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Cell-programmed nutrient partitioning in the tumour microenvironment.

ABSTRACT: Cancer cells characteristically consume glucose through Warburg metabolism¹, a process that forms the basis of tumour imaging by positron emission tomography (PET). Tumour-infiltrating immune cells also rely on glucose, and impaired immune cell metabolism in the tumour microenvironment (TME) contributes to immune evasion by tumour cells^2-4. However, whether the metabolism of immune cells is dysregulated in the TME by cell-intrinsic programs or by competition with cancer cells for limited nutrients remains unclear. Here we used PET tracers to measure the access to and uptake of glucose and glutamine by specific cell subsets in the TME. Notably, myeloid cells had the greatest capacity to take up intratumoral glucose, followed by T cells and cancer cells, across a range of cancer models. By contrast, cancer cells showed the highest uptake of glutamine. This distinct nutrient partitioning was programmed in a cell-intrinsic manner through mTORC1 signalling and the expression of genes related to the metabolism of glucose and glutamine. Inhibiting glutamine uptake enhanced glucose uptake across tumour-resident cell types, showing that glutamine metabolism suppresses glucose uptake without glucose being a limiting factor in the TME. Thus, cell-intrinsic programs drive the preferential acquisition of glucose and glutamine by immune and cancer cells, respectively. Cell-selective partitioning of these nutrients could be exploited to develop therapies and imaging strategies to enhance or monitor the metabolic programs and activities of specific cell populations in the TME.

SUBMITTER: Reinfeld BI

PROVIDER: S-EPMC8122068 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Diatoms are important phytoplankton and contribute greatly to the primary productivity of marine ecosystems. Despite the ecological significance of diatoms and the importance of programmed cell death (PCD) in the fluctuation of diatom populations, little is known about the molecular mechanisms of PCD triggered by different nutrient stresses. Here we describe the physiological, morphological, biochemical, and molecular changes in response to low levels of nutrients in the ubiquitous diatom Skeletonema marinoi The levels of gene expression involved in oxidation resistance and PCD strongly increased upon nitrogen (N) or phosphorus (P) starvation. The enzymatic activity of caspase 3-like protein also increased. Differences in mRNA levels and protein activities were observed between the low-N and low-P treatments, suggesting that PCD could have a differential response to different nutrient stresses. When cultures were replete with N or P, the growth inhibition stopped. Meanwhile, the enzymatic activity of caspase 3-like protein and the number of cells with damaged membranes decreased. These results suggest that PCD is an important cell fate decision mechanism in the marine diatom S. marinoi Our results provide important insight into how diatoms adjust phenotypic and genotypic features of their cell-regulated death programs when stressed by nutrient limitations. Overall, this study could allow us to better understand the molecular mechanism behind the formation and termination of diatom blooms in the marine environment.IMPORTANCE Our study showed how the ubiquitous diatom S. marinoi responded to different nutrient limitations with PCD in terms of physiological, morphological, biochemical, and molecular characteristics. Some PCD-related genes (PDCD4, GOX, and HSP90) induced by N deficiency were relatively upregulated compared to those induced by P deficiency. In contrast, the expression of the TSG101 gene in S. marinoi showed a clear and constant increase during P limitation compared to N limitation. These findings suggest that PCD is a complex mechanism involving several different proteins. The systematic mRNA level investigations provide new insight into understanding the oxidative stress- and cell death-related functional genes of diatoms involved in the response to nutrient fluctuations (N or P stress) in the marine environment.

Project description:BackgroundTranslationally controlled tumour protein (TCTP), a well known protein of the animal kingdom, was shown to be a Ca(2+)-binding protein with important functions in many different cellular processes (e.g. protection against stress and apoptosis, cell growth, cell cycle progression, and microtubule organization). However, only little is known about TCTP in plants. Transcript and protein levels of plant TCTPs were shown to be altered by various stress conditions (e.g. cold, salt, draught, aluminium, and pathogen infection), and Arabidopsis thaliana TCTP (AtTCTP) was described as an important regulator of growth. The aim of this study was to further characterize plant TCTP relating to one of its major functions in animals: the protection against cell death.ResultsWe used two different activators of programmed cell death (PCD) in plants: the mammalian pro-apoptotic protein BAX and tunicamycin, an inhibitor of glycosylation and trigger of unfolded protein response (UPR). Over-expression of AtTCTP significantly decreased cell death in tobacco leaf discs in both studies. A (45)Ca overlay assay showed AtTCTP to be a Ca(2+)-binding protein and localization experiments revealed cytosolic distribution of AtTCTP-GFP in Arabidopsis seedlings.ConclusionsOur study showed cytoprotective effects of plant TCTP for the first time. Furthermore, we showed the ability of AtTCTP to bind to Ca(2+) and its cytosolic distribution within the cell. If these results are combined, two putative modes of action can be assumed: 1) AtTCTP acts as Ca(2+) sequester, preventing PCD by reducing cytosolic Ca(2+) levels as described for animals. 2) AtTCTP could directly or indirectly interact with other cytosolic or membrane-bound proteins of the cell death machinery, thereby inhibiting cell death progression. As no homologous proteins of the anti-apoptotic machinery of animals were found in plants, and functional homologues still remain to be elucidated, future work will provide more insight.

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Cell-programmed nutrient partitioning in the tumour microenvironment.

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