Similar Datasets
Project description:The identification of oncohistones underscores the neoplasm-driving role of chromatin dysfunction. However, we have limited understanding of how these perturbations alter communication in the tumour microenvironment (TME) and the functional implications of this crosstalk. In this respect, clinical evidence shows that the maturation block of the H3F3A (H3.3G34W)-mutated osteoblastic stromal population in benign giant cell tumours (GCTs), a neoplasm characterised by a prominent mutation-free osteoclast component, is reversed on osteoclast depletion, suggesting aberrant interactions between these two cell populations. Here, we reveal a bidirectional paracrine mechanism at the root of oncohistone-driven neoplasia in this bone tumour. H3.3G34W fails to induce stromal cell proliferation but inhibits their maturation. Altered chromatin landscape of these cells leads to enhancer remodelling, including at SCUBE3, a Tgfbeta family member. Reduced SCUBE3 expression contributes to increased osteoclasts that secrete high levels of SEMA4D, which disproportionately blocks maturation of H3.3G34W-expressing cells. Together, our findings suggest that non-cell autonomous provision of a growth advantage to a cancer driver-bearing cell represents a paradigm for a benign neoplasm.
2022-08-05 | GSE152921 | GEO
Project description:The identification of oncohistones underscores the neoplasm-driving role of chromatin dysfunction. However, we have limited understanding of how these perturbations alter communication in the tumour microenvironment (TME) and the functional implications of this crosstalk. In this respect, clinical evidence shows that the maturation block of the H3F3A (H3.3G34W)-mutated osteoblastic stromal population in benign giant cell tumours (GCTs), a neoplasm characterised by a prominent mutation-free osteoclast component, is reversed on osteoclast depletion, suggesting aberrant interactions between these two cell populations. Here, we reveal a bidirectional paracrine mechanism at the root of oncohistone-driven neoplasia in this bone tumour. H3.3G34W fails to induce stromal cell proliferation but inhibits their maturation. Altered chromatin landscape of these cells leads to enhancer remodelling, including at SCUBE3, a Tgfbeta family member. Reduced SCUBE3 expression contributes to increased osteoclasts that secrete high levels of SEMA4D, which disproportionately blocks maturation of H3.3G34W-expressing cells. Together, our findings suggest that non-cell autonomous provision of a growth advantage to a cancer driver-bearing cell represents a paradigm for a benign neoplasm.
2022-08-05 | GSE152148 | GEO
Project description:Oncohistones represent compelling evidence for a causative role of epigenetic perturbations in cancer. Giant cell tumours of bone (GCTs) are characterised by a mutated histone H3.3 as the sole genetic driver present in bone-forming osteoprogenitor cells but absent from abnormally large bone-resorbing osteoclasts which represent the hallmark of these neoplasms. While these striking features imply a pathogenic interaction between mesenchymal and myelomonocytic lineages during GCT development, the underlying mechanisms remain unknown. We show that the changes in the transcriptome and epigenome in the mesenchymal cells caused by the H3.3-G34W mutation contribute to increase osteoclast recruitment in part via reduced expression of the TGFβ-like soluble factor, SCUBE3. Transcriptional changes in SCUBE3 are associated with altered histone marks and H3.3G34W enrichment at its enhancer regions. In turn, osteoclasts secrete unregulated amounts of SEMA4D which enhances proliferation of mutated osteoprogenitors arresting their maturation. These findings provide a mechanism by which GCTs undergo differentiation in response to denosumab, a drug that depletes the tumour of osteoclasts. In contrast, hTERT alterations, commonly found in malignant GCT, result in the histone-mutated neoplastic cells being independent of osteoclasts for their proliferation, predicting unresponsiveness to denosumab. We provide a mechanism for the initiation of GCT, the basis of which is dysfunctional cross-talk between bone-forming and bone-resorbing cells. The findings highlight the role of tumour/microenvironment bidirectional interactions in tumorigenesis and how this is exploited in the treatment of GCT.
| S-EPMC9750984 | biostudies-literature
Project description:Aberrant paracrine signalling underlies oncohistone-driven giant cell tumour of bone.
