Biology subjects

McGann, J.

Publications and source records attributed to McGann, J..

4 recordsLinked to original sources

bioRxiv2026

Spatial epigenomics reveals ancestry-associated regulatory states linked to aggressive prostate cancer biology

Prostate cancer (PCa) exhibits substantial biological heterogeneity, including population associated differences in tumor aggressiveness and clinical outcomes. Although socioeconomic and environmental factors contribute to these disparities, intrinsic tumor regulatory programs may also influence disease behavior. Here, we investigated whether differences in chromatin regulation contribute to distinct tumor states in Black and White men with localized PCa. We performed spatial chromatin accessibility profiling (ATAC-seq) of prostatectomy specimens from Black and White patients receiving equal healthcare access at the Center for Prostate Disease Research (USUHS) and Walter Reed National Military Medical Center. Tumors showed distinct chromatin accessibility landscapes between the two populations, with tumors from Black patients exhibiting reduced accessibility of motifs associated with the chromatin architectural regulator CTCF and enrichment of motifs linked to epithelial-mesenchymal transition and inflammatory programs. Reduced CTCF expression was independently validated by immunohistochemistry in 99 prostatectomy specimens. These findings identify population-associated differences in chromatin regulation in localized PCa and suggest that altered CTCF-associated regulation, inflammatory signaling, and epithelial plasticity may contribute to the biological heterogeneity underlying ancestry-dependent PCa disparities.

cancer biology↗

bioRxiv2026

Mutant ASXL1 Drives Transcriptional Activation and Repression in Human Hematopoiesis

Mutations in the epigenetic regulator ASXL1 are common in myeloid malignancies and portend a near-universally poor prognosis. While multiple mechanisms for mutant ASXL1-dependent oncogenesis have been proposed, none have been functionally validated in the context of the human hematopoietic stem cell, where these mutations almost certainly arise. Here, we extensively characterized a CRISPR-engineered human hematopoietic stem and progenitor cell model of ASXL1 mutations. In this context, mutant ASXL1 expression decreases differentiation, increases clonogenicity in serial replating experiments, and improves engraftment in immunodeficient mice. We also show that endogenous truncating mutations in ASXL1 drive protein stabilization and confirm that mutant ASXL1 is resistant to proteasomal degradation. At the transcriptional level, these phenotypes are driven by significant repression of the stress-response genes and by increased expression of bromodomain and extra-terminal family protein targets. Using protein-interaction screens, genomic and functional approaches, we link the positive transcriptional changes in ASXL1-mutant cells to BRD4-dependent RNA polymerase II pause release and identify a mechanism for transcriptional repression via a previously uncharacterized interaction with the transcription factor MECOM. Finally, we demonstrate that ASXL1-mutant AML exhibits increased MECOM activity consistent with our gene-editing models. Collectively, these studies highlight a highly reproducible model of mutant ASXL1 in the appropriate cell context. Further, they are the first to functionally describe the mutant ASXL1 interactome in the context of the human HSC, identifying new dependencies with therapeutic potential.

cancer biology↗

bioRxiv2025

Serial Imaging of Tumor and microEnvironment (SITE) platform for live-cell ex vivo modeling of primary and metastatic cancer dynamics.

Understanding cancer initiation and progression is extremely challenging, in part due to experimental limitations in measuring and interpreting key signalling and tumour-microenvironment (TME) interactions that determine changes in cell and tissue behaviours over time. Here we developed SITE (Serial Imaging of Tumour and microEnvironment), a spatially-and temporally integrated, modular, ex vivo platform enabling quantitative analysis of TME interaction dynamics, signalling, and cell fate at single cell and tissue scales. Applied to modelling primary and lung metastatic breast cancer, SITE revealed tissue-specific TME interactions and ERK signalling patterns linked to distinct single-cell behaviours. We found that the earliest steps in tumour establishment and metastatic seeding involved active cell protrusion and the establishment of a multicellular niche interfacing tumour and host. Experimental and mathematical modelling showed that ERK signalling was co-influenced by these interactions, where cancer cluster formation increased signalling via the establishment of local signalling circuits. Disruption of these signalling circuits led to tissue-specific impacts on cancer intrinsic and TME interaction dynamics. Here, we modelled breast cancer as a test case, demonstrating the broad utility of SITE for quantitative exploration of TME interaction dynamics- closing a significant gap in experimental capabilities between in vivo models and in vitro systems.

cancer biology↗

bioRxiv2018

Multisensory expectations shape olfactory input to the brain

The mammalian brain interprets sensory input based on prior multisensory knowledge of the external world, but it is unknown how this knowledge influences neural processing in individual sensory modalities. We found that GABAergic periglomerular interneuron populations in the olfactory bulb endogenously respond not only to odors but also to visual, auditory, and somatosensory stimuli in waking (but not anesthetized) mice. When these stimuli predict future odors, they evoke enhanced interneuron activity during the time odor normally occurs. When expectations are violated by omitting an expected \"warning tone\" before an odor, odor presentation evokes a burst of interneuron activity. The resulting GABA release presynaptically suppresses neurotransmitter release from the axon terminals of olfactory sensory neurons, the cells that transduce odor in the nasal epithelium and communicate this information to the brain. Expectations, even those evoked by cues in other sensory modalities, can thus affect the very first neurons in the olfactory system.

animal behavior and cognition↗