Metabolic profiling of patient-derived organoids reveals nucleotide synthesis as a metabolic vulnerability in malignant rhabdoid tumors.

Malignant rhabdoid tumor (MRT) is one of the most aggressive childhood cancers for which no effective treatment options are available. Reprogramming of cellular metabolism is an important hallmark of cancer, with various metabolism-based drugs being approved as a cancer treatment. In this study, we use patient-derived tumor organoids (tumoroids) to map the metabolic landscape of several pediatric cancers.

Stable Isotope Tracing Experiments Using LC-MS.

Metabolomics has emerged as a pivotal field in understanding cellular function, particularly in the context of disease. In numerous diseases, including cancer, alterations in metabolism play an essential role in disease progression and drug response. Hence, unraveling the metabolic rewiring is of importance to find novel diagnostic and therapeutic strategies.

P53-dependent hypusination of eIF5A affects mitochondrial translation and senescence immune surveillance.

Cellular senescence is characterized by a permanent growth arrest and is associated with tissue aging and cancer. Senescent cells secrete a number of different cytokines referred to as the senescence-associated secretory phenotype (SASP), which impacts the surrounding tissue and immune response. Here, we find that senescent cells exhibit higher rates of protein synthesis compared to proliferating cells and identify eIF5A as a crucial regulator of this process.

Immune suppression by human thymus-derived effector Tregs relies on glucose/lactate-fueled fatty acid synthesis.

Regulatory T cells (Tregs) suppress pro-inflammatory conventional T cell (Tconv) responses. As lipids impact cell signaling and function, we compare the lipid composition of CD4 thymus-derived (t)Tregs and Tconvs. Lipidomics reveal constitutive enrichment of neutral lipids in Tconvs and phospholipids in tTregs.

AMPK activation induces RALDH+ tolerogenic dendritic cells by rewiring glucose and lipid metabolism.

Dendritic cell (DC) activation and function are underpinned by profound changes in cellular metabolism. Several studies indicate that the ability of DCs to promote tolerance is dependent on catabolic metabolism. Yet the contribution of AMP-activated kinase (AMPK), a central energy sensor promoting catabolism, to DC tolerogenicity remains unknown.

Extracellular vesicles from seminal plasma interact with T cells in vitro and drive their differentiation into regulatory T-cells.

Seminal plasma induces immune tolerance towards paternal allogenic antigens within the female reproductive tract and during foetal development. Recent evidence suggests a role for extracellular vesicles in seminal plasma (spEVs). We isolated spEVs from seminal plasma that was donated by vasectomized men, thereby excluding any contributions from the testis or epididymis.

Oral β-RA induces metabolic rewiring leading to the rescue of diet-induced obesity.

Obesity represents a significant health challenge, intricately linked to conditions such as type II diabetes, metabolic syndrome, and hepatic steatosis. Several existing obesity treatments exhibit limited efficacy, undesirable side effects or a limited capability to maintain therapeutics effects in the long-term. Recently, modulation Coenzyme Q (CoQ) metabolism has emerged as a promising target for treatment of metabolic syndrome.

Arginine deprivation enriches lung cancer proteomes with cysteine by inducing arginine-to-cysteine substitutants.

Many types of human cancers suppress the expression of argininosuccinate synthase 1 (ASS1), a rate-limiting enzyme for arginine production. Although dependency on exogenous arginine can be harnessed by arginine-deprivation therapies, the impact of ASS1 suppression on the quality of the tumor proteome is unknown. We therefore interrogated proteomes of cancer patients for arginine codon reassignments (substitutants) and surprisingly identified a strong enrichment for cysteine (R>C) in lung tumors specifically.

Modulation of nucleotide metabolism by picornaviruses.

Viruses actively reprogram the metabolism of the host to ensure the availability of sufficient building blocks for virus replication and spreading. However, relatively little is known about how picornaviruses-a large family of small, non-enveloped positive-strand RNA viruses-modulate cellular metabolism for their own benefit. Here, we studied the modulation of host metabolism by coxsackievirus B3 (CVB3), a member of the enterovirus genus, and encephalomyocarditis virus (EMCV), a member of the cardiovirus genus, using steady-state as well as 13C-glucose tracing metabolomics.

