Biology subjects

Copperman, N.

Publications and source records attributed to Copperman, N..

2 recordsLinked to original sources

bioRxiv2025

Inhibition Of One-Carbon Metabolism In Ewing Sarcoma Results In Profound And Prolonged Growth Suppression Associated With Purine Depletion

Ewing sarcoma (EWS) is the second most common primary bone malignancy in adolescents and young adults. Patients who present with localized disease have experienced a steadily improving survival rate over the years, whereas those who present with metastatic disease have the same dismal prognosis as 30 years ago, with long term survival rates less than 20%, despite maximal intensification of chemotherapy. Thus, novel treatment approaches are a significant unmet clinical need. Targeting metabolic differences between EWS and normal cells offers a promising approach to improve outcomes for these patients. One-carbon metabolism utilizes serine and folate to generate glycine and tetrahydrofolate (THF)-bound one-carbon units required for de novo nucleotide biosynthesis. Elevated expression of several one-carbon metabolism genes is significantly associated with reduced survival in EWS patients. We show that both genetic and pharmacological inhibition of a key enzyme of the mitochondrial arm of the one-carbon metabolic pathway, serine hydroxymethyltransferase 2 (SHMT2), leads to substantial inhibition of EWS cell proliferation and colony-forming ability, and that this effect is primarily caused by depletion of glycine and one-carbon units required for synthesis of purine nucleotides. Inhibition of one-carbon metabolism at a different node, using the clinically relevant dihydrofolate reductase inhibitor Pralatrexate, similarly yields a profound growth inhibition, with depletion of thymidylate and purine nucleotides. Genetic depletion of SHMT2 dramatically impairs tumor growth in a xenograft model of EWS. Together, these data establish the upregulation of the one-carbon metabolism as a novel and targetable vulnerability of EWS cells, which can be exploited for therapy. Statement of SignificanceUsing both genetic and pharmacologic approaches, this study identifies Ewing sarcomas dependence on the mitochondrial arm, but not the cytoplasmic arm, of one-carbon metabolism as a targetable vulnerability that can be effectively harnessed for therapy.

cancer biology↗

bioRxiv2025

Cycling Molecular Assemblies for Selective Cancer Cell Golgi Disruption

The Golgi apparatus is a critical organelle responsible for intracellular trafficking and signaling, orchestrating essential processes such as protein and lipid sorting1-5. Dysregulation of its function has been implicated in various pathologies, including obesity, diabetes, and cancer, highlighting its importance as a potential therapeutic target. Despite this, the development of tools to selectively target the Golgi in specific cell types remain a significant unmet challenge in imaging and drug discovery. Golgi-specific enzyme activities, such as those mediated by protein acyltransferases and thioesterases6, offer an untapped opportunity to develop subcellularly localized therapeutics. Current approaches predominantly rely on direct protein binding but lack the necessary cell selectivity7, underscoring the unmet need for innovative strategies to selectively disrupt Golgi function in cancer cells. Here, we report the development of cycling molecular assemblies (CyMA), a novel class of small peptide derivatives (e.g., dipeptides), which exploit the unique enzymatic environment of the Golgi to establish futile cycles of reversible S-acylation. These assemblies selectively accumulate in cancer cell Golgi, interfering with protein S-acylation cycles and disrupting organelle homeostasis. CyMA impair key Golgi functions, including protein trafficking, glycosylation, and secretion, while demonstrating selective sparing hepatocytes and immune cells such as M1 macrophages. This selective activity represents a paradigm shift, utilizing an enzyme switch and leveraging intracellular environment rather than direct protein binding. Unlike conventional approaches, CyMA reduce tumor growth, drug resistance, and metastasis by pleiotropically disrupting Golgi related functions. By demonstrating the potential of futile cycles as a therapeutic strategy8, this study introduces a generalizable method for targeting organelle-specific enzyme activities. These findings not only underscore the therapeutic potential of CyMA in cancer but also pave the way for future applications in other Golgi-associated diseases.

biochemistry↗