Biology subjects

Zare, R. N.

Publications and source records attributed to Zare, R. N..

7 recordsLinked to original sources

bioRxiv2026

FASN Inhibition Resensitizes Chordoma to Radiotherapy by Targeting Adaptive Unsaturated Fatty Acid Metabolism

SUMMARYChordoma, a rare malignant notochordal tumor of the skull base and spine, is typically resistant to chemotherapy and radiotherapy and exhibits aggressive local recurrence. Here we show that chordoma recurrence correlates with a coordinated upregulation of monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs), a low PFA/MUFA ratio and an adaptive, lipid peroxidation-resistant state that protects against DNA damage and cell death. Single-cell metabolic profiling identified a tumor subpopulation marked by a fatty acid biosynthesis-high state coupled to stemness. RT-tolerance was directly linked to elevated FASN and lipid droplet (LD) expansion, and MUFA-loading phenocopied RT-tolerance in chordoma cells. Mechanistically, LDs accumulated in response to RT via generation of ROS, and subsequent activation of ER-stress, SREBP1 and Fatty Acid Synthetase (FASN). DESI-MS showed that low-dose irradiation was sufficient to increase MUFAs early and build peroxidation resistant MUFA-LDs, whereas PUFA induction required a higher radiation dose. In a spatially defined manner in a patient-derived xenograft. Finally, in silico knockout and pharmacologic FASN blockade restored radiosensitivity and apoptosis in vitro and in vivo. Collectively, our result support a unifying model in which RT resistance in chordoma is shaped by an adaptive fatty acid metabolic program that buffers oxidative injury and increases survival of RT-resistant, stem-like tumor subpopulations. These findings further support FASN inhibition as a practical radiosensitization strategy for chordoma particulary where RT dose escalation is constrained by anatomy. KEYPOINTSO_LIRecurrent chordoma exhibits fatty acid-associated metabolic reprogramming. C_LIO_LIMUFA-associated lipid droplet accumulation is linked to radioresistance in chordoma cells. C_LIO_LITargeting FASN restores radiotherapy sensitivity of chordoma in vitro and in vivo. C_LI IMPORTANCE OF STUDYThis study underscores the clinical importance of targeting metabolic vulnerabilities to restore radiosensitivity in chordoma. By integrating transcriptomics, metabolomics, and in vitro and in vivo models, we identified adaptive fatty acid metabolic reprogramming as a central mechanism of RT resistance in chordoma. Recurrent tumors were characterized by coordinated enrichment of unsaturated fatty acids, especially monounsaturated fatty acids (MUFAs), together with a low PUFA/MUFA ratio and a lipid peroxidation-resistant state. Mechanistically, RT-tolerance chordoma cells exhibited a high-FASN state driven by activation of the ROS-ER stress-PERK/SREBP1/FASN axis, leading to intracellular lipid droplet expansion. Importantly, genetic and pharmacologic inhibition of FASN restored radiosensitivity and enhanced apoptosis in both in vitro and in vivo models, suggesting a translatable therapeutic strategy. Together, these findings link adaptive metabolic reprogramming to RT resistance and support new therapeutic approaches for chordoma management.

cancer biology↗

bioRxiv2025

Computational method for mapping mass signatures along developmental gradients reveals a novel role for a monosaccharide tetrose in maize salt-stress response.

