bims-glucam 2023-09-03 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023–09–03
fiveteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine metabolic reprogramming in hepatocellular carcinoma.
ASCT2-mediated glutamine uptake promotes Th1 differentiation via ROS-EGR1-PAC1 pathway in oral lichen planus.
Zinc Modulates Glutamine Metabolism in T Cells.
Lobetyolin inhibits cell proliferation and induces cell apoptosis by downregulating ASCT2 in gastric cancer.
System analysis based on glutamine catabolic-related enzymes identifies GPT2 as a novel immunotherapy target for lung adenocarcinoma.
Metabolic partitioning in the brain and its hijacking by glioblastoma.
Spotlight on GOT2 in Cancer Metabolism.
Participation of protein metabolism in cancer progression and its potential targeting for the management of cancer.
Lysosomal cystine governs ferroptosis sensitivity in cancer via cysteine stress response.
Evaluation of (2S,4S)-4-[18F]FEBGln as a Positron Emission Tomography Tracer for Tumor Imaging.
Biomimetic nanovesicle co-delivery system impairs energy metabolism for cancer treatment.
Glutamine protects intestinal immunity through microbial metabolites rather than microbiota.
Adipocytes reprogram cancer cell metabolism by diverting glucose towards glycerol-3-phosphate thereby promoting metastasis.
Machine learning of cellular metabolic rewiring.
In situ and dynamic SERS monitoring of glutathione levels during cellular ferroptosis metabolism.

Front Mol Biosci. 2023 ;10 1242059

Glutamine metabolic reprogramming in hepatocellular carcinoma.

Yanyan Ye, Bodong Yu, Hua Wang, Fengming Yi.

  Hepatocellular carcinoma (HCC) is a lethal disease with limited management strategies and poor prognosis. Metabolism alternations have been frequently unveiled in HCC, including glutamine metabolic reprogramming. The components of glutamine metabolism, such as glutamine synthetase, glutamate dehydrogenase, glutaminase, metabolites, and metabolite transporters, are validated to be potential biomarkers of HCC. Increased glutamine consumption is confirmed in HCC, which fuels proliferation by elevated glutamate dehydrogenase or upstream signals. Glutamine metabolism also serves as a nitrogen source for amino acid or nucleotide anabolism. In addition, more glutamine converts to glutathione as an antioxidant in HCC to protect HCC cells from oxidative stress. Moreover, glutamine metabolic reprogramming activates the mTORC signaling pathway to support tumor cell proliferation. Glutamine metabolism targeting therapy includes glutamine deprivation, related enzyme inhibitors, and transporters inhibitors. Together, glutamine metabolic reprogramming plays a pivotal role in HCC identification, proliferation, and progression.

Keywords:  glutamine metabolic reprogramming; glutamine-related metabolites; hepatocellular carcinoma; mTORC; metabolic targeting therapy

DOI:  https://doi.org/10.3389/fmolb.2023.1242059
Biochem Pharmacol. 2023 Aug 25. pii: S0006-2952(23)00358-1. [Epub ahead of print]216 115767

ASCT2-mediated glutamine uptake promotes Th1 differentiation via ROS-EGR1-PAC1 pathway in oral lichen planus.

Wei Li, Zihang Ling, Jinmei Wang, Zhangci Su, Jingyi Lu, Xi Yang, Bin Cheng, Xiaoan Tao.

  Oral lichen planus (OLP) is a T cell-mediated autoimmune disease of oral mucosa concerning with the redox imbalance. Although glutamine uptake mediated by alanine-serine-cysteine transporter 2 (ASCT2) is critical to T cell differentiation, the exact mechanism remains ambiguous. Here, we elucidate a novel regulatory mechanism of ASCT2-mediated uptake in the differentiation and proliferation of T cells through maintaining redox balance in OLP. The results of immunohistochemistry (IHC) showed that both ASCT2 and glutaminase (GLS) were obviously upregulated compared to controls in OLP. Moreover, correlation analyses indicated that ASCT2 expression was significantly related to GLS level. Interestingly, the upregulation of glutamine metabolism in epithelial layer was consistent with that in lamina propria. Functional assays in vitro revealed the positive association between glutamine metabolism and lymphocytes infiltration. Additionally, multiplex immunohistochemistry (mIHC) uncovered a stronger colocalization among ASCT2 and CD4 and IFN-γ, which was further demonstrated by human Th1 differentiation assay in vitro. Mechanistically, targeting glutamine uptake through interference with ASCT2 using L-γ-Glutamyl-p-nitroanilide (GPNA) decreased the glutamine uptake of T cells and leaded to the accumulation of intracellular reactive oxygen species (ROS), which promoted dual specificity phosphatase 2 (DUSP2/PAC1) expression through activation of early growth response 1 (EGR1) to induce dephosphorylation of signal transducer and activator of transcription 3 (STAT3) and inhibit Th1 differentiation in turn. These results demonstrated that glutamine uptake mediated by ASCT2 induced Th1 differentiation by ROS-EGR1-PAC1 pathway, and restoring the redox dynamic balance through targeting ASCT2 may be a potential treatment for T cell-mediated autoimmune diseases.

