Biology subjects

Shevzov-Zebrun, A.

Publications and source records attributed to Shevzov-Zebrun, A..

7 recordsLinked to original sources

bioRxiv2026

Physiological folate levels constrain nucleotide synthesis and increase dependence on nucleotide salvage

Proliferating cells must acquire nucleotides to support DNA replication, yet how cells meet these nucleotide demands for proliferation under physiological conditions remains understudied. Here, we investigated how physiological nutrient availability shapes nucleotide acquisition strategies in a mouse model of B-cell acute lymphoblastic leukemia (B-ALL). To assess how environmental nutrients impact nucleotide metabolism, we formulated a mouse plasma-like medium (MPM) that reproduces the circulating metabolite composition of plasma from mice with B-ALL and assessed how this influenced nucleotide metabolism relative to standard culture conditions, where nucleotide acquisition has historically been studied. We find that leukemia cells cultured in MPM acquire nucleotides through salvage pathways, and that select nucleotide salvage pathways are required for proliferation under physiological conditions. Of note, this dependency on nucleotide salvage in plasma-like conditions was not caused by precursor metabolite limitation for de novo synthesis. Instead, we found that physiological folate levels are insufficient to support deoxynucleotide triphosphate (dNTP) synthesis for genome replication, leading to DNA replication stress and impaired proliferation when nucleotide salvage is disrupted. Consistently, dietary folate restriction exacerbates the impaired leukemia progression phenotype of nucleotide salvage-deficient B-ALL cells. Together, these findings demonstrate that access to folates is an endogenous limitation for nucleotide synthesis in plasma-like nutrient conditions, increasing the relevance of nucleotide salvage pathways for leukemia progression. More broadly, this work highlights how micronutrient abundance can influence metabolic dependencies and reveals that folate levels shape nucleotide metabolism under physiological conditions.

cancer biology↗

bioRxiv2026

TRANSSULFURATION LINKS ASPARTATE-ASPARAGINE METABOLISM AND REDOX HOMEOSTASIS TO DRIVE TUMOR GROWTH

Cytosolic redox balance is tightly coupled to aspartate synthesis through the malate-aspartate shuttle, and limiting the malate-aspartate shuttle has been proposed to constrain tumor growth by restricting aspartate availability. Here we show that tumors derived from cancer cells lacking GOT1 and GOT2, the cytosolic and mitochondrial aspartate aminotransferases essential for as-partate production and malate-aspartate shuttle function, grow despite impaired canonical as-partate synthesis. This is because cytosolic redox state, not aspartate supply, is the primary metabolic bottleneck in GOT1/GOT2 knockout cells. Using single-cell transcriptomics, metabo-lite tracing, and a loss-of-function CRISPR screen, we find that these tumors engage an adaptive bypass in which availability of asparagine, a product of aspartate, enables serine- and methio-nine-dependent transsulfuration to generate -ketobutyrate, whose reduction regenerates cy-tosolic NAD and restores redox homeostasis. Pharmacological inhibition or genetic ablation of transsulfuration abrogates this asparagine-driven rescue. These findings define asparagine as a regulator of cytosolic NAD/NADH balance and reveal a link between amino acid metabolism and redox control that suggests transsulfuration as a targetable vulnerability in tumor redox maintenance. Significance statementAspartate synthesis and cytosolic redox balance are both coupled through the malate-aspartate shuttle. We show that the cytosolic NAD/NADH ratio, not aspartate supply, is a critical output of the malate-aspartate shuttle for tumor growth. Availability of asparagine, a product of aspar-tate, enables serine- and methionine-dependent transsulfuration to restore cytosolic NAD/NADH balance, proliferation and tumor growth independently of canonical aspartate pro-duction by the malate-aspartate shuttle. This defines asparagine as a regulator of cytosolic re-dox and identifies transsulfuration as a targetable vulnerability in tumor redox maintenance.

cancer biology↗

bioRxiv2026

Nuclear adenosine metabolism defines a metabolic vulnerability unmasked by TP53 loss

Metabolic adaptation is essential for cells experiencing chronic genomic stress, yet how such adaptations are organized at the nuclear level remains poorly understood. Loss of TP53 is associated with elevated genomic instability, DNA damage and altered metabolic requirements, creating context specific dependencies. Here, we identify a requirement for de novo purine biosynthesis in TP53-deficient cells, with a pronounced dependence on adenosine related metabolism. Perturbation of purine synthesis increases DNA damage and reduces nuclear ATP availability, particularly in TP53-deficient cells, and is accompanied by a rapid increase in histone methylation. This chromatin response is also induced by acute DNA damage and occurs with fast kinetics, indicating that histone methylation is an early, intrinsic feature of the nuclear stress response rather than a secondary epigenetic remodeling. Interfering with histone methylation is associated with reduced nuclear ATP levels and impaired DNA damage resolution, linking chromatin state to nuclear energy homeostasis. Genetic disruption of the purine biosynthesis enzyme PFAS selectively impairs the growth of TP53-deficient tumours in vivo, establishing the physiological relevance of this metabolic dependency. Together, these findings reveal nuclear adenosine metabolism as a compartmentalised adaptive response to genotoxic stress and highlight chromatin associated methylation as a key feature of nuclear metabolic regulation unmasked by TP53 loss.

