Biology subjects

Soto, C. M.

Publications and source records attributed to Soto, C. M..

3 recordsLinked to original sources

bioRxiv2026

Systemic hypoxia drives glycogen-fueled progression of lung adenocarcinoma

In advanced stages, lung adenocarcinoma obstructs airways and disrupts ventilation-perfusion relationships in the lung, causing systemic hypoxemia and enabling a feed-forward loop that accelerates malignancy. Systemic hypoxemia is also experienced due to common respiratory comorbidities such as chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA), potentially accelerating malignancy. In a statewide electronic health record network, pre-existing COPD (598 matched pairs) or sleep apnea (235 matched pairs) independently predicted worse survival following incident lung cancer diagnosis. Since the mechanistic basis of the link between malignancy and hypoxia is not well understood, we created systemic hypoxia in KrasLSL-G12D/+;Trp53fl/fl (KP) mice by delivering low inspired oxygen concentrations (8% inspired oxygen; 8 h daily). Hypoxia nearly doubled tumor multiplicity and selectively remodeled cancer central carbon metabolism. Spatially resolved metabolomics revealed marked tumor-compartment glycogen accumulation, elevated tricarboxylic-acid cycle intermediates, and depleted glycolytic pools. Quantitative proteomics across cellular models and autochthonous tumors demonstrated that systemic hypoxia drives glycogen mobilization selectively through the lysosomal enzyme acid -glucosidase (GAA). Tumor-cell-autonomous deletion of GAA eliminated the hypoxia-driven growth advantage and disrupted downstream anabolic biosynthetic pathways. Thus, systemic hypoxia drives lung adenocarcinoma expansion by mobilizing lysosomal glycogen reserves through GAA to sustain proliferative growth.

cancer biology↗

bioRxiv2026

A multi-organ spatial metabolomic atlas of exercising mice reveals neuronal Complex I as a convergent and sufficient axis for tau pathology reduction in PS19

We constructed a spatially resolved metabolomic atlas of long-term exercise across six major organs in wild-type mice: brain, heart, lung, liver, kidney, and skeletal muscle, cataloguing 224 metabolic features and revealing coordinated inter-organ remodeling. Surprisingly, the brain showed particularly pronounced region-specific adaptation. Because pathological tau associates with synaptic mitochondria from early stages of tauopathy, we extended this multi-organ spatial metabolomic approach to PS19 mice and found that exercise reduced over 70% of observable tau pathology in PS19 hippocampus and restored the mitochondrial-related metabolome. Integrated proteomic and spatial metabolomic analyses identified NADH dehydrogenase Complex I as the convergent node. To test this finding biologically, we expressed the yeast NADH dehydrogenase, Ndi1, in PS19 neurons in the absence of exercise. This increased cerebral antioxidants, restored shuttle-linked metabolites, and reduced tau pathology. Increasing NADH dehydrogenase activity through NDI1 reproduces the core anti-tau and metabolic effects of exercise. These findings provide a molecular mechanism for how exercise may prevent or slow tau pathology accumulation, complementing the human-cohort literature linking exercise to delayed cognitive decline.

neuroscience↗

bioRxiv2025

Hyper-Glycosylation as a Central Metabolic Driver of Alzheimers Disease

Alzheimers disease (AD) is a neurodegenerative disorder characterized by devastating degenerative decline. Metabolic disruptions are widely observed, yet their involvement in the molecular etiology of AD remains underexplored. Utilizing spatial metabolomics, lipidomics, and glycomics in both mouse models and human post-mortem samples, we identified a hyper-glycosylation phenotype as a hallmark of AD. To investigate the underlying mechanisms and whether the observed effect was a driver of the observed decline, we developed an advanced spatial isotopic tracing pulse-chase method to study the dynamics of N-linked glycans. Our analysis revealed enhanced glycan biosynthesis in AD mouse models. Based on these findings, we performed genetic and dietary interventions to modulate glycan biosynthesis. Genetic knockdown of glycan biosynthetic enzymes ameliorated the hyper-glycosylation and improved cognitive and behavioral outcomes in AD mice. In contrast, oral glucosamine supplementation drove hyper-glycosylation and exacerbated cognitive and behavioral deficits. To assess the clinical relevance of these findings, we conducted a retrospective analysis of a large population of patients with mild cognitive impairment (MCI), AD, and Alzheimers Disease Related Dementias (ADRD) stratified by glucosamine use, leveraging electronic health records. Consistently, glucosamine supplementation was associated with increased mortality in AD and ADRD patient cohorts, and significantly elevated progression from MCI to AD compared to age-matched controls. Collectively, our findings establish hyper-glycosylation as a pathological driver of AD and highlight glycan metabolism as an actional target in the fight against AD.

neuroscience↗