Biology subjects

Brady, N.

Publications and source records attributed to Brady, N..

5 recordsLinked to original sources

bioRxiv2026

Phenotype-dependent subtyping exposes high MYC activity as a targetable dependency in LuAd

C-MYC (MYC) occupies a critical nexus of oncogenic signalling and deregulated expression of MYC is widespread across most human cancer types, suggesting that MYC should be an attractive target for therapeutic intervention. Although 30-40% of human Non-Small Cell lung cancers show low level amplification of c-MYC and genetic evidence has shown that c-Myc is a key downstream effector of KRas-driven lung tumourigenesis in mouse models, the functional contribution of MYC to human lung cancer remains unclear. We applied a phenotype-based classifier to the TCGA Lung Adenocarcinoma (LuAd) cohort and found that high MYC transcriptional activity identifies a subset of LuAd with significantly reduced survival. Application of the same methodology to a panel of genetically engineered mouse models identified multiple genotypes that give rise to the high MYC activity phenotype, disease positioning such models as reflective of a distinct subset of human LuAd. We show that high MYC activity predicts sensitivity to a small molecule dual-inhibitor of the MYC co-factors, EZH2 and G9A, HKMTi-1-005, and that treatment with HKMTi-1-005 strongly reduced MYC protein expression, induced B cell-mediated immune surveillance and suppressed growth of autochthonous KRasG12D-driven lung tumours. Statement of significanceThis work establishes the principle of indirectly targeting MYC in LuAd, via inhibition of associated enzymatic cofactors, EZH2 and G9A, and identifies a large subset of aggressive human LuAd with a high MYC activity signature that may benefit from this approach.

cancer biology↗

bioRxiv2023

Segmentation of supragranular and infragranular layers in ultra-high resolution 7T ex vivo MRI of the human cerebral cortex

Accurate labeling of specific layers in the human cerebral cortex is crucial for advancing our understanding of neurodevelopmental and neurodegenerative disorders. Lever-aging recent advancements in ultra-high resolution ex vivo MRI, we present a novel semi-supervised segmentation model capable of identifying supragranular and infragranular layers in ex vivo MRI with unprecedented precision. On a dataset consisting of 17 whole-hemisphere ex vivo scans at 120 {micro}m, we propose a multi-resolution U-Nets framework (MUS) that integrates global and local structural information, achieving reliable segmentation maps of the entire hemisphere, with Dice scores over 0.8 for supra- and infragranular layers. This enables surface modeling, atlas construction, anomaly detection in disease states, and cross-modality validation, while also paving the way for finer layer segmentation. Our approach offers a powerful tool for comprehensive neuroanatomical investigations and holds promise for advancing our mechanistic understanding of progression of neurodegenerative diseases.

neuroscience↗

bioRxiv2023

cMYC-mediated immune repression is reversed by inhibition of H3K9/H3K27 methylation maintenance

Aberrant cMYC activity is a key driver of cancer, involved in several hallmark processes. Alongside the canonical hallmark of proliferation, cMYC represses immune signalling in a cell-intrinsic manner. The histone methyltransferases EZH2 and G9a interact with cMYC to modulate gene expression, including repression of immune genes via H3K27 and H3K9 histone methylation. Analyses of 565 cell lines derived from solid cancers demonstrated that greater cMYC-G9a/EZH2-mediated repression correlates with lower immune gene scores in a cell-intrinsic manner (innate, Type I and Type II IFN response), an effect most evident in MYC-amplified cell lines. In ovarian high-grade serous carcinoma (HGSC) cell lines and an in vivo murine model of HGSC, HKMTi-1-005, an inhibitor of H3K27/H3K9 methylation maintenance, relieved cMYC-G9a/EZH2 repression whilst inducing an immune response. A 7-gene immune signature (7ISG), related to viral mimicry signalling, is at the core of the HGSC immune response to HKMTi-1-005. In MYC-amplified HGSC patients, a low 7ISG score was associated with poor survival. Additionally, MYC-amplified cell lines were significantly more sensitive to HKMTi-1-005, whilst a low 7ISG score was associated with greater HKMTi-1-005 sensitivity, effects that were independent of canonical cMYC transcriptional activation. Examining the effects of HKMTi-1-005 treatment in a MYC-deregulated lung adenocarcinoma (LuAd) revealed induction of an immune response in vitro and prolonged survival in vivo. This suggests that inhibition of H3K27/H3K9 methylation maintenance will have efficacy in cMYC-deregulated tumours with low 7ISG scores, via disruption of cMYC-mediated repression of cell autonomous immune signalling and induction of an anti-tumour immune response. Statement of significanceOver 70% of cancers are cMYC-deregulated. We show that inhibition of H3K27/H3K9 methylation maintenance relieves cMYC-dependent immune repression and prolongs survival of animal tumour models, suggesting a novel approach to treating cMYC-deregulated tumours.

cancer biology↗

bioRxiv2023

ERBB signalling contributes to immune evasion in KRAS-driven lung adenocarcinoma

Immunotherapy is increasingly viewed as treatment of choice for lung cancer, however, clinical responses to immune checkpoint blockade remain highly unpredictable and are largely transient. A deeper mechanistic understanding of the dynamics of tumour:immune interactions is needed to drive rational development of improved treatment strategies. Progress is hampered by a paucity of autochthonous model systems in which to interrogate the 2-way interactions of immune responses to evolving tumours and vice-versa. Specifically, commonly used genetically engineered mouse models typically lack the genetic diversity needed to drive an adaptive immune response. APOBEC mutagenesis signatures are prominent in lung cancer and APOBEC activity is predicted to drive immune visibility through Cytidine deaminase activity, coupled with inaccurate DNA-repair responses. We therefore generated a CRE-inducible APOBEC3B allele, interbred with multiple oncogenic drivers of lung adenocarcinoma, and used the resulting mice to investigate the response to PD1 blockade at single cell resolution. SIGNIFICANCE Using our novel immune-visible model of KRas-driven autochthonous lung adenocarcinoma, we uncovered a surprising increase in tumour-cell expression of EGFR/ERBB ligands following treatment with -PD1 and present evidence that transient ERBB blockade can restore immune surveillance in KRas mutant LuAd and combine effectively with immune checkpoint blockade.

cancer biology↗

bioRxiv2019

Design principles of ROS dynamic networks relevant to precision therapies for age-related diseases

The eminently complex regulatory network protecting the cell against oxidative stress, surfaces in several disease maps, including that of Parkinsons disease (PD). How this molecular networking achieves its various functionalities and how processes operating at the seconds-minutes time scale cause a disease at a time scale of multiple decennia is enigmatic.\n\nBy computational analysis, we here disentangle the reactive oxygen species (ROS) regulatory network into a hierarchy of subnetworks that each correspond to a different functionality. The detailed dynamic model of ROS management obtained integrates these functionalities and fits in vitro data sets from two different laboratories.\n\nThe model shows effective ROS-management for a century, followed by a sudden systems collapse due to the loss of p62 protein. PD related conditions such as lack of DJ-1 protein or increased -synuclein accelerated the systems collapse. Various in-silico interventions (e.g. addition of antioxidants or caffeine) slowed down the collapse of the system in silico, suggesting the model may help discover new medicinal and nutritional therapies.

systems biology↗