Biology subjects

Antoniou, A.

Publications and source records attributed to Antoniou, A..

6 recordsLinked to original sources

bioRxiv2026

Inferring somatic copy number aberrations from spatial transcriptomics data to study early cancer development

Understanding the spatial organisation of cells undergoing early transformation and their interactions with the local microenvironment is critical to studying the earliest stages of cancer development. Somatic copy number aberrations (SCNAs) are among the earliest genomic alterations observed in many cancers, but their spatial context remains difficult to study using conventional sequencing approaches. We developed a computational framework to infer SCNAs directly from Xenium spatial transcriptomics data, enabling the identification and spatial mapping of cell populations sharing common SCNA profiles. Applying this approach to ovarian, cervical and breast cancer datasets identified spatially coherent SCNA-defined populations that recapitulated known tumour-associated copy number aberrations and pathological states. In high-grade serous ovarian cancer, we identified an intermediate epithelial population within the fallopian tube exhibiting features of early transformation accompanied by immune remodelling. Together, our pipeline establishes a scalable framework for reconstructing the spatial architecture of SCNA-defined clones, providing new opportunities to identify and characterise candidate early transforming cell populations in situ.

cancer biology↗

bioRxiv2021

Neuronal extracellular vesicles mediate BDNF-dependent dendritogenesis and synapse maturation via microRNAs

Extracellular vesicles (EVs) have emerged as novel regulators of several biological processes, in part via the transfer of EV content such as microRNA; small non-coding RNAs that regulate protein production, between cells. However, how neuronal EVs contribute to trans-neuronal signaling is largely elusive. We examined the role of neuron-derived EVs in neuronal morphogenesis downstream signaling induced by brain-derived neurotrophic factor (BDNF). We found that EVs perpetuated BDNF induction of dendrite complexity and synapse maturation in naive hippocampal neurons, which was dependent on the activity of three microRNAs, miR-132-5p, miR-218 and miR-690. These microRNAs were up-regulated in BDNF-stimulated EVs. Moreover, supplementation with BDNF-EVs rescued the block of BDNF-induced phenotypes upon inhibition of miRNA activity. Our data therefore suggest a major role for EVs in BDNF-dependent morphogenesis, and provide new evidence for the functional transfer of microRNAs between neurons. This is not only an important step towards understanding the function of EVs in inter-neuronal signaling, but is also relevant for many disorders characterized by decreased BDNF signaling, such as major depression or cognitive impairment.

neuroscience↗

bioRxiv2020

Stabilising selection causes grossly altered but stable karyotypes in metastatic colorectal cancer

Aneuploidy, the loss and gain of whole and part chromosomes, is near-ubiquitous in cancer genomes and likely defines cancer cell biology. However, the temporal evolutionary dynamics that select for aneuploidy remain uncharacterised. Here we perform longitudinal genomic analysis of 755 samples from a total of 167 patients with colorectal-derived neoplastic lesions that represent distinct stages of tumour evolution through metastasis and treatment. Adenomas typically had few copy number alterations (CNAs) and most were subclonal, whereas cancers had many clonal CNAs, suggesting that progression goes through a CNA bottleneck. Individual CRC glands from the same tumour typically had very similar karyotypes, despite evidence of ongoing instability at the cell level in patient tumours, cell lines and organoids. CNAs in metastatic lesions sampled from liver and other organs, after chemotherapy or targeted therapies, and in late recurrences were typically similar to the primary tumour. Mathematical modelling and statistical inference indicated that these data are consistent with the action of negative selection on CNAs that traps cancer cell genomes on a fitness peak defined by the specific pattern of chromosomal aberrations. These data suggest that the initial progression of colorectal cancer requires the traversal of a rugged fitness landscape and subsequent CNA evolution, including metastatic dissemination and therapeutic resistance, is constrained by negative selection.

cancer biology↗

bioRxiv2019

Chromatin interactome mapping at 139 independent breast cancer risk signals

Genome-wide association studies have identified 196 high confidence independent signals associated with breast cancer susceptibility. Variants within these signals frequently fall in distal regulatory DNA elements that control gene expression. We designed a Capture Hi-C array to enrich for chromatin interactions between the credible causal variants and target genes in six human mammary epithelial and breast cancer cell lines. We show that interacting regions are enriched for open chromatin, histone marks for active enhancers and transcription factors relevant to breast biology. We exploit this comprehensive resource to identify candidate target genes at 139 independent breast cancer risk signals, and explore the functional mechanism underlying altered risk at the 12q24 risk region. Our results demonstrate the power of combining genetics, computational genomics and molecular studies to rationalize the identification of key variants and candidate target genes at breast cancer GWAS signals.

molecular biology↗

bioRxiv2018

Shared heritability and functional enrichment across six solid cancers

Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (rg=0.57, p=4.6x10-8), breast and ovarian cancer (rg=0.24, p=7x10-5), breast and lung cancer (rg=0.18, p=1.5x10-6) and breast and colorectal cancer (rg=0.15, p=1.1x10-4). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.

genomics↗

bioRxiv2017

Distinctive desmoplastic 3D morphology associated with BRAFV600E in papillary thyroid cancers

Textbooks suggest that cancers are compact balls with an inner core and an invasive front in contact with non-cancerous cells, and that tumor growth is driven by tumor cell proliferation subsequent to oncogenic genome mutations. We reconstructed at histological scale the 3D volume occupied by tumor cells in two regions of a BRAFV600E-mutated papillary thyroid carcinoma (PTC) with low tumor purity, as determined by sequencing, but initially considered high purity during pathology review. In contrast with a compact ball, tumor cells formed a sparse mesh deeply embedded within the stroma. The concepts of inner core and invasive front broke down in this morphology: all tumor cells were within short distance from the stroma. The fibrous stroma was highly cellular and proliferative, a result confirmed in an independent series. This case was not unique: 3.5% of The Cancer Genome Atlas PTCs had purities <25%, 27% were below the 60% purity inclusion criterion. Moreover, the presence of BRAFV600E was associated with extensive fibrosis, high stromal activation, and dedifferentiation. Thus, non-tumor cells make most of the tumor mass and contribute to its expansion in a significant fraction of BRAFV600E PTCs. Therapeutics targeting the tumor-stroma crosstalk could be beneficial in this context.

cancer biology↗