with other signaling pathways to control social behavior.
A central question in glioblastoma multiforme (GBM) research is the identity of the tumor-initiating cell, and its contribution to the malignant phenotype and genomic state. We examine the potential ...of adult lineage-restricted progenitors to induce fully penetrant GBM using CNS progenitor-specific inducible Cre mice to mutate Nf1, Trp53, and Pten. We identify two phenotypically and molecularly distinct GBM subtypes governed by identical driver mutations. We demonstrate that the two subtypes arise from functionally independent pools of adult CNS progenitors. Despite histologic identity as GBM, these tumor types are separable based on the lineage of the tumor-initiating cell. These studies point to the cell of origin as a major determinant of GBM subtype diversity.
•Adult lineage-restricted CNS progenitors, like stem cells, can give rise to GBM•Two different GBM-initiating CNS progenitors are induced by identical mutations•Histologically and molecularly distinct GBMs arise from different CNS progenitors•The cell of origin emerges as a major determinant of GBM molecular subtype
Alcantara Llaguno et al. examine the potential of adult CNS lineage-restricted progenitors to induce fully penetrant glioblastoma multiforme (GBM) and show that the same genetic drivers in different cells of origin generate molecularly distinct GBM subtypes.
Malignant glioma remains incurable despite tremendous advancement in basic research and clinical practice. The identification of the cell(s) of origin should provide deep insights into leverage ...points for one to halt disease progression. Here we summarize recent studies that support the notion that neural stem cell (NSC), astrocyte, and oligodendrocyte precursor cell (OPC) can all serve as the cell of origin. We also lay out important considerations on technical rigor for further exploring this subject. Finally, we share perspectives on how one could apply the knowledge of cell of origin to develop effective treatment methods. Although it will be a difficult battle, victory should be within reach as along as we continue to assimilate new information and facilitate the collaboration among basic scientists, translational researchers, and clinicians.
Appropriate responses to an imminent threat brace us for adversities. The ability to sense and predict threatening or stressful events is essential for such adaptive behaviour. In the mammalian ...brain, one putative stress sensor is the paraventricular nucleus of the thalamus (PVT), an area that is readily activated by both physical and psychological stressors. However, the role of the PVT in the establishment of adaptive behavioural responses remains unclear. Here we show in mice that the PVT regulates fear processing in the lateral division of the central amygdala (CeL), a structure that orchestrates fear learning and expression. Selective inactivation of CeL-projecting PVT neurons prevented fear conditioning, an effect that can be accounted for by an impairment in fear-conditioning-induced synaptic potentiation onto somatostatin-expressing (SOM(+)) CeL neurons, which has previously been shown to store fear memory. Consistently, we found that PVT neurons preferentially innervate SOM(+) neurons in the CeL, and stimulation of PVT afferents facilitated SOM(+) neuron activity and promoted intra-CeL inhibition, two processes that are critical for fear learning and expression. Notably, PVT modulation of SOM(+) CeL neurons was mediated by activation of the brain-derived neurotrophic factor (BDNF) receptor tropomysin-related kinase B (TrkB). As a result, selective deletion of either Bdnf in the PVT or Trkb in SOM(+) CeL neurons impaired fear conditioning, while infusion of BDNF into the CeL enhanced fear learning and elicited unconditioned fear responses. Our results demonstrate that the PVT-CeL pathway constitutes a novel circuit essential for both the establishment of fear memory and the expression of fear responses, and uncover mechanisms linking stress detection in PVT with the emergence of adaptive behaviour.
Adult neurogenesis persists in the rodent dentate gyrus and is stimulated by chronic treatment with conventional antidepressants through BDNF/TrkB signaling. Ketamine in low doses produces both rapid ...and sustained antidepressant effects in patients. Previous studies have shed light on post-transcriptional synaptic NMDAR mediated mechanisms underlying the acute effect, but how ketamine acts at the cellular level to sustain this anti-depressive function for prolonged periods remains unclear. Here we report that ketamine accelerates differentiation of doublecortin-positive adult hippocampal neural progenitors into functionally mature neurons. This process requires TrkB-dependent ERK pathway activation. Genetic ablation of TrkB in neural stem/progenitor cells, or pharmacologic disruption of ERK signaling, or inhibition of adult neurogenesis, each blocks the ketamine-induced behavioral responses. Conversely, enhanced ERK activity via Nf1 gene deletion extends the response and rescues both neurogenic and behavioral deficits in mice lacking TrkB. Thus, TrkB-dependent neuronal differentiation is involved in the sustained antidepressant effects of ketamine.
Malignant astrocytomas are infiltrative and incurable brain tumors. Despite profound therapeutic implications, the identity of the cell (or cells) of origin has not been rigorously determined. We ...previously reported mouse models based on conditional inactivation of the human astrocytoma-relevant tumor suppressors
p53,
Nf1, and
Pten, wherein through somatic loss of heterozygosity, mutant mice develop tumors with 100% penetrance. In the present study, we show that tumor suppressor inactivation in neural stem/progenitor cells is both necessary and sufficient to induce astrocytoma formation. We demonstrate in vivo that transformed cells and their progeny undergo infiltration and multilineage differentiation during tumorigenesis. Tumor suppressor heterozygous neural stem/progenitor cultures from presymptomatic mice show aberrant growth advantage and altered differentiation, thus identifying a pretumorigenic cell population.
The transcription factor ATF4 enhances bone formation by favoring amino acid import and collagen synthesis in osteoblasts, a function requiring its phosphorylation by RSK2, the kinase inactivated in ...Coffin-Lowry Syndrome. Here, we show that in contrast, RSK2 activity, ATF4-dependent collagen synthesis, and bone formation are increased in mice lacking neurofibromin in osteoblasts (
Nf1
ob
−/−
mice). Independently of RSK2, ATF4 phosphorylation by PKA is enhanced in
Nf1
ob
−/−
mice, thereby increasing
Rankl expression, osteoclast differentiation, and bone resorption. In agreement with ATF4 function in amino acid transport, a low-protein diet decreased bone protein synthesis and normalized bone formation and bone mass in
Nf1
ob
−/−
mice without affecting other organ weight, while a high-protein diet overcame
Atf4
−/−
and
Rsk2
−/−
mice developmental defects, perinatal lethality, and low bone mass. By showing that ATF4-dependent skeletal dysplasiae are treatable by dietary manipulations, this study reveals a molecular connection between nutrition and skeletal development.
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