Biology subjects

Atkinson, A.

Publications and source records attributed to Atkinson, A..

8 recordsLinked to original sources

bioRxiv2026

SWI/SNF Alterations Define a Chromatin-Dependent Subtype of Urothelial Carcinoma

PurposeSWI/SNF (BAF) chromatin remodeling complex alterations are common in urothelial carcinoma, yet no biomarker-directed therapeutic strategies have been established for this population. We investigated whether BAF alterations delineate a biologically distinct, therapeutically actionable urothelial carcinoma subtype. Experimental DesignWe performed integrative genomic and transcriptomic analyses of 792 urothelial carcinoma tumors from the Oncology Research Information Exchange Network (ORIEN) and validated findings in the TCGA-BLCA cohort. Mechanistic studies incorporated RNA sequencing and ATAC-seq following histone deacetylase (HDAC) inhibition. Functional dependencies were assessed using patient-derived xenograft organoids and cell line models. Clinical relevance was explored in a biomarker-enriched investigator-initiated trial. ResultsApproximately half of urothelial carcinoma tumors exhibited BAF alterations, defining a previously unrecognized chromatin-altered molecular subtype characterized by activation of proliferative programs, loss of lineage identity, and altered metabolic signaling. This subtype was enriched for transcriptomic programs associated with HDAC inhibitor sensitivity and depleted of HDAC inhibitor resistance signatures. Mechanistically, HDAC inhibition induced widespread chromatin remodeling with reduced accessibility at AP-1 and TEAD-associated regions, and downregulation of E2F- and MYC-driven transcriptional networks. Functional studies confirmed enhanced HDAC inhibition sensitivity in ARID1A-mutated cell lines and a patient-derived organoid model. Early clinical observations demonstrated a durable responder treated with HDAC inhibitors and immunotherapy. ConclusionsBAF alterations define a chromatin-dependent tumor state in urothelial carcinoma that is selectively vulnerable to HDAC inhibition. Integrating genomic, epigenomic, functional, and early clinical evidence, these findings provide a rationale for biomarker-enriched clinical trials and HDAC inhibitor-based combination strategies in urothelial carcinoma.

cancer biology↗

bioRxiv2025

Assessment of Imaging Mass Cytometry (IMC) as a Tool to Characterize Circulating Tumor Cells (CTCs) in Preclinical Mouse Models

Circulating tumor cells (CTCs), particularly multicellular clusters, are associated with poor prognosis and may provide insight into mechanisms of metastasis and therapy resistance. Unbiased approaches for functionally characterizing CTCs in liquid biopsies are therefore urgently needed. Here, we evaluate multiplex imaging mass cytometry (IMC) for CTC analysis in mice bearing human xenograft tumors. In a single-step workflow, IMC uses metal-conjugated antibodies to simultaneously detect numerous proteins and post-translational modifications in minimally processed, small-volume blood samples collected from the tail vein or heart. Using breast cancer cell lines and a patient-derived xenograft (PDX), we assessed a panel of antibodies, including human-specific markers such as Lamin B1 (LMNB1), to enable cross-species interpretation. Combined with manual review, HALO AI-based cell segmentation was used to identify CTCs and quantify marker expression. This approach enables studies of how genetic and pharmacologic interventions alter the properties of single CTCs and CTC clusters in tumor-bearing mice.

cancer biology↗

bioRxiv2025

A gene expression atlas of a juvenile nervous system

Although the fundamental architecture of metazoan nervous systems is typically established in the embryo, substantial numbers of neurons are added during post-natal development while existing neurons expand in size, refine connectivity, and undergo additional differentiation. To reveal the underlying molecular determinants of postembryonic neurogenesis and maturation, we have produced gene expression profiles of all neuron types and their progenitors in the first larval stage (L1) of C. elegans. Comparisons of the L1 profile to the embryo and to the later L4 larval stage identified thousands of differentially expressed genes across individual neurons throughout the nervous system. Key neuropeptide signaling networks, for example, are remodeled during larval development. Gene regulatory network analysis revealed potential transcription factors driving the temporal changes in gene expression across the nervous system, including a broad role for the heterochronic transcription factor lin-14. We utilized available connectomic data of juvenile animals in combination with our neuron-specific atlas to identify potential molecular determinants of membrane contact and synaptic connectivity. These expression data are available through a user-friendly interface at CeNGEN.org for independent investigations of the maturation, connectivity and function of a developing nervous system.

neuroscience↗

bioRxiv2025

Mapping global fisheries climate risks to guide sustainable marine management

Ocean warming is projected to reduce the capacity of the global ocean to support fish biomass. The severity of projected biomass declines, however, is distributed highly unevenly at the global scale, meaning some nations face disproportionate socioeconomic risks from resultant fisheries declines. Here, we apply the IPCC climate risk framework through the lens of fishing grounds to identify global hotspots where climate-driven declines in supportable pelagic fish biomass pose the greatest threat to socioeconomic security. By integrating empirical size-spectrum projections of fish biomass declines (hazard) with present-day fishing effort (exposure) and a novel area-based index of fishing ground socioeconomic vulnerability, we identify risk hotspots around Southeast Asia, the western seaboard of Africa, and the West Pacific. Our projections are corroborated by an ensemble of ecosystem models and compared with historical observations of declining zooplankton biomass in the Northeast Atlantic, suggesting climate-driven fish biomass declines are already underway. Many of the regions we assessed as highest-risk are predominantly targeted by nations with relatively low adaptive capacity and who therefore face the greatest barriers to redistributing fishing effort to lower-risk fishing grounds. Socioeconomic risks could thus be partly mitigated by targeting risk hotspots with area-based interventions that directly support fish stocks, such as the restoration of essential fish habitats and the designation of Marine Protected Areas. Resourcing the development of regionally tailored models for high-risk regions will provide the best evidence for designing specific area-based measures that effectively reduce societal risks, but enforcing such measures will depend upon addressing illegal, unregulated and untracked fishing.

ecology↗

bioRxiv2024

A precision oncology-focused deep learning framework for personalized selection of cancer therapy

Precision oncology matches tumors to targeted therapies based on the presence of actionable molecular alterations. However, most tumors lack actionable alterations, restricting treatment options to cytotoxic chemotherapies for which few data-driven prioritization strategies currently exist. Here, we report an integrated computational/experimental treatment selection approach applicable for both chemotherapies and targeted agents irrespective of actionable alterations. We generated functional drug response data on a large collection of patient-derived tumor models and used it to train ScreenDL, a novel deep learning-based cancer drug response prediction model. ScreenDL leverages the combination of tumor omic and functional drug screening data to predict the most efficacious treatments. We show that ScreenDL accurately predicts response to drugs with diverse mechanisms, outperforming existing methods and approved biomarkers. In our preclinical study, this approach achieved superior clinical benefit and objective response rates in breast cancer patient-derived xenografts, suggesting that testing ScreenDL in clinical trials may be warranted.

cancer biology↗

bioRxiv2024

Zinc Alpha-2-Glycoprotein (ZAG/AZGP1) secreted by triple-negative breast cancer promotes tumor microenvironment fibrosis.

Obesity is a predisposition factor for breast cancer, suggesting a localized, reciprocal interaction between breast cancer cells and the surrounding mammary white adipose tissue. To investigate how breast cancer cells alter the composition and function of adipose tissue, we screened the secretomes of ten human breast cancer cell lines for the ability to modulate the differentiation of adipocyte stem and progenitor cells (ASPC). The screen identified a key adipogenic modulator, Zinc Alpha-2-Glycoprotein (ZAG/AZGP1), secreted by triple-negative breast cancer (TNBC) cells. TNBC-secreted ZAG inhibits adipogenesis and instead induces the expression of fibrotic genes. Accordingly, depletion of ZAG in TNBC cells attenuates fibrosis in white adipose tissue and inhibits tumor growth. Further, high expression of ZAG in TNBC patients, but not other clinical subtypes of breast cancer, is linked to poor prognosis. Our findings suggest a role of TNBC-secreted ZAG in promoting the transdifferentiation of ASPCs into cancer-associated fibroblasts to support tumorigenesis.

cancer biology↗

bioRxiv2023

Valuing carbon sequestration by Antarctic krill faecal pellets

Marine life contribute to carbon stores helping lock carbon away from the atmosphere. Open-ocean pelagic ecosystems are vastly under-reported in terms of carbon sequestration conservation potential, compared to coastal vegetation blue carbon systems. Here we show that a harvested organism, Antarctic krill, has similar carbon sequestration potential through its sinking faecal pellets as coastal blue carbon stores, namely seagrasses, mangroves and marshes. Building upon recent advances in krill abundance and faecal pellet carbon flux data, and combining these with an ocean circulation model, we show that from Austral spring to early autumn Antarctic krill sequester 20 Mt C into the deep ocean for at least 100 years. This equates to USD$ 4 - 46 billion per spring/summer season depending on the price of carbon. The footprint of remineralised krill pellet carbon has a global extent, with some reaching as far as the North Pacific. The vast area of ocean krill inhabit and their high abundance make their total carbon sequestered each year similar to that from coastal vegetated blue carbon stores. As Antarctic krill are being impacted by rapid polar climate change and they are harvested, both krill populations and their habitat warrant protection to preserve this valuable carbon sink.

ecology↗

bioRxiv2022

Multiple lineages of Monkeypox virus detected in the United States, 2021-2022

Monkeypox is a viral zoonotic disease endemic in Central and West Africa. In May 2022, dozens of non-endemic countries reported hundreds of monkeypox cases, most with no epidemiological link to Africa. We identified two lineages of Monkeypox virus (MPXV) among nine 2021 and 2022 U.S. monkeypox cases. A 2021 case was highly similar to the 2022 MPXV outbreak variant, suggesting a common ancestor. Analysis of mutations among these two lineages revealed an extreme preference for GA-to-AA mutations indicative of APOBEC3 cytosine deaminase activity that was shared among West African MPXV since 2017 but absent from Congo Basin lineages. Poxviruses are not thought to be subject to APOBEC3 editing; however, these findings suggest APOBEC3 activity has been recurrent and dominant in recent West African MPXV evolution.

genomics↗