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SLC7A11-mediated cystine uptake is critical for maintaining redox balance and cell survival. Here we show that this comes at a significant cost for cancer cells with high levels of SLC7A11. Actively importing cystine is potentially toxic due to its low solubility, forcing cancer cells with high levels of SLC7A11 (SLC7A11high) to constitutively reduce cystine to the more soluble cysteine. This presents a significant drain on the cellular NADPH pool and renders such cells dependent on the pentose phosphate pathway. Limiting glucose supply to SLC7A11high cancer cells results in marked accumulation of intracellular cystine, redox system collapse and rapid cell death, which can be rescued by treatments that prevent disulfide accumulation. We further show that inhibitors of glucose transporters selectively kill SLC7A11high cancer cells and suppress SLC7A11high tumour growth. Our results identify a coupling between SLC7A11-associated cystine metabolism and the pentose phosphate pathway, and uncover an accompanying metabolic vulnerability for therapeutic targeting in SLC7A11high cancers.Liu et al. show that cancer cells with high levels of SLC7A11 have increased dependency on the pentose phosphate pathway and consequently accumulate disulfide, and can be therapeutically targeted by limiting glucose supply.

Serine, glycine and other nonessential amino acids are critical for tumour progression, and strategies to limit their availability are emerging as potential therapies for cancer 1 – 3 . However, the molecular mechanisms driving this response remain unclear and the effects on lipid metabolism are relatively unexplored. Serine palmitoyltransferase (SPT) catalyses the de novo biosynthesis of sphingolipids but also produces noncanonical 1-deoxysphingolipids when using alanine as a substrate 4 , 5 . Deoxysphingolipids accumulate in the context of mutations in SPTLC1 or SPTLC2 6 , 7 —or in conditions of low serine availability 8 , 9 —to drive neuropathy, and deoxysphinganine has previously been investigated as an anti-cancer agent 10 . Here we exploit amino acid metabolism and the promiscuity of SPT to modulate the endogenous synthesis of toxic deoxysphingolipids and slow tumour progression. Anchorage-independent growth reprogrammes a metabolic network involving serine, alanine and pyruvate that drives the endogenous synthesis and accumulation of deoxysphingolipids. Targeting the mitochondrial pyruvate carrier promotes alanine oxidation to mitigate deoxysphingolipid synthesis and improve spheroid growth, similar to phenotypes observed with the direct inhibition of SPT or ceramide synthesis. Restriction of dietary serine and glycine potently induces the accumulation of deoxysphingolipids while decreasing tumour growth in xenograft models in mice. Pharmacological inhibition of SPT rescues xenograft growth in mice fed diets restricted in serine and glycine, and the reduction of circulating serine by inhibition of phosphoglycerate dehydrogenase (PHGDH) leads to the accumulation of deoxysphingolipids and mitigates tumour growth. The promiscuity of SPT therefore links serine and mitochondrial alanine metabolism to membrane lipid diversity, which further sensitizes tumours to metabolic stress. In xenograft tumour models in mice, modulation of dietary serine, serine palmitoyltransferase or phosphoglycerate dehydrogenase activity enables control of the endogenous synthesis of deoxysphingolipids, sensitizing the tumours to metabolic stress and slowing their progression.

Macular telangiectasia type 2 (MacTel) is a progressive, late-onset retinal degenerative disease linked to decreased serum levels of serine that elevate circulating levels of a toxic ceramide species, deoxysphingolipids (deoxySLs); however, causal genetic variants that reduce serine levels in patients have not been identified. Here we identify rare, functional variants in the gene encoding the rate-limiting serine biosynthetic enzyme, phosphoglycerate dehydrogenase (PHGDH), as the single locus accounting for a significant fraction of MacTel. Under a dominant collapsing analysis model of a genome-wide enrichment analysis of rare variants predicted to impact protein function in 793 MacTel cases and 17,610 matched controls, the PHGDH gene achieves genome-wide significance ( P  = 1.2 × 10 −13 ) with variants explaining ~3.2% of affected individuals. We further show that the resulting functional defects in PHGDH cause decreased serine biosynthesis and accumulation of deoxySLs in retinal pigmented epithelial cells. PHGDH is a significant locus for MacTel that explains the typical disease phenotype and suggests a number of potential treatment options. Rare variants in the gene encoding PHGDH, the rate-limiting enzyme in de novo serine biosynthesis, are identified as responsible for serine deficiency associated with the macular degenerative disease MacTel.