Keywords:  ASCT2; Glutamine; Oral Lichen Planus; PAC1; ROS

DOI:  https://doi.org/10.1016/j.bcp.2023.115767
Mol Nutr Food Res. 2023 Sep 01. e2300155

Zinc Modulates Glutamine Metabolism in T Cells.

Nergis Güzel, Lothar Rink, Henrike Josephine Fischer.

   SCOPE: Zinc and glutamine are well known to be essential for the function and polarization of immune cells. TH 17 cells are more frequently induced during zinc deficiency and cover their energy requirement mainly through glutaminolysis. A dysregulation of TH 17 cells can contribute to the development of autoimmune diseases. Both inhibition of glutaminolysis and zinc supplementation suppress experimental autoimmune encephalomyelitis in mice. Therefore, the aim of this study is to investigate whether zinc modulates glutaminolysis in T cells.
METHODS AND RESULTS: CD3/CD28 stimulation and mixed lymphocytes culture are used as in vitro models for T cell activation. Then, the glutaminolysis is investigated on mRNA, protein, and functional level. Zinc deficiency and glutaminase (GLS) inhibition decrease immune responses in vitro. Furthermore, extracellular zinc and glutamine levels both modulate glutaminolysis by changing the expression of glutamine transporters and key enzymes. Intriguingly, zinc directly interferes with the activity of GLS both in a cell free system and in the cytosol.
CONCLUSION: Besides T cell subset differentiation, zinc also impacts on the cellular metabolism by inhibiting glutaminolysis. This suggests that zinc deficiency can contribute to the development of autoimmune diseases whereas zinc supplementation can support their therapy.

Keywords:  T cell; glutamine; glutaminolysis; immunology; zinc

DOI:  https://doi.org/10.1002/mnfr.202300155
Cytotechnology. 2023 Oct;75(5): 435-448

Lobetyolin inhibits cell proliferation and induces cell apoptosis by downregulating ASCT2 in gastric cancer.

Lin Cheng, Haoqing Zhai, Juan Du, Gang Zhang, Gan Shi.

  Gastric cancer (GC) is a heterogeneous disease and is the fifth most common cancer worldwide. Lobetyolin, as a bioactive ingredient extracted from Codonopsis pilosula (Franch.) Nannf., has been reported to exert anti-tumor effects in several cancer types. This study was aimed to investigate the role of lobetyolin in GC and the associated mechanism. MKN-45 and MKN-28 cells were incubated with concentrations of lobetyolin for 24 h. The viability and survival of GC cells were evaluated by performing MTT assay. Glutamine uptake, Adenosine Triphosphate, reactive oxygen species (ROS), and glutathione levels were measured by corresponding kits. Apoptosis and mitochondrial membrane potential of GC cells were determined by flow cytometry. Alanine, serine, cysteine-preferring transporter 2 (ASCT2) and the AKT/GSK3β/c-Myc pathway protein levels were examined by western blotting. Xenograft model and immunohistochemical staining were used to evaluate the pharmacological effects of lobetyolin in mice in vivo. We found that lobetyolin treatment suppressed the proliferative capacity of both MKN-45 and MKN-28 cells in a concentration-dependent manner. Lobetyolin reduced the uptake of glutamine and downregulated the expression levels of ASCT2 in GC cells and xenograft tumors. Lobetyolin effectively restrained the growth of tumors in vivo. In addition, lobetyolin induced the accumulation of ROS to attenuate mitochondria-mediated apoptosis via downregulation of ASCT2 expression. Lobetyolin promoted the phosphorylation of c-Myc and suppressed the phosphorylation of GSK3β and AKT in both MKN-45 and MKN-28 cells. The level of total Nrf2 protein was reduced after lobetyolin treatment. Overall, lobetyolin exerts anti-cancer effects by repressing cell proliferation and inducing cell apoptosis via downregulation of ASCT2 in GC.

Keywords:  Alanine, Serine, Cysteine-preferring transporter 2; Gastric cancer; Glutamine metabolism; Lobetyolin

DOI:  https://doi.org/10.1007/s10616-023-00588-w
Comput Biol Med. 2023 Aug 29. pii: S0010-4825(23)00880-6. [Epub ahead of print]165 107415

System analysis based on glutamine catabolic-related enzymes identifies GPT2 as a novel immunotherapy target for lung adenocarcinoma.