cancer biology↗

bioRxiv2025

Intraoperative arteriovenous patient sampling to assess in situ non-small cell lung cancer metabolism

We performed intraoperative arteriovenous sampling in participants undergoing surgical resection for non-small cell lung cancer (NSCLC) to characterize in situ tumor metabolism, directly measuring metabolite consumption and secretion in tumor-bearing lung versus normal lung and the systemic circulation. Healthy lung tissue secreted lower levels of lactate, pyruvate, and tricarboxylic acid (TCA) intermediates and consumed less glucose compared to the systemic circulation. In contrast, tumor-bearing lung demonstrated elevated lactate secretion, along with increased efflux of succinate, fumarate, glycine, and aspartate, despite similar glucose uptake. Lactate secretion correlated with tumor PET avidity but not size, and overall metabolic profiles distinguished cancerous from normal lung tissue. These findings confirm enhanced glycolysis in NSCLC in vivo, while also revealing context-dependent patterns of TCA metabolite accumulation and amino acid secretion. Our results demonstrate the utility of intraoperative sampling to uncover metabolic features of human tumors.

cancer biology↗

bioRxiv2025

Cancer cells differentially modulate mitochondrial respiration to alter redox state and enable biomass synthesis in nutrient-limited environments

The cell NAD+/NADH ratio can constrain biomass synthesis and influence proliferation in nutrient-limited environments. However, which cell processes regulate the NAD+/NADH ratio is not known. Here, we find that some cancer cells elevate the NAD+/NADH ratio in response to serine deprivation by increasing mitochondrial respiration. Cancer cells that elevate mitochondrial respiration have higher serine production and proliferation in serine limiting conditions than cells with no mitochondrial respiration response, independent of serine synthesis enzyme expression. Increases in mitochondrial respiration and the NAD+/NADH ratio promote serine synthesis regardless of whether serine is environmentally limiting. Lipid deprivation can increase the NAD+/NADH ratio via mitochondrial respiration in some cells, including cells that do not increase respiration following serine deprivation. Thus, in cancer cells where lipid depletion raises the NAD+/NADH ratio, proliferation in serine depleted environments improves when lipids are also depleted. Taken together, these data suggest that changes in mitochondrial respiration in response to nutrient deprivation can influence the NAD+/NADH ratio in a cell-specific manner to impact oxidative biomass synthesis and proliferation. Given the complexity of tumor microenvironments, this work provides a metabolic framework for understanding how levels of more than one environmental nutrient affect cancer cell proliferation.

cancer biology↗

bioRxiv2024

Site of breast cancer metastasis is independent of single nutrient levels

Cancer metastasis is a major contributor to patient morbidity and mortality1, yet the factors that determine the organs where cancers can metastasize are incompletely understood. In this study, we quantify the absolute levels of over 100 nutrients available across multiple tissues in mice and investigate how this relates to the ability of breast cancer cells to grow in different organs. We engineered breast cancer cells with broad metastatic potential to be auxotrophic for specific nutrients and assessed their ability to colonize different organs. We then asked how tumor growth in different tissues relates to nutrient availability and tumor biosynthetic activity. We find that single nutrients alone do not define the sites where breast cancer cells can grow as metastases. Additionally, we identify purine synthesis as a requirement for tumor growth and metastasis across many tissues and find that this phenotype is independent of tissue nucleotide availability or tumor de novo nucleotide synthesis activity. These data suggest that a complex interplay of multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth, and highlights the interdependence between extrinsic environmental factors and intrinsic cellular properties in influencing where breast cancer cells can grow as metastases.

cancer biology↗

bioRxiv2022

Mitochondria dysregulation contributes to secondary neurodegeneration progression post-contusion injury in human 3D in vitro triculture brain tissue model.

Traumatic Brain injury-induced disturbances in mitochondrial fission-and-fusion dynamics have been linked to the onset and propagation of neuroinflammation and neurodegeneration. However, cell-type-specific contributions and crosstalk between neurons, microglia, and astrocytes in mitochondria-driven neurodegeneration after brain injury remain undefined. We developed a human three-dimensional in vitro triculture tissue model of a contusion injury, composed of neurons, microglia, and astrocytes, and examined the contributions of mitochondrial dysregulation to neuroinflammation and progression of injury-induced neurodegeneration. Pharmacological studies presented here suggest that fragmented mitochondria released by microglia are a key contributor to secondary neuronal damage progression after contusion injury, a pathway that requires astrocyte-microglia crosstalk. Controlling mitochondrial dysfunction thus offers an exciting option for the development of therapies for TBI patients.

neuroscience↗