Combined deletion of Glut1 and Glut3 impairs lung adenocarcinoma growth.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA577053 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10261500.fastq.gz | Fastqsanger.gz | |||
| SRR10261501.fastq.gz | Fastqsanger.gz | |||
| SRR10261502.fastq.gz | Fastqsanger.gz | |||
| SRR10261503.fastq.gz | Fastqsanger.gz | |||
| SRR10261504.fastq.gz | Fastqsanger.gz |
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Project description:The microenvironment of solid tumors is dynamic and frequently contain pockets of low oxygen levels (hypoxia) surrounded by regions of normal oxygen levels. Indeed, a compromised vascular is a is hallmark of the tumor microenvironment, creating gradients of hypoxia. Notably, hypoxia associates with increased metastasis and poor survival in patients. Therefore, to aid therapeutic decisions and better understand hypoxia's role in cancer progression, it is critical to identify endogenous biomarkers of hypoxia to spatially phenotype oncogenic lesions in human tissue, whether precancerous, benign, or malignant. Here, we characterize the glucose transporter GLUT3/SLC2A3 as a biomarker of hypoxia prostate epithelial cells and prostate tumors. Transcriptomic analyses of hypoxic immortalized prostate epithelial cells revealed a highly significant increase in GLUT3 expression. GLUT3 upregulation was also detected by immunostaining in hypoxic prostate epithelial cells and prostate cancer cell lines. Additionally, GLUT3 dramatically co-localized with the hypoxia-marker pimonidazole in xenograft tumors formed from prostate cancer cells and showed distinct concentration gradients within patient-derived xenograft tumors from primary and metastatic prostate cancer. Compared to established hypoxia-response genes, GLUT1 and CA9, GLUT3 shows a higher degree of hypoxia labeling within tumor tissue and may serve as a alternative endogenous biomarker of hypoxia.
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Project description:The tumor microenvironment presents many obstacles to effective CAR T cell therapy, including glucose competition from tumor and myeloid cells. Using mouse models of acute lymphoblastic leukemia (ALL), renal cell carcinoma (RCC), and glioblastoma (GBM), we show that enforced expression of the glucose transporter GLUT1 enhances anti-tumor efficacy and promotes favorable CAR T cell phenotypes for two clinically relevant CAR designs, 19-28z and IL13Ra2-BBz. In the NALM6 ALL model, 19-28z-GLUT1 promotes Tscm formation and prolongs survival. RNA sequencing of these CAR T cells reveals that overexpression of GLUT1, but not GLUT3, enriches for genes involved in glycolysis, mitochondrial respiration, and memory precursor phenotypes. Extending these data, 19-28z-GLUT1 CAR T cells improve tumor control and response to rechallenge in an RCC patient derived xenograft model. Furthermore, IL13Ra2-BBz CAR T cells overexpressing GLUT1 prolong survival of mice bearing orthotopic GBMs and exhibit decreased exhaustion markers. This novel engineering approach can offer a competitive advantage to CAR T cells in harsh tumor environments where glucose is limiting.
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Project description:Macrophages (MΦs) are heterogeneous and metabolically flexible with metabolism strongly affecting immune activation. A classic response to pro-inflammatory activation is increased flux through glycolysis with a downregulation of oxidative metabolism, while alternative activation is primarily oxidative which begs the question of whether targeting glucose metabolism is a viable approach to control MΦ activation. We created a murine model of myeloid-specific glucose transporter GLUT1 (Slc2a1) deletion. Bone marrow derived MΦs (BMDM) from Slc2a1M-/- mice failed to uptake glucose and demonstrated reduced glycolysis and Pentose Phosphate Pathway activity. Activated BMDMs displayed elevated metabolism of oleate and glutamine, yet maximal respiratory capacity was blunted in MΦ lacking GLUT1 demonstrating an incomplete metabolic reprogramming. Slc2a1M-/- BMDMs displayed a mixed inflammatory phenotype with reductions of the classically-activated pro- and anti-inflammatory markers, yet less oxidative stress. Slc2a1M-/- BMDMs had reduced pro-inflammatory metabolites, whereas metabolites indicative of alternative activation - such as ornithine and polyamines - were greatly elevated in the absence of GLUT1. Adipose tissue MΦs of lean Slc2a1M-/- mice had increased alternative M2-like activation marker mannose receptor CD206, yet lack of GLUT1 was not a critical mediator in the development of obesity-associated metabolic dysregulation. However, Ldlr-/- mice lacking myeloid GLUT1 developed unstable atherosclerotic lesions. Defective phagocytic capacity in Slc2a1M-/- BMDMs may have contributed to unstable atheroma formation. Together our findings suggest that while lack of GLUT1 blunted glycolysis and PPP, MΦ were metabolically flexible enough that inflammatory cytokine release was not dramatically regulated yet phagocytic defects hindered MΦ function in chronic diseases. Control mice are noted as WT or Slc2a1 fl/fl and myeloid GLUT1 deficient are KO or Slc2a1M-/- (LysMCre X Slc2a1fl/fl) for myeloid deficiency.
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Project description:Glucose transporters are the first and rate-limiting step for cellular glucose usage, which is often exacerbated in tumour cells enabling their growth and proliferation. Although inhibiting glucose metabolism in lung tumours could become an efficient treatment strategy, whether and which glucose transporter(s) should be targeted remains unclear because of their possible functional redundancy, and because other nutrients or transporter-independent metabolic processes including autophagy and macropinocytosis can fuel tumour cell growth in certain contexts. Here we show that glucose transporter Glut1 gene deletion in tumour cells does not impact tumour initiation and only slightly delays progression in a genetically-engineered mouse model of lung adenocarcinoma. Using 13C-glucose tracing with correlated nanoscale secondary ion mass spectrometry (NanoSIMS) and electron microscopy, we report the presence of multiple lamellar body-like organelles produced by tumour cells. Glucose-derived biomass accumulates in these organelles, and this accumulation is decreased in Glut1-deficient tumour cells. Ex vivo, tumour cell glycolysis is impaired in absence of Glut1 except in case of strong expression of another glucose transporter, Glut3. We show that Glut3 is dispensable for Glut1 wild-type tumour development. In contrast, their combined deletion diminishes tumour growth and prevents the appearance of big lesions. Our results demonstrate the requirement for two glucose transporters in lung adenocarcinoma; dual blockade could reach therapeutic responses not achieved by individual targeting.
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