Metabolic processes are essential for regulating and maintaining developmental transitions, from stem cell quiescence through differentiation. However, the distinct metabolite-driven mechanisms that are critical for development remain poorly characterized due to inherent challenges in measuring their production, localization, and function in situ. We employed desorption electrospray ionization mass spectrometry imaging (DESI-MSI) to map metabolites in the developing maize root, which has a well-characterized longitudinal gradient that encompasses developmental transitions from quiescence through proliferation and maturation. DESI-MSI enables in situ analysis of the chemical composition of tissue sections with high spatial resolution ([~]50-100 {micro}m). To identify metabolites with specific developmental enrichment patterns, we developed a computational approach called Developmental Imaging Mass Spectrometry Pipeline for Linear Evaluation (DIMPLE). DIMPLE processes mass signatures along linear gradients, generating clusters of metabolites with specific developmental enrichment patterns in the maize root. We employed this method to compare developmental enrichment of metabolites in a salt-resilient maize variety, Oaxacan Green, and a salt-susceptible variety, B73. DIMPLE identifies specific differences in the mass signatures and the overall enrichment patterns between these varieties. DIMPLE also revealed a metabolite, D-erythrose, that had different localization patterns in these varieties. We found that in salt-sensitive maize varieties, treatment with D-erythrose improves stress tolerance by increasing primary root length. Overall, DIMPLE enables comprehensive and rapid analysis of metabolite patterns along a linear gradient, revealing new biology in plant growth and stress response.

plant biology↗

bioRxiv2024

Biomolecular condensates can function as inherent catalysts

We report the discovery that chemical reactions can be catalyzed by condensates formed by intrinsically disordered proteins (IDPs). The proteins themselves lack any catalytic activities. Catalytic functions of condensates emerge as a consequence of sequence-dependent mesoscale electrochemical microenvironments created by phase separation. Stimulated Raman spectroscopy suggests that the catalytic behaviors of condensates are attributable to the spatial variations of water activities across condensate interiors and interfaces. We show that condensates are capable of catalyzing diverse cellularly relevant hydrolysis reactions. Through sequence design, the electrochemical properties of condensates can be programmed to exert control over catalytic behaviors. Incorporation of synthetic condensates into live cells alters transcription profiles and enables the activation of gene circuits that depend on products of hydrolysis reactions catalyzed by condensates. Our discovery of suggests that condensates, depending on their composition-dependent electrochemical properties, can be "Condenzymes", which contribute unexpected emergent chemical functions in cells.

biophysics↗

bioRxiv2023

A developmental gradient reveals biosynthetic pathways to eukaryotic toxins in monocot geophytes

Numerous eukaryotic toxins that accumulate in geophytic plants are valuable in the clinic, yet their biosynthetic pathways have remained elusive. A lead example is the >150 Amaryllidaceae alkaloids (AmAs) including galantamine, an FDA-approved treatment for Alzheimers disease. We show that while AmAs accumulate to high levels in many tissues in daffodils, biosynthesis is localized to nascent, growing tissue at the base of leaves. A similar trend is found for the production of steroidal alkaloids (e.g. cyclopamine) in corn lily. This model of active biosynthesis enabled elucidation of a complete set of biosynthetic genes for the production of AmAs. Taken together, our work sheds light on the developmental and enzymatic logic of diverse alkaloid biosynthesis in daffodil. More broadly, it suggests a paradigm for biosynthesis regulation in monocot geophytes where plants are protected from herbivory through active charging of newly formed cells with eukaryotic toxins that persist as aboveground tissue develops.

biochemistry↗

bioRxiv2022

Chemical Imaging Reveals Diverse Functions of Tricarboxylic Acid Metabolites in Root Growth and Development

Understanding how plants grow is critical for agriculture and fundamental for illuminating principles of multicellular development 1. Here, we apply chemical mapping of the developing maize root using desorption electrospray ionization mass spectrometry imaging (DESI-MSI) 2. This technique reveals a range of small molecule distribution patterns across the gradient of stem cell differentiation in the root. To understand the developmental logic of these patterns, we examined tricarboxylic acid (TCA) cycle metabolites. In both Arabidopsis and maize, TCA metabolites are enriched in developmentally opposing regions, suggesting that stem-cell specific TCA metabolite localization may be conserved in evolutionarily divergent species. We find that these metabolites, particularly succinate, aconitate, citrate, and -ketoglutarate, control root development in diverse and distinct ways. Critically, the effects of metabolites on stem cell behavior can be independent of their canonical role in ATP production. These results present new insights into development and suggest practical means for controlling plant growth.