Specific labeling of newly synthesized lipopolysaccharide via metabolic incorporation of azido-galactose.

Gram-negative bacteria possess an asymmetric outer membrane (OM) primarily composed of lipopolysaccharides (LPS) on the outer leaflet and phospholipids on the inner leaflet. The outer membrane functions as an effective permeability barrier to compounds such as antibiotics. Studying LPS biosynthesis is therefore helpful to explore novel strategies for new antibiotic development.

Deciphering metabolic crosstalk in context: lessons from inflammatory diseases.

Metabolism plays a crucial role in regulating the function of immune cells in both health and disease, with altered metabolism contributing to the pathogenesis of cancer and many inflammatory diseases. The local microenvironment has a profound impact on the metabolism of immune cells. Therefore, immunological and metabolic heterogeneity as well as the spatial organization of cells in tissues should be taken into account when studying immunometabolism.

Mesenchymal stromal cells secretome restores bioenergetic and redox homeostasis in human proximal tubule cells after ischemic injury.

Background: Ischemia/reperfusion injury is the leading cause of acute kidney injury (AKI). The current standard of care focuses on supporting kidney function, stating the need for more efficient and targeted therapies to enhance repair. Mesenchymal stromal cells (MSCs) and their secretome, either as conditioned medium (CM) or extracellular vesicles (EVs), have emerged as promising options for regenerative therapy; however, their full potential in treating AKI remains unknown.

S-adenosylmethionine biosynthesis is a targetable metabolic vulnerability in multiple myeloma.

Multiple myeloma (MM) is the second most prevalent hematologic malignancy and is incurable because of the inevitable development of drug resistance. Methionine adenosyltransferase 2α (MAT2A) is the primary producer of the methyl donor S-adenosylmethionine (SAM) and several studies have documented MAT2A deregulation in different solid cancers. As the role of MAT2A in MM has not been investigated yet, the aim of this study was to clarify the potential role and underlying molecular mechanisms of MAT2A in MM, exploring new therapeutic options to overcome drug resistance.

Retinyl Ester Analysis by Orbitrap Mass Spectrometry.

Retinoids are light-sensitive molecules that are normally detected by UV absorption techniques. Here we describe the identification and quantification of retinyl ester species by high-resolution mass spectrometry. Retinyl esters are extracted by the method of Bligh and Dyer and subsequently separated by HPLC in runs of 40 min.

Metabolic changes underlying drug resistance in the multiple myeloma tumor microenvironment.

Multiple myeloma (MM) is characterized by the clonal expansion of malignant plasma cells in the bone marrow (BM). MM remains an incurable disease, with the majority of patients experiencing multiple relapses from different drugs. The MM tumor microenvironment (TME) and in particular bone-marrow stromal cells (BMSCs) play a crucial role in the development of drug resistance.

Hyperlipidaemia elicits an atypical, T helper 1-like CD4 T-cell response: a key role for very low-density lipoprotein.

Aims: Hyperlipidemia and T cell driven inflammation are important drivers of atherosclerosis, the main underlying cause of cardiovascular disease. Here, we detailed the effects of hyperlipidemia on T cells.

Methods And Results: In vitro, exposure of human and murine CD4+ T cells to very low-density lipoprotein (VLDL), but not to low-density lipoprotein (LDL) resulted in upregulation of Th1 associated pathways.

Fatty acid metabolism in aggressive B-cell lymphoma is inhibited by tetraspanin CD37.

The importance of fatty acid (FA) metabolism in cancer is well-established, yet the mechanisms underlying metabolic reprogramming remain elusive. Here, we identify tetraspanin CD37, a prognostic marker for aggressive B-cell lymphoma, as essential membrane-localized inhibitor of FA metabolism. Deletion of CD37 on lymphoma cells results in increased FA oxidation shown by functional assays and metabolomics.