The single-chained sphingolipid sphingosine is an essential structural lipid and signaling molecule. Abnormal sphingosine metabolism is observed in several diseases, including cancer, diabetes, and Alzheimer's. Despite its biological importance, there are a lack of tools for detecting sphingosine in living cells. This is likely due to the broader challenge of developing highly selective and live-cell compatible affinity probes for hydrophobic lipid species. In this work, we have developed a small molecule fluorescent turn-on probe for labeling sphingosine in living cells. This probe utilizes a selective reaction between sphingosine and salicylaldehyde esters to fluorescently label sphingosine molecules. We demonstrate that this probe exhibits a dose-dependent response to sphingosine and is able to detect endogenous pools of sphingosine. Using our probe, we successfully detected sphingosine accumulation in live Niemann-Pick type C1 (NPC1) patient cells, a lipid transport disorder in which increased sphingosine mediates disease progression. This work provides a simple and accessible method for the detection of sphingosine and should facilitate study of this critical signaling lipid in biology and disease. Competing Interest Statement The authors have declared no competing interest.

Skeletal muscle regeneration is reliant on a population of muscle specific adult stem cells (muscle progenitor cells; MPCs). During regeneration, the MPC population undergoes a transient and rapid period of population expansion, which is necessary to repair damaged myofibers and restore muscle homeostasis. Much research has focused on the age-related accumulation of negative regulators of regeneration, while the age-related decline of nutrient and metabolic determinants of the regenerative process needs examination. We hypothesized that older individuals, a population that is at risk for protein malnutrition, have diminished availability of amino acids that are necessary for MPC function. Here, we identified that levels of the non-essential amino acid serine are reduced in the skeletal muscle of healthy, older individuals. Furthermore, using stable-isotope tracing studies, we demonstrate that primary, human MPCs (hMPCs) exhibit a limited capacity for de novo biosynthesis of serine and the closely related amino acid glycine. We identified that serine and glycine are essential for hMPC proliferation and, therefore, population expansion. Serine and glycine were necessary to support synthesis of the intracellular antioxidant glutathione, and restriction of serine and glycine was sensed in an EIF2α-dependent manner resulting in cell cycle arrest in G0/G1. In conclusion, we elucidate that, despite an absolute requirement of serine/glycine for hMPC proliferation, availability of serine in the skeletal muscle microenvironment is limited to the hMPCs of healthy older adults and is a likely underlying mechanism for impaired skeletal muscle regeneration with advancing age.

A decline in mitochondrial function is associated with neurodegeneration and aging. Progressive mitochondrial defects have diverse metabolic consequences that could drive some of the pathophysiological changes that occur with aging. Here, we comprehensively characterized metabolic alterations in PolgD257A mitochondrial DNA mutator mice. Plasma alanine increased dramatically with time, with lactate and other organic acids accumulating to a lesser extent. These changes were reflective of increased glycolysis, rapid gluconeogenesis, and hypoglycemia. Tracing with [15N]ammonium revealed impairment of the urea cycle and diversion to purine catabolism. We also measured alterations in the lipidome, observing a general reduction in canonical lipids and the accumulation of 1-deoxysphingolipids, which are synthesized from alanine via promiscuous serine palmitoyltransferase activity. Consistent with 1-deoxysphingolipid’s association with peripheral neuropathy, PolgD257A mice exhibited thermal hypoalgesia. These results highlight the distinct changes that occur in carbon and nitrogen metabolism upon mitochondrial impairment and key metabolic mechanisms which can drive aging-associated neuropathy.

Vital sign monitoring is fundamental to patient care. Although traditional intermittent systems are flawed, barriers to implementing continuous monitoring systems remain. The SMART MAT is a novel continuous monitoring device that detects vital signs remotely via fibre optic technology. The study aims to validate the SMART MAT and its paired devices against gold/clinical standard measurements for measuring heart rate (HR), respiratory rate (RR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and oxygen saturation (SpO2). Healthy adults aged 21 to 80 were recruited for this cross-sectional study. Participants rested supine on a standardised mattress with the SMART MAT below. Vital signs were recorded over three five-minute intervals. Statistical analysis included descriptive statistics, two-way ANOVA, Mean Absolute Percentage Error (MAPE), and Bland–Altman plots. Among 321 participants recruited, HR and most RR measurements saw non-statistically significant differences (p > 0.05). Statistically significant differences were observed for SBP, SpO2, and most DBP measurements (p < 0.05). Only SBP measurements exceeded the acceptable limits of differences. Effect sizes were small to negligible (n2 < 0.04) and MAPE values were <20%. The SMART MAT has demonstrated reasonable accuracy and validity in monitoring vital signs in healthy adults. Alternative paired BP devices are recommended to enhance SBP measurement accuracy.

Background Single-cell RNA sequencing (scRNA-seq) is a powerful tool for studying complex biological systems, such as tumor heterogeneity and tissue microenvironments. However, the sources of technical and biological variation in primary solid tumor tissues and patient-derived mouse xenografts for scRNA-seq are not well understood. Results We use low temperature (6 °C) protease and collagenase (37 °C) to identify the transcriptional signatures associated with tissue dissociation across a diverse scRNA-seq dataset comprising 155,165 cells from patient cancer tissues, patient-derived breast cancer xenografts, and cancer cell lines. We observe substantial variation in standard quality control metrics of cell viability across conditions and tissues. From the contrast between tissue protease dissociation at 37 °C or 6 °C, we observe that collagenase digestion results in a stress response. We derive a core gene set of 512 heat shock and stress response genes, including FOS and JUN, induced by collagenase (37 °C), which are minimized by dissociation with a cold active protease (6 °C). While induction of these genes was highly conserved across all cell types, cell type-specific responses to collagenase digestion were observed in patient tissues. Conclusions The method and conditions of tumor dissociation influence cell yield and transcriptome state and are both tissue- and cell-type dependent. Interpretation of stress pathway expression differences in cancer single-cell studies, including components of surface immune recognition such as MHC class I, may be especially confounded. We define a core set of 512 genes that can assist with the identification of such effects in dissociated scRNA-seq experiments.

Background Contemporary data of peripheral T‐cell lymphoma (PTCL) and natural‐killer/T‐cell lymphoma (NKTL) patients treated with ifosfamide, carboplatin and etoposide (ICE) are limited. Aims We performed a retrospective analysis to estimate outcomes of ICE‐treated PTCL and NKTL patients at three tertiary cancer centres in Singapore. Methods and Results Patients were identified through lymphoma databases from National Cancer Centre Singapore (NCCS), National University Hospital, Singapore (NUHS), and Singapore General Hospital (SGH). Responses and survival outcomes were determined from electronic medical records. A total of 75 patients with a median age of 50 were included. ICE was used as first‐line treatment in 14 patients (19%) and as subsequent lines of treatment in 61 patients (81%). The overall response rates (ORR) for all patients was 63% (40% complete response [CR]). The ORR and CR in the first line were 86% and 64% respectively. At a median follow‐up duration of 71.0 months, the median progression‐free (PFS) and overall survival (OS) for all patients were 4.4 months (95%CI, 2.7–6.0) and 16 months (95%CI, 8.3–45.4) respectively. Conclusion In summary, ICE showed high ORR but poor PFS in relapsed/refractory PTCL and NKTL. ORR of ICE in the first line setting appears better than real‐world CHOP data and warrants further study.