Bolin Wang, Jinli Pei, Shengnan Xu, Jie Liu, Jinming Yu.

   BACKGROUND: In recent years, targeting glutamine metabolism has gained attention as a promising therapeutic approach. Glutamine catabolic-related enzymes play a crucial role in modulating glutamine metabolism and influencing immune responses in the tumor immune microenvironment (TME). However, current literature on the function of glutamine catabolic enzymes in lung adenocarcinoma (LUAD) is limited.
METHODS: We validated the glutamine dependency of LUAD cells in vitro, followed by transcriptome data to identify differentially expressed genes (DEGs), with transcriptome and single-cell data analysis utilized to explore the role of such genes within the tumor immune microenvironment. We performed employed subcutaneous injection of lewis lung carcinoma cells in C57BL/6 mice to confirm the role of candidate genes in tumor growth and anti-tumor immunity.
RESULTS: Our study revealed that glutamine is essential for the growth of LUAD cells. Subsequently, we identified four DEGs - glutamate pyruvate transaminase 1 (GPT1), glutamate pyruvate transaminase 2 (GPT2), glutamic-oxaloacetic transaminase 1 (GOT1), and glutamic-oxaloacetic transaminase 2 (GOT2) - in LUAD patients, which were highly expressed in tumor tissue and associated with an immunosuppressive TME. Single-cell sequencing analysis detected high expression levels of GOT1 and GOT2 in immune and stromal cell subpopulations, while GPT1 and GPT2 showed relatively lower expression. Based on the lower immune score and lower expression in immune and stromal cells, we validated the role of GPT2 in vivo for modulating the TME and tumor growth. Inhibition of GPT2 resulted in suppressed tumor growth and increased the expression of CD4 and CD8. Additionally, GPT2 inhibitors induced a stronger antitumor immunity when used in combination with anti-programmed cell death ligand 1.
CONCLUSION: This study is the first to show the critical role of glutamine catabolic-related enzymes in the TME, and identified GPT2 as a promising therapeutic target for inhibiting tumor growth and improving anti-tumour immune responses for LUAD. Additional studies will be required to define the roles glutamine catabolic-related enzymes play in LUAD.

Keywords:  GPT2; Glutamate pyruvate transaminase 2; Glutamine metabolism; Immunotherapy; Lung adenocarcinoma; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.compbiomed.2023.107415
Genes Dev. 2023 Aug 30.

Metabolic partitioning in the brain and its hijacking by glioblastoma.

Jed de Ruiter Swain, Evdokia Michalopoulou, Evan K Noch, Michael J Lukey, Linda Van Aelst.

  The different cell types in the brain have highly specialized roles with unique metabolic requirements. Normal brain function requires the coordinated partitioning of metabolic pathways between these cells, such as in the neuron-astrocyte glutamate-glutamine cycle. An emerging theme in glioblastoma (GBM) biology is that malignant cells integrate into or "hijack" brain metabolism, co-opting neurons and glia for the supply of nutrients and recycling of waste products. Moreover, GBM cells communicate via signaling metabolites in the tumor microenvironment to promote tumor growth and induce immune suppression. Recent findings in this field point toward new therapeutic strategies to target the metabolic exchange processes that fuel tumorigenesis and suppress the anticancer immune response in GBM. Here, we provide an overview of the intercellular division of metabolic labor that occurs in both the normal brain and the GBM tumor microenvironment and then discuss the implications of these interactions for GBM therapy.

Keywords:  IDH mutation; brain metabolism; cancer metabolism; glioblastoma; glioma; glioma therapy; immune suppression; tumor microenvironment

DOI:  https://doi.org/10.1101/gad.350693.123
Onco Targets Ther. 2023 ;16 695-702

Spotlight on GOT2 in Cancer Metabolism.

Samuel A Kerk, Javier Garcia-Bermudez, Kivanc Birsoy, Mara H Sherman, Yatrik M Shah, Costas A Lyssiotis.

  GOT2 is at the nexus of several critical metabolic pathways in homeostatic cellular and dysregulated cancer metabolism. Despite this, recent work has emphasized the remarkable plasticity of cancer cells to employ compensatory pathways when GOT2 is inhibited. Here, we review the metabolic roles of GOT2, highlighting findings in both normal and cancer cells. We emphasize how cancer cells repurpose cell intrinsic metabolism and their flexibility when GOT2 is inhibited. We close by using this framework to discuss key considerations for future investigations into cancer metabolism.

Keywords:  mitochondria; nucleotides; pancreatic cancer; redox; transaminