Biology subjects

Atkinson, S.

Publications and source records attributed to Atkinson, S..

8 recordsLinked to original sources

bioRxiv2026

A combined program of induced stemness and differentiation in response to interferon gamma drives acute myeloid leukaemia growth

How inflammation shapes acute myeloid leukaemia (AML) has come under scrutiny, as it may explain the disease resistance to immunotherapy approaches. IFNg has emerged as a key cytokine with paradoxical roles in suppressing and supporting AML growth, and the fundamental question of how leukemic stem cells (LSCs) respond to IFNg and whether IFNg signaling influences LSC quiescence and their capacity to regenerate disease over the long term remains unanswered. Here, we study primary human AML cells and murine models and combine bioinformatics analyses and functional assays to show that AML hierarchical heterogeneity is responsive to IFNg challenge. We uncover that IFNg triggers parallel stemness and differentiation programs; HSC/MPP-like cells enter deeper stemness, associated with quiescence and high leukaemia regeneration potential, while the surviving pool of progenitor-like cells divides faster but produces progeny that is quickly lost. Finally, with murine models we show that exposure to inflammation in vivo results in only transient impairment of leukaemia propagating capacity. This mechanism is driven by a previously unrecognised intraclonal fate bifurcation, relevant for the development of more effective therapeutic approaches.

cancer biology↗

bioRxiv2025

Patient-derived liver biopsy organoids enable precision alcohol-associated liver disease modeling

Background & AimsAlcohol-associated liver disease (ALD) is a major cause of liver disease worldwide with scarce therapeutic options. Animal models poorly recapitulate advanced ALD precluding the development of new treatments. Organoids have emerged as a powerful human-based preclinical tool. However, current patient-derived liver organoids fail to recapitulate the epithelial heterogeneity and its generation requires liver surgical resections, thus limiting personalized disease modeling. Here, we report the development of organoids from liver needle biopsies (b-Orgs) from patients with ALD. Methodsb-Orgs were generated from tru-cut biopsies from patients at early (n=28) and advanced (n=34) stages of ALD. b-Orgs were characterized by immunofluorescence, bulk and single cell RNA-sequencing and compared to parental tissues. b-Orgs were used to model ALD progression, identify pathogenic drivers, induce alcohol-associated hepatitis (AH) and evaluate response to prednisolone. ResultsPhenotypic and functional analysis of b-Orgs showed hepatocyte- enriched features. Single-cell RNA-sequencing revealed a heterogeneous cell composition comprising hepatocyte, biliary and progenitor populations, mirroring the epithelial landscape found in patients with advanced ALD. Moreover, b-Orgs preserved disease-stage features and allowed to identify the association of ELF3 with cell plasticity and disease progression. Finally, stimulation of b-Orgs with drivers of ALD induced pathophysiological features of alcohol-associated hepatitis, including ROS production, lipid accumulation, inflammation and decreased cell proliferation, which were mitigated in response to prednisolone. Conclusions Overall, we provide a human-based model that recapitulates epithelial complexity and patient specific features, allowing to identify drivers of cell plasticity and expanding organoid-based liver disease modeling for personalized medicine. Impact and implications Here, we describe the generation of biopsy-derived organoids (b-Orgs) from patients with liver disease. b-Orgs reproduce the liver epithelial cell composition found in patients liver tissue and are efficiently generated from different stages of the disease, providing a platform for patient- tailored disease modeling and drug testing.

cell biology↗

bioRxiv2024

Differential responses and recovery dynamics of HSPC populations following Plasmodium chabaudi infection.

Severe infections such as malaria are on the rise worldwide, driven by both climate change and increasing drug-resistance. It is therefore paramount that we better understand how the hosts organism responds to severe infection. Hematopoiesis is particularly of interest in this context because hematopoietic stem and progenitor cells (HSPCs) maintain the turnover of all blood cells, including all immune cells. Severe infections have been widely acknowledged to affecting HSPCs, however this disruption has been mainly studied during the acute phase, and the process and level of HSPC recovery remains understudied. Using a self-resolving model of natural rodent malaria, infection by Plasmodium chabaudi, here we systematically assess HSPCs acute response and recovery upon pathogen clearance. We demonstrate that during the acute phase of infection the most quiescent and functional stem cells are depleted, multipotent progenitor compartments are drastically enlarged, and oligopotent progenitors virtually disappear, underpinned by dramatic, population-specific and sometimes unexpected changes in proliferation rates. HSPC populations return to homeostatic size and proliferation rate again through specific patterns of recovery. Overall, our data demonstrate that HSPC populations adopt different responses to cope with severe infection and suggest that the ability to adjust proliferative capacity becomes more restricted as differentiation progresses.

developmental biology↗

bioRxiv2023

Mitochondrial dsRNA from B-ALL cells stimulates mesenchymal stromal cells to become cancer associated fibroblasts

