Aberrant paracrine signalling underlies oncohistone-driven giant cell tumour of bone.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA641026 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11968766.fastq.gz | Fastqsanger.gz | |||
| SRR11968766_1.fastq.gz | Fastqsanger.gz | |||
| SRR11968766_2.fastq.gz | Fastqsanger.gz | |||
| SRR11968767.fastq.gz | Fastqsanger.gz | |||
| SRR11968767_1.fastq.gz | Fastqsanger.gz |
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Project description:Aberrant paracrine signalling underlies oncohistone-driven giant cell tumour of bone [RNA-seq]
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Project description:Aberrant paracrine signalling underlies oncohistone-driven giant cell tumour of bone [ChIP-seq]
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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:This SuperSeries is composed of the SubSeries listed below.
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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.
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Project description:Giant cell granulomas of the jaws often occur sporadically as single central or peripheral lesions. They are characterized by KRAS, FGFR1, or TRPV4 somatic mutations, the latter occurring exclusively in the central form. Less commonly, multiple giant cell lesions can develop in the context of syndromes such as cherubism, which is an autosomal dominant bone disease. Morphologically, giant cell granulomas can closely resemble other giant cell-rich lesions such as non-ossifying fibroma and aneurysmal bone cyst, and to a minor extent giant cell tumour of bone and chondroblastoma. The epigenetic basis of these giant cell-rich tumours is unclear and, recently, DNA methylation profile has been shown to be clinically useful for the diagnosis of other tumour types, including brain tumours as well as bone and soft tissue sarcomas. Therefore, we aimed to assess the DNA methylation profile of central and peripheral sporadic giant cell granulomas of the jaws and cherubism to test whether DNA methylation patterns can help to distinguish these entities. Additionally, we further compared the DNA methylation profile of these lesions with those of other giant cell-rich mimics to investigate if the microscopic similarities extend to the epigenetic level. Our results showed that central and peripheral sporadic giant cell granulomas of the jaws and cherubism share a related DNA methylation pattern with that of peripheral sporadic giant cell granulomas and cherubism appearing slightly distinct, while central sporadic giant cell granulomas show overlap with both of the former. Non-ossifying fibroma, aneurysmal bone cyst, giant cell tumour of bone, and chondroblastoma, on the other hand, have distinct methylation patterns. Therefore, DNA methylation profiling is currently not capable of clearly distinguishing sporadic and cherubism-associated giant cell lesions of the jaws. Conversely, it could discriminate sporadic giant cell granulomas from their giant cell-rich mimics.
2023-10-18 | GSE218252 | GEO
Project description:Glycine 34 to tryptophan (G34W) substitutions in H3.3 arise in ~90% of giant cell tumour of bone (GCT). Here, we show H3.3G34W is necessary for tumour formation. Profiling the epigenome, transcriptome and secreted proteome of patient samples and tumour-derived cells CRISPR/Cas9-edited for H3.3G34W shows that H3.3K36me3 loss on mutant H3.3 induces a shift of the repressive H3K27me3 mark from intergenic to genic regions, beyond areas of H3.3 deposition. This promotes the redistribution of antagonistic chromatin marks and aberrant downregulation of contractile myofibroblast-associated genes altering cell fate in mesenchymal progenitors. Single-cell transcriptomics reveals that H3.3G34W stromal cells recapitulate a neoplastic trajectory from an SPP1+ osteoblast progenitor-like population towards an ACTA2+ myofibroblast population, which secretes extracellular matrix ligands predicted to recruit and activate osteoclasts. Our findings suggest that H3.3G34W leads to GCT by sustaining a transformed state in osteoblast-like progenitors which promotes neoplastic growth, pathological recruitment of giant osteoclasts, and bone destruction.
2020-10-01 | GSE149198 | GEO
Project description:Glycine 34 to tryptophan (G34W) substitutions in H3.3 arise in ~90% of giant cell tumour of bone (GCT). Here, we show H3.3G34W is necessary for tumour formation. Profiling the epigenome, transcriptome and secreted proteome of patient samples and tumour-derived cells CRISPR/Cas9-edited for H3.3G34W shows that H3.3K36me3 loss on mutant H3.3 induces a shift of the repressive H3K27me3 mark from intergenic to genic regions, beyond areas of H3.3 deposition. This promotes the redistribution of antagonistic chromatin marks and aberrant downregulation of contractile myofibroblast-associated genes altering cell fate in mesenchymal progenitors. Single-cell transcriptomics reveals that H3.3G34W stromal cells recapitulate a neoplastic trajectory from an SPP1+ osteoblast progenitor-like population towards an ACTA2+ myofibroblast population, which secretes extracellular matrix ligands predicted to recruit and activate osteoclasts. Our findings suggest that H3.3G34W leads to GCT by sustaining a transformed state in osteoblast-like progenitors which promotes neoplastic growth, pathological recruitment of giant osteoclasts, and bone destruction.
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Project description:RNA-Seq analysis for giant cell tumour of the bone
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