Depleting regulatory T cells (T reg cells) to counteract immunosuppressive features of the tumor microenvironment (TME) is an attractive strategy for cancer treatment; however, autoimmunity due to systemic impairment of their suppressive function limits its therapeutic potential. Elucidating approaches that specifically disrupt intratumoral T reg cells is direly needed for cancer immunotherapy. We found CD36 was selectively up-regulated in intrautumoral T reg cells as a central metabolic modulator. CD36 fine-tuned mitochondrial fitness via PPAR-β signaling, programming T reg cells to adapt to a lactic acid-enriched TME. Genetic ablation of Cd36 in T reg cells suppressed tumor growth accompanied by a decrease in intratumoral T reg cells and enhancement of anti-tumor activity in tumor-infiltrating lymphocytes without disrupting immune homeostasis. Furthermore, CD36 targeting elicited additive anti-tumor responses with anti-PD-1 therapy. Our findings uncover the unexplored metabolic adaptation that orchestrate survival and functions of intratumoral T reg cells, and the therapeutic potential of targeting this pathway for reprogramming the TME.

Most tumors have an aberrantly activated lipid metabolism 1 , 2 , which enables them to synthesize, elongate and desaturate fatty acids to support proliferation. However, only particular subsets of cancer cells are sensitive toward approaches targeting fatty acid metabolism, and in particular fatty acid desaturation 3 . This suggests that many cancer cells harbor an unexplored plasticity in their fatty acid metabolism. Here, we discover that some cancer cells can exploit an alternative fatty acid desaturation pathway. We identify various cancer cell lines, murine hepatocellular carcinomas (HCC), and primary human liver and lung carcinomas that desaturate palmitate to the unusual fatty acid sapienate to support membrane biosynthesis during proliferation. Accordingly, we found that sapienate biosynthesis enables cancer cells to bypass the known stearoyl-CoA desaturase (SCD)-dependent fatty acid desaturation. Thus, only by targeting both desaturation pathways the in vitro and in vivo proliferation of sapienate synthesizing cancer cells is impaired. Our discovery explains metabolic plasticity in fatty acid desaturation and constitutes an unexplored metabolic rewiring in cancers.

The validity of the Stokes-Millikan equation is examined in light of mass and mobility measurements of clusters of the ionic liquid 1-ethyl-3-methyl-imidazolium tetrafluoroborate (EMI-BF 4 ) in ambient air. The mobility diameter d Z based on the measured mobility and the Stokes-Millikan law is compared with the volume diameter d v , which generalizes the mass diameter for binary substances such as salts. d v is based on the sum of anion and cation volumes in the cluster corrected for the void fraction of the bulk ionic liquid.For d v > 1.5 nm, d Z is within 1.4% of d v + 0.3 nm. For smaller clusters 3.84 and 14.3% deviations are observed at d v = 1.21 nm and 0.68 nm, respectively. These differences are smaller than expected due to a cancellation of competing effects. The increasing difference seen for d v < 1.5 nm is due primarily to the interaction between the cluster and the dipole it induces in the gas molecules. Other potential sources of disagreement are non-globular cluster geometries, and departures of the cluster void fraction from the bulk value. These two effects are examined via molecular dynamics simulations, which confirm that the volume diameter concept is accurate for EMI-BF 4 nanodrops with d v as small as 1.6 nm.

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Metabolism is at the cornerstone of all cellular functions and mounting evidence of its deregulation in different diseases emphasizes the importance of a comprehensive understanding of metabolic regulation at the whole-organism level. Stable-isotope measurements are a powerful tool for probing cellular metabolism and, as a result, are increasingly used to study metabolism in in vivo settings. The additional complexity of in vivo metabolic measurements requires paying special attention to experimental design and data interpretation. Here, we review recent work where in vivo stable-isotope measurements have been used to address relevant biological questions within an in vivo context, summarize different experimental and data interpretation approaches and their limitations, and discuss future opportunities in the field. Metabolism: A Central Node for Cellular Processes Metabolism can be seen as the engine of the cell, providing energy, redox cofactors, and building blocks for cell maintenance, growth, and renewal, as well as playing a key role in modulating cell signaling [1,2]. To orchestrate all these functions, metabolism consists of a complex network of genes, enzymes, and metabolites, steadily modulated in response to different stimuli [3-5]. Defining the mechanisms at the basis of this regulation and understanding their physiological role is among the most important pursuits in biological and medical research [6], particularly since the realization that many pathologies are driven by metabolic deregulations [7]. An in-depth understanding of metabolic pathways in vivo and how these are deregulated in different diseases is thus fundamental for the discovery of new therapeutic targets and clinical biomarkers, enabling the development of more robust diagnosis approaches and personalized treatments, eventually improving the overall outcome for patients [8]. In this context, stable-isotope tracers (see Glossary) have become a standard for probing cellular metabolism [9] and their increasing implementation in in vivo settings has revolutionized our current understanding of mammalian metabolism in health and disease, unraveling novel regulatory principles at both the cellular and whole-organism level [10,11]. In this review, we summarize the latest advances in in vivo metabolic measurements using stable-isotope tracers, highlighting the importance of systems-level integrative approaches and careful experimental design, pointing out open challenges and opportunities for advancing the field, and outlining strategies and potential pitfalls when interpreting these measurements (Figure 1). Tracer-Based Methods for Measuring Cellular Metabolism In Vivo Many complementary methods exist to study metabolism in vivo and, consequently, the selection of a specific approach (or set of approaches) depends largely on the biological question being addressed. Nontracer-based methods, such as assessing bioenergetics by measuring dynamic changes in oxygen consumption [12] or evaluating changes in metabolite levels via metabolomics [13],...

Cancer metastasis requires the transient activation of cellular programs enabling dissemination and seeding in distant organs. Genetic, transcriptional and translational intra-tumor heterogeneity contributes to this dynamic process. Beyond this, metabolic intra-tumor heterogeneity has also been observed, yet its role for cancer progression remains largely elusive. Here, we discovered that intra-tumor heterogeneity in phosphoglycerate dehydrogenase (PHGDH) protein expression drives breast cancer cell dissemination and metastasis formation. Specifically, we observed intra-tumor heterogeneous PHGDH expression in primary breast tumors, with low PHGDH expression being indicative of metastasis in patients. In mice, Phgdh protein, but not mRNA, expression is low in circulating tumor cells and early metastatic lesions, leading to increased dissemination and metastasis formation. Mechanistically, low PHGDH protein expression induces an imbalance in glycolysis that can activate sialic acid synthesis. Consequently, cancer cells undergo a partial EMT and show increased p38 as well as SRC phosphorylation, which activate cellular programs of dissemination. In turn, inhibition of sialic acid synthesis through knock-out of cytidine monophosphate N-acetylneuraminic acid synthetase (CMAS) counteracts the increased cancer cell dissemination and metastasis induced by low PHGDH expression. In conclusion, we find that heterogeneity in PHGDH protein expression promotes cancer cell dissemination and metastasis formation.

Highlights d TAM subsets are transcriptionally and metabolically distinct d TAM subsets differentially use lactate as a carbon source to fuel the TCA cycle d Lactate differentially affects TAM subset metabolism, derogating MHC-II hi TAMs d Lactate affects the MHC-II lo TAM transcriptome, stimulating T cell suppression

Hepatic fat accumulation is associated with diabetes and hepatocellular carcinoma (HCC). Here we characterize the metabolic response that high fat availability elicits in livers prior to disease development. After a short term on a high fat diet, otherwise healthy mice showed elevated hepatic glucose uptake and increased glucose contribution to serine and pyruvate carboxylase activity compared to control diet mice. This glucose phenotype occurred independently from transcriptional or proteomic programming, which identifies increased peroxisomal and lipid metabolism pathways. High fat diet-fed mice exhibited increased lactate production when challenged with glucose. Consistently, administration of an oral glucose bolus to healthy individuals revealed a correlation between waist circumference and lactate secretion in a human cohort. In vitro, palmitate exposure stimulated production of reactive oxygen species and subsequent glucose uptake and lactate secretion in hepatocytes and liver cancer cells.Furthermore, high fat diet enhanced the formation of HCC compared to control diet in mice exposed to a hepatic carcinogen. Regardless of the dietary background, all murine tumors showed similar alterations in glucose metabolism to those identified in fat exposed non-transformed mouse livers; however, particular lipid species were elevated in high fat diet tumor and nontumor-bearing high fat diet liver tissue. These findings suggest that fat can induce glucosemediated metabolic changes in non-transformed liver cells similar to those found in HCC.Significance: With obesity-induced hepatocellular carcinoma on a rising trend, this study shows in normal, non-transformed livers that fat induces glucose metabolism similar to an oncogenic transformation.