Cancer associated fibroblasts (CAF) arising from bone marrow-derived mesenchymal stromal cells (MSC) are prominent in B-precursor acute lymphoblastic leukaemia (B-ALL). We have previously shown that CAF formation is triggered by exposure to reactive oxygen species-inducing chemotherapy and that CAF support chemoresistance by donating mitochondria to the cancer cells, through tunnelling nanotubes. In the present study, we show that exposure of MSC to ALL cell lines, PDX and primary cells or their conditioned media can also trigger CAF formation, in an oncogene-dependent manner. Using bulk RNA sequencing in cell lines, we show that the MSC to CAF transition is accompanied by a robust interferon pathway response and we have validated this finding in primary cells. Using confocal microscopy and flow cytometry, we identify the take up of leukaemia cell-derived mitochondrial dsRNA by MSC as a proximate trigger for the MSC to CAF transition. We show that degradation of dsRNA in ALL cell conditioned media by DMSO ablates the ability of the conditioned media to stimulate MSC to CAF transition. Since we find that only specific primary driver genetic subtypes of B-ALL possess the property to directly generate CAFs, we propose this phenomenon as the first mechanistic insight into the strong relationship between acute lymphoblastic leukaemia genetic subtype and survival outcomes. Key pointsX Exposure of MSC to B-precursor ALL cell lines triggers cancer-associated fibroblast formation in an oncogene-dependent manner The proximate trigger for CAF formation is ALL-derived mitochondrial double stranded RNA

cancer biology↗

bioRxiv2023

SCD inhibition eradicates AML displaying high de novo fatty acid desaturation and synergizes with chemotherapy

Identification of specific and therapeutically actionable vulnerabilities in acute myeloid leukaemia (AML) is needed to improve patients outcome. These features should be ideally present in many patients independently of mutational background. Here we identify de novo fatty acid (FA) desaturation, specifically stearoyl-CoA desaturase (SCD) inhibition, as a therapeutic vulnerability across multiple AML models in vitro and in vivo. We use the novel clinical grade SCD inhibitor SSI-4 to show that SCD inhibition induces AML cell death via pleiotropic effects, and sensitivity is based on their dependency on FA desaturation regardless of mutational profile. SSI-4 efficacy is enhanced by driving FA biosynthesis in vitro while stroma confers protective effects that extend to in vivo models. SCD inhibition increases DNA damage and its combination with standard DNA damage-inducing chemotherapy prolongs survival in aggressive murine AML models. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their therapeutic potential. One Sentence SummarySCD inhibition is toxic to AML cells with high rates of fatty acid desaturation and in combination with chemotherapy prolongs survival in murine AML models.

cancer biology↗

bioRxiv2022

Parity modulates impact of BMI and Gestational Weight Gain on gut microbiota in human pregnancy

Pregnancy requires maternal adaptations to support fetal growth: whether these adaptations include temporal shifts in the gut microbiome is still unclear. We investigated the maternal gut microbiome longitudinally over the course of pregnancy and the impact of pre-pregnancy BMI (pBMI) and GWG. We also determined whether parity modulated observed associations. We show that the gut microbiota of participants with higher pBMI changed less over the course of pregnancy in primiparous, but not multiparous participants. This suggests that previous pregnancies may have persistent impacts on maternal adaptations to pregnancy. This ecological memory appears to be passed to the next generation, as parity modulated the impact of maternal GWG on the infant gut microbiome. This work supports a role for the gut microbiome in maternal adaptations to pregnancy and highlights the need for longitudinal sampling and accounting for parity as key considerations for studies of the microbiome in pregnancy and infants.

microbiology↗

bioRxiv2020

Change in terrestrial human footprint drives continued loss of intact ecosystems

Our ability to map humanitys influence across Earth has evolved, thanks to powerful computing, a network of earth observing satellites, and new bottom-up census and crowd-sourced data. Here, we provide the latest temporally inter-comparable maps of the terrestrial Human Footprint, and assessment of change in human pressure at global, biome, and ecoregional scales. In 2013, 42% of terrestrial Earth could be considered relatively free of anthropogenic disturbance, and 25% could be classed as wilderness (the least degraded end of the human footprint spectrum). Between 2000 and 2013, 1.9 million km2 - an area the size of Mexico - of land relatively free of human disturbance became highly modified. The majority of this occurred within tropical and subtropical grasslands, savannah, and shrubland ecosystems, but the rainforests of Southeast Asia also underwent rapid modification. Our results show that humanitys footprint is eroding Earths last intact ecosystems, and greater efforts are urgently needed to retain them.

ecology↗

bioRxiv2017

A quantitative PCR based environmental DNA assay for detecting Atlantic salmon (Salmo salar L.)

O_LIThe Atlantic salmon (Salmo salar L.) has worldwide ecological, cultural and economic importance. The species has undergone extensive decline across its native range, yet concerns have been raised about its invasive potential in the Pacific. Knowledge on the distribution of this species is vital for addressing conservation goals.\nC_LIO_LIThis study presents an eDNA assay to detect S. salar in water samples, using quantitative PCR (qPCR) technology. Species-specific primers and a minor groove binding (MGB) probe were designed for the assay, based on the mitochondrial cytochrome oxidase I (COI) gene.\nC_LIO_LIThe results of this study indicate that eDNA is a highly sensitive tool for detecting S. salar in situ, and could potentially provide an alternative, non-invasive method for determining the distribution of this species.\nC_LI

genetics↗