plant biology↗

bioRxiv2022

Lipidomic profiling reveals age-dependent changes in complex plasma membrane lipids that regulate neural stem cell aging

The aging brain exhibits a decline in the regenerative populations of neural stem cells (NSCs), which may underlie age-associated defects in sensory and cognitive functions1-6. While mechanisms that restore old NSC function have started to be identified7-23, the role of lipids - especially complex lipids - in NSC aging remains largely unclear. Using lipidomic profiling by mass spectrometry, we identify age-related lipidomic signatures in young and old quiescent NSCs in vitro and in vivo. These analyses reveal drastic changes in several complex membrane lipid classes, including phospholipids and sphingolipids in old NSCs. Moreover, poly-unsaturated fatty acids (PUFAs) strikingly increase across complex lipid classes in quiescent NSCs during aging. Age-related changes in complex lipid levels and side chain composition are largely occurring in plasma membrane lipids, as revealed by lipidomic profiling of isolated plasma membrane vesicles. Experimentally, we find that aging is accompanied by modifications in plasma membrane biophysical properties, with a decrease in plasma membrane order in old quiescent NSCs in vitro and in vivo. To determine the functional role of plasma membrane lipids in aging NSCs, we performed genetic and supplementation studies. Knockout of Mboat2, which encodes a phospholipid acyltransferase, exacerbates age-related lipidomic changes in old quiescent NSCs and impedes their ability to activate. As Mboat2 expression declines with age, Mboat2 deficiency may drive NSC decline during aging. Interestingly, supplementation of plasma membrane lipids derived from young NSCs boosts the ability of old quiescent NSCs to activate. Our work could lead to lipid-based strategies for restoring the regenerative potential of NSCs in old individuals, which has important implications for countering brain decline during aging.

molecular biology↗

bioRxiv2019

Metabolite therapy guided by liquid biopsy proteomics delays retinal neurodegeneration

Neurodegenerative diseases are debilitating, incurable disorders caused by progressive neuronal cell death. Retinitis pigmentosa (RP) is a blinding neurodegenerative disease that results in retinal photoreceptor cell death and progresses to the loss of the entire neural retinal network. We previously found that proteomic analysis of the adjacent vitreous serves as way to indirectly biopsy the neural retina and identify changes in the retinal proteome. We therefore analyzed protein expression in liquid vitreous biopsies from autosomal recessive retinitis pigmentosa (arRP) patients with PDE6A mutations and arRP mice with Pde6[a] mutations. Proteomic analysis of retina and vitreous samples identified molecular pathways affected at the onset of photoreceptor cell death. Based on affected molecular pathways, arRP mice were treated with a ketogenic diet or metabolites involved in fatty-acid synthesis, oxidative phosphorylation, and the tricarboxylic acid (TCA) cycle. Dietary supplementation of a single metabolite, [a]-ketoglutarate, increased docosahexaeonic acid (DHA) levels, provided neuroprotection, and enhanced visual function in arRP mice. A ketogenic diet delayed photoreceptor cell loss, while vitamin B supplementation had a limited effect. Finally, desorption electrospray ionization mass spectrometry imaging (DESI-MSI) revealed restoration of key metabolites that correlated with our proteomic findings: pyrimidine and purine metabolism (uridine, dihydrouridine, and thymidine), glutamine and glutamate (glutamine/glutamate conversion), and succinic and aconitic acid (TCA cycle). This study demonstrates that replenishing TCA cycle metabolites via oral supplementation prolongs vision and provides a neuroprotective effect on the photoreceptor cells and inner retinal network.\n\nOne Sentence SummaryThe study shows protein and metabolite pathways affected during neurodegeneration and that replenishing metabolites provides a neuroprotective effect on the retina.

biochemistry↗