Biology subjects

Angelova, M.

Publications and source records attributed to Angelova, M..

7 recordsLinked to original sources

bioRxiv2025

Multicellular Calcium Waves in Cancer-Associated Fibroblasts Regulate Neuronal Mimicry and Anisotropy Leading to Immune Exclusion

Stromal barriers exclude CD8+ T cells from accessing cancer cells and hamper immune-mediated tumour control. Through multi-pronged analysis of tumours that transition from immune inflamed to immune excluded, we reveal that the formation of stromal barriers is associated with the acquisition of neuronal gene expression programmes in cancer-associated fibroblasts (CAFs), including TUBB3 expression. This leads to neuronal mimicry, with stromal barrier formation underpinned by coordinated transient bursts of intracellular calcium release, similar to those observed in neuronal tissue. Blockade of calcium release through either pharmacological or molecular interventions, such as STC2 depletion, prevents CAF alignment and the build-up of CD8+ T cells at stromal boundaries. Nintedanib treatment prevents neuronal mimicry and restores immune-mediated tumour control. Thus, we uncover unexpected mimicry of neuronal behaviour in CAFs, document the mechanism by which it leads to immune exclusion, and identify ways to prevent the induction of neuronal mimicry and restore immune-mediated tumour control. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/684281v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@938ee5org.highwire.dtl.DTLVardef@18a9c48org.highwire.dtl.DTLVardef@11a5982org.highwire.dtl.DTLVardef@ea6a79_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Entropy of the resting state cortex in epilepsy

BackgroundEpilepsy has long been conceptualised as a disorder in which aberrant brain dynamics extend beyond the epileptogenic zone. Evidence demonstrates that loss of entropy is a generic feature of pathological dynamics in the brain, including the ictal state. However, the impact of recurrent seizures on entropy in the interictal state remains unknown. MethodsResting state magnetoencephalography (MEG) scans and resection masks of 32 individuals with epilepsy who had Engel I outcome post-surgery were retrospectively retrieved. Using co-registered FreeSurfer parcellations, we reconstructed the source localised MEG time series and computed sample entropy for 114 regions of interest. We then tested the association of entropy with the resected volume of the brain, and additional clinical variables including the age of seizure onset, seizure frequency and duration of epilepsy. To further understand the temporal relationship between seizure onset and entropy in the interictal state, we collected and computed sample entropy for week-long EEG traces from leucine-rich glioma inactivated 1 monoclonal antibody (LGI1-mAb) rodent models of autoimmune encephalitis (n=5) and control rats (n=5). ResultsIn individuals with epilepsy, a lower age of seizure onset was associated with lower mean sample entropy of the whole cortex (Spearmans rho =0.60, p<0.001; partial correlation =0.41, p=0.021). Entropy did not differ between the resected and non-resected regions of the brain. Furthermore, LGI1-mAb treated rodents showed a persistent decrease in sample entropy as compared to control rats, after the onset of seizures, and this difference was greatest during periods of highest seizure frequency (p<0.001). ConclusionRecurrent seizures are associated with a persistent decrease in entropy, even in the interictal state, and this decrease was found to be most profound and affecting the whole cortex in patients who had a lower age of seizure onset.

neuroscience↗

bioRxiv2024

Spatial proteomic analysis of a lung cancer model reveals regulatory T cells attenuate KRAS-G12C inhibitor-induced immune responses

We recently showed that lung tumor specific KRAS-G12C inhibition causes remodelling of the tumor immune microenvironment from cold to hot. As a result, KRAS-G12C inhibition is able to synergise with anti-PD-1 treatment, but only in tumor models that were already moderately responsive to immune checkpoint blockade at baseline. To investigate mechanisms that restrain immunotherapy sensitivity in non-responsive tumors, we used multiplex imaging mass cytometry to explore spatial patterns in the tumor microenvironment of the highly immune evasive KRAS mutant murine Lewis Lung Cancer model. Clustering of close neighbour information per cell allowed characterisation of spatial patterns or communities in the tissue. We identified a community harbouring features of localised T-cell activation, where CD4+ and CD8+ T cells and dendritic cells were gathered together. KRAS-G12C inhibition led to increased expression of PD-1 on T cells, CXCL9 expression by dendritic cells, together with increased proliferation and potential cytotoxicity of CD8+ T cells, indicating an effector response. However, we also observed a high incidence of regulatory T cells (Tregs) within this community, which had frequent contact with effector T cells, suggesting that Tregs may be able to dampen anti-tumoral immune responses following KRAS-G12C inhibition. Similar communities were detected in human lung adenocarcinoma clinical samples. Depleting Tregs in vivo with anti-CTLA-4 antibody rescued the anti-tumor immune response and led to enhanced tumor control in combination with anti-PD-1 and KRAS-G12C inhibitor. We therefore propose use of KRAS-G12C inhibitor in combination with Treg depletion as a therapeutic opportunity that increases anti-tumoral immune responses and initiates tumor regression. One sentence summarySpatial analysis identified regulatory T cells as potential source of local T cell repression, mediating resistance to KRAS-G12Ci and anti-PD1 therapy.