| PRJNA641026 | ENA
Project description:Aberrant paracrine signalling underlies oncohistone-driven giant cell tumour of bone [ChIP-seq]
| PRJNA640937 | ENA
Project description:Aberrant paracrine signalling underlies oncohistone-driven giant cell tumour of bone [RNA-seq]
| PRJNA638412 | ENA
Project description:N-Methyl-d-aspartate receptor (NMDAR) activation is implicated in the malignant progression of many cancer types, as previously shown by the growth-inhibitory effects of NMDAR antagonists. NMDAR-mediated calcium influx and its downstream signalling depend critically, however, on the dynamics of membrane potential and ambient glutamate concentration, which are poorly characterized in cancer cells. Here, we have used low-noise whole-cell patch-clamp recording to investigate the electrophysiology of glutamate signalling in pancreatic neuroendocrine tumour (PanNET) cells derived from a genetically-engineered mouse model (GEMM) of PanNET, in which NMDAR signalling is known to promote cancer progression. Activating NMDARs caused excitation and intracellular calcium elevation, and intracellular perfusion with physiological levels of glutamate led to VGLUT-dependent autocrine NMDAR activation. Necrotic cells, which are often present in rapidly-growing tumours, were shown to release endogenous cytoplasmic glutamate, and necrosis induced by mechanical rupture of the plasma membrane produced intense NMDAR activation in nearby cells. Computational modelling, based on these results, predicts that NMDARs in cancer cells can be strongly activated in the tumour microenvironment by both autocrine glutamate release and necrosis.
| S-EPMC5746548 | biostudies-literature
Project description:Fragile X syndrome (FXS), caused by the loss of functional FMRP, is a leading cause of autism. Neurons lacking FMRP show aberrant mRNA translation and intracellular signalling. Here, we identify that, in Fmr1 knockout neurons, type 1 adenylyl cyclase (Adcy1) mRNA translation is enhanced, leading to excessive production of ADCY1 protein and insensitivity to neuronal stimulation. Genetic reduction of Adcy1 normalizes the aberrant ERK1/2- and PI3K-mediated signalling, attenuates excessive protein synthesis and corrects dendritic spine abnormality in Fmr1 knockout mice. Genetic reduction of Adcy1 also ameliorates autism-related symptoms including repetitive behaviour, defective social interaction and audiogenic seizures. Moreover, peripheral administration of NB001, an experimental compound that preferentially suppresses ADCY1 activity over other ADCY subtypes, attenuates the behavioural abnormalities in Fmr1 knockout mice. These results demonstrate a connection between the elevated Adcy1 translation and abnormal ERK1/2 signalling and behavioural symptoms in FXS.
| S-EPMC5321753 | biostudies-literature
Project description:The rare benign giant cell tumour of bone (GCTB) is defined by an almost unique mutation in the H3.3 family of histone genes H3-3A or H3-3B; however, the same mutation is occasionally found in primary malignant bone tumours which share many features with the benign variant. Moreover, lung metastases can occur despite the absence of malignant histological features in either the primary or metastatic lesions. Herein we investigated the genetic events of 17 GCTBs including benign and malignant variants and the methylation profiles of 122 bone tumour samples including GCTBs. Benign GCTBs possessed few somatic alterations and no other known drivers besides the H3.3 mutation, whereas all malignant tumours harboured at least one additional driver mutation and exhibited genomic features resembling osteosarcomas, including high mutational burden, additional driver event(s), and a high degree of aneuploidy. The H3.3 mutation was found to predate the development of aneuploidy. In contrast to osteosarcomas, malignant H3.3-mutated tumours were enriched for a variety of alterations involving TERT, other than amplification, suggesting telomere dysfunction in the transformation of benign to malignant GCTB. DNA sequencing of the benign metastasising GCTB revealed no additional driver alterations; polyclonal seeding in the lung was identified, implying that the metastatic lesions represent an embolic event. Unsupervised clustering of DNA methylation profiles revealed that malignant H3.3-mutated tumours are distinct from their benign counterpart, and other bone tumours. Differential methylation analysis identified CCND1, encoding cyclin D1, as a plausible cancer driver gene in these tumours because hypermethylation of the CCND1 promoter was specific for GCTBs. We report here the genomic and methylation patterns underlying the rare clinical phenomena of benign metastasising and malignant transformation of GCTB and show how the combination of genomic and epigenomic findings could potentially distinguish benign from malignant GCTBs, thereby predicting aggressive behaviour in challenging diagnostic cases. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
| S-EPMC8432151 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2020-10-01 | GSE149211 | GEO