Serine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers.

Resistance to platinum-based chemotherapy represents a major clinical challenge for many tumors, including epithelial ovarian cancer. Patients often experience several response-relapse events, until tumors become resistant and life expectancy drops to 12-15 months. Despite improved knowledge of the molecular determinants of platinum resistance, the lack of clinical applicability limits exploitation of many potential targets, leaving patients with limited options.

The Q-junction and the inflammatory response are critical pathological and therapeutic factors in CoQ deficiency.

Defects in Coenzyme Q (CoQ) metabolism have been associated with primary mitochondrial disorders, neurodegenerative diseases and metabolic conditions. The consequences of CoQ deficiency have not been fully addressed, and effective treatment remains challenging. Here, we use mice with primary CoQ deficiency (Coq9), and we demonstrate that CoQ deficiency profoundly alters the Q-junction, leading to extensive changes in the mitochondrial proteome and metabolism in the kidneys and, to a lesser extent, in the brain.

TNFR2 Costimulation Differentially Impacts Regulatory and Conventional CD4 T-Cell Metabolism.

CD4 conventional T cells (Tconvs) mediate adaptive immune responses, whereas regulatory T cells (Tregs) suppress those responses to safeguard the body from autoimmunity and inflammatory diseases. The opposing activities of Tconvs and Tregs depend on the stage of the immune response and their environment, with an orchestrating role for cytokine- and costimulatory receptors. Nutrient availability also impacts T-cell functionality metabolic and biosynthetic processes that are largely unexplored.

Targeting coenzyme Q10 synthesis overcomes bortezomib resistance in multiple myeloma.

During the development of drug resistance, multiple myeloma (MM) cells undergo changes to their metabolism. However, how these metabolic changes can be exploited to improve treatment efficacy is not known. Here we demonstrate that targeting coenzyme Q10 (CoQ) biosynthesis through the mevalonate pathway works in synergy with the proteasome inhibitor bortezomib (BTZ) in MM.

Omega-3 Fatty Acids DHA and EPA Reduce Bortezomib Resistance in Multiple Myeloma Cells by Promoting Glutathione Degradation.

Multiple myeloma (MM) is a hematological malignancy that exhibits aberrantly high levels of proteasome activity. While treatment with the proteasome inhibitor bortezomib substantially increases overall survival of MM patients, acquired drug resistance remains the main challenge for MM treatment. Using a combination treatment of docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) and bortezomib, it was demonstrated previously that pretreatment with DHA/EPA significantly increased bortezomib chemosensitivity in MM cells.

Oncogene-dependent sloppiness in mRNA translation.

mRNA translation is a highly conserved and tightly controlled mechanism for protein synthesis. Despite protein quality control mechanisms, amino acid shortage in melanoma induces aberrant proteins by ribosomal frameshifting. The extent and the underlying mechanisms related to this phenomenon are yet unknown.

Cysteamine-bicalutamide combination therapy corrects proximal tubule phenotype in cystinosis.

Nephropathic cystinosis is a severe monogenic kidney disorder caused by mutations in CTNS, encoding the lysosomal transporter cystinosin, resulting in lysosomal cystine accumulation. The sole treatment, cysteamine, slows down the disease progression, but does not correct the established renal proximal tubulopathy. Here, we developed a new therapeutic strategy by applying omics to expand our knowledge on the complexity of the disease and prioritize drug targets in cystinosis.

Treatment with HIV-Protease Inhibitor Nelfinavir Identifies Membrane Lipid Composition and Fluidity as a Therapeutic Target in Advanced Multiple Myeloma.

The HIV-protease inhibitor nelfinavir has shown broad anticancer activity in various preclinical and clinical contexts. In patients with advanced, proteasome inhibitor (PI)-refractory multiple myeloma, nelfinavir-based therapy resulted in 65% partial response or better, suggesting that this may be a highly active chemotherapeutic option in this setting. The broad anticancer mechanism of action of nelfinavir implies that it interferes with fundamental aspects of cancer cell biology.