cancer biology↗

bioRxiv2021

H3 acetylation selectively promotes basal progenitor proliferation and neocortex expansion by activating TRNP1 expression

Increase in the size of human neocortex, acquired in evolution, accounts for the unique cognitive capacity of humans. This expansion appears to reflect the evolutionarily-enhanced proliferative ability of basal progenitors (BPs) in mammalian cortex, which may have been acquired through epigenetic alterations in BPs. However, whether or how the epigenome in BPs differs across species is not known. Here, we report that histone H3 acetylation is a key epigenetic regulation in BP amplification and cortical expansion. Through epigenetic profiling of sorted BPs, we show that H3K9 acetylation is low in murine BPs and high in human BPs. Elevated H3K9ac preferentially increases BP proliferation, increasing the size and folding of the normally smooth mouse neocortex. Mechanistically, H3K9ac drives BP amplification by increasing expression of the evolutionarily regulated gene, TRNP1, in the developing cortex. Our findings demonstrate a previously unknown mechanism that controls cortical architecture. One Sentence SummaryH3K9ac promotes basal progenitor amplification, neocortex expansion and gyrification by activating TRNP1 expression in evolution.

developmental biology↗

bioRxiv2021

Characterisation of tumour immune microenvironment remodelling following oncogene inhibition in preclinical studies using an optimised imaging mass cytometry workflow

Mouse models are critical in pre-clinical studies of cancer therapy, allowing dissection of mechanisms through chemical and genetic manipulations that are not feasible in the clinical setting. In studies of the tumour microenvironment (TME), multiplexed imaging methods can provide a rich source of information. However, the application of such technologies in mouse tissues is still in its infancy. Here we present a workflow for studying the TME using imaging mass cytometry with a panel of 27 antibodies on frozen mouse tissues. We optimise and validate image segmentation strategies and automate the process in a Nextflow-based pipeline (imcyto) that is scalable and portable, allowing for parallelised segmentation of large multi-image datasets. With these methods we interrogate the remodelling of the TME induced by a KRAS G12C inhibitor in an immune competent mouse orthotopic lung cancer model, highlighting the infiltration and activation of antigen presenting cells and effector cells.

cancer biology↗

bioRxiv2020

Somatic chromosomal number alterations affecting driver genes inform in-vitro and clinical drug response in high-grade serous ovarian cancer

The genomic complexity and heterogeneity of high-grade serous ovarian cancer (HGSOC) has hampered the realisation of successful therapies and effective personalised treatment is an unmet clinical need. Here we show that primary HGSOC spheroid models can be used to predict drug response and use them to demonstrate that somatic copy number alterations (SCNAs) in frequently amplified HGSOC cancer genes significantly correlate with gene expression and drug response. These genes are often located in areas of the genome with frequent clonal SCNAs. MYC chromosomal copy number is associated with ex-vivo and clinical response to paclitaxel and ex-vivo response to mTORC1/2 inhibition. Activation of the mTOR survival pathway in the context to MYC-amplified HGSOC is mostly due to increased prevalence of SCNAs in genes from the PI3K pathway. These results suggest that SCNAs encompassing driver genes could be used to inform therapeutic response in the context of clinical trials testing personalised medicines.

cancer biology↗

bioRxiv2020

Multiple roles for the ESCRT machinery in maintaining plasma membrane homeostasis

The endosomal sorting complexes required for transport (ESCRT) execute evolutionary conserved membrane remodeling processes. Here we used budding yeast to explore how the ESCRT machinery contributes to plasma membrane (PM) homeostasis. In response to reduced membrane tension and inhibition of the target of rapamycin complex 2 (TORC2), ESCRT-III/Vps4 assemblies form at the PM and help to maintain membrane integrity. Conversely, the growth of ESCRT mutants strongly depends on TORC2-mediated homeostatic regulation of sphingolipid (SL) metabolism. This is caused by calcineurin phosphatase activity which causes Orm2 to accumulate at the endoplasmic reticulum (ER) in ESCRT mutants. Orm2 is a repressor of SL biosynthesis and its accumulation provokes increased membrane stress. This necessitates TORC2 signaling through its downstream kinase Ypk1 to control Orm2 protein levels and prevent a detrimental imbalance of SL metabolism. Our findings reveal new aspects of antagonistic calcineurin/TORC2 signaling for the regulation of SL biosynthesis and the maintenance of PM homeostasis, and suggest that the ESCRT machinery contributes directly and indirectly to these processes.

cell biology↗