Biology subjects

Bowles, A.

Publications and source records attributed to Bowles, A..

4 recordsLinked to original sources

bioRxiv2025

Hyperlipidemia drives tumor growth in a mouse model of obesity-accelerated breast cancer growth.

Obesity is an established risk factor for breast cancer (BC), yet the specific mechanisms driving this association remain unclear. Dysregulated lipid metabolism has emerged as a key factor in cancer cell biology. While obesity is often accompanied by hyperlipidemia, the isolated impact of elevated lipid levels on BC growth has not been experimentally tested. Using the E0771 orthotopic model of obesity-accelerated BC growth in immune-competent mice, we investigated the direct role of systemic lipids in tumor growth. Combining dietary and genetic mouse models, we show that elevated circulating lipids are sufficient to accelerate BC tumor growth even in the absence of obesity or alterations in blood glucose and/or insulin levels. Pharmacological lowering of systemic lipid levels attenuates BC growth in obese mice, suggesting a direct role for lipids in fueling tumor expansion. Notably, we also show that weight loss alone, without a corresponding reduction in lipid levels such as that induced by a ketogenic diet, fails to protect against BC, highlighting the necessity of targeting lipid metabolism in obesity-associated BC. Our findings establish hyperlipidemia as a critical driver of BC progression and suggest that lipid-lowering interventions may be a promising strategy to mitigate BC risk in obese individuals.

cancer biology↗

bioRxiv2024

SLC7A5 is required for citrulline-dependent growth in arginine limited conditions

Tumor cells must optimize metabolite acquisition between synthesis and uptake from their surroundings. The tumor microenvironment is characterized by hypoxia, lactate accumulation, and depletion of many circulating metabolites, including amino acids such as arginine. We performed a metabolism-focused functional screen using CRISPR/Cas9 in a melanoma cell line to identify pathways and factors that enable tumor growth in an arginine-depleted environment. Our screen identified the SLC-family transporter SLC7A5 as required for growth, and we hypothesized that this protein functions as a high-affinity citrulline transporter. Citrulline, an essential precursor to arginine synthesis, is present in human serum at 40 M and supports localized arginine synthesis across diverse tissues. Using isotopic tracing experiments, we show that citrulline uptake and metabolism are dependent upon expression of this transporter. Pharmacological inhibition of SLC7A5 blocks growth in low arginine conditions across a diverse group of cancer cell lines. Loss of SLC7A5 reduces tumor growth and citrulline import in a mouse tumor model. Overall, we identify a conditionally essential role for SLC7A5 in arginine metabolism as a mediator of citrulline uptake, and we propose that SLC7A5-targeting therapeutic strategies in cancer may be especially effective in the context of arginine limitation. Key PointsO_LISLC7A5 is required for proliferation in arginine-free conditions when citrulline is present. C_LIO_LISLC7A5 loss impairs arginine metabolism. C_LIO_LICitrulline import is uniquely dependent on SLC7A5. C_LIO_LISmall molecule inhibitors of SLC7A5 can be paired with senolytic drugs to drive apoptosis. C_LIO_LISLC7A5 knockout decreases citrulline import in a xenograft model. C_LI

biochemistry↗

bioRxiv2024

SAUSI: a novel assay for measuring social anxiety and motivation

Social aversion is a key feature of numerous mental health disorders such as Social Anxiety and Autism Spectrum Disorders. Nevertheless, the biobehavioral mechanisms underlying social aversion remain poorly understood. Progress in understanding the etiology of social aversion has been hindered by the lack of comprehensive tools to assess social aversion in model systems. Here, we created a new behavioral task - Selective Access to Unrestricted Social Interaction (SAUSI), which integrates elements of social motivation, hesitancy, decision-making, and free interaction to enable the wholistic assessment of social aversion in mice. Using this novel assay, we found that social isolation-induced social aversion in mice is largely driven by increases in social fear and social motivation. Deep learning analyses revealed a unique behavioral footprint underlying the socially aversive state produced by isolation, demonstrating the compatibility of modern computational approaches with SAUSI. Social aversion was further assessed using traditional assays - including the 3-chamber sociability assay and the resident intruder assay - which were sufficient to reveal fragments of a social aversion phenotype, including changes to either social motivation or social interaction, but which failed to provide a wholistic assessment of social aversion. Critically, these assays were not sufficient to reveal key components of social aversion, including social freezing and social hesitancy behaviors. Lastly, we demonstrated that SAUSI is generalizable, as it can be used to assess social aversion induced by non-social stressors, such as foot shock. Our findings debut a novel task for the behavioral toolbox - one which overcomes limitations of previous assays, allowing for both social choice as well as free interaction, and offers a new approach for assessing social aversion in rodents.

neuroscience↗

bioRxiv2019

CD146+CD107a+ Mesenchymal Stem/Stromal Cells with Signature Attributes Correlate to Therapeutic Potency as \"First Responders\" to Injury and Inflammation

CD146+ bone marrow-derived Mesenchymal Stem/Stromal Cells (BM-MSC) play key roles in the perivascular niche, skeletogenesis and hematopoietic support, however elucidation of therapeutic potency has yet to be determined. Here, inflammatory challenge to crude BM-MSC captured a baseline of signatures including enriched expression of CD146+ with CD107a+, CXCR4+, and LepR+, transcriptional profile, enhanced secretory capacity, robust secretome and immunomodulatory function with stimulated target immune cells. These responses were significantly more pronounced in CD146+ (POS)-selected subpopulation than in the CD146- (NEG). Mechanistically, POS uniquely mediated robust immunosuppression while inducing significant frequencies of Naive and Regulatory T cells in vitro. Moreover, POS promoted a pivotal M1-to-M2 macrophage shift in vivo, ameliorating inflammation/fibrosis of joint synovium and fat pad of the knee, failed by NEG. This study provides high-content evidence of CD146+CD107a+ BM-MSC, herein deemed first responders to inflammation, as the underrepresented subpopulation within crude BM-MSC with innately higher secretory capacity and therapeutic potency.\n\nHIGHLIGHTSO_LISignature phenotypic, transcriptional, and secretome profiles were identified and enriched in human CD146+ (POS)-selected subpopulation in response to inflammation\nC_LIO_LIInflammatory challenge consistently altered stemness (LIF) and differentiation master regulators (SOX9, RUNX2, PPAR{gamma}) in crude, POS, and NEG BM-MSC, and deduced unique expressions in POS compared to NEG\nC_LIO_LIPOS BM-MSC mediated the strongest immunomodulation, e.g. target immune cell suppression, Treg induction, diminished T cell differentiation\nC_LIO_LIPOS BM-MSC promoted the largest M1-to-M2 shift in vivo alleviating induced synovitis and infrapatellar fat pad fibrosis of the knee\nC_LI

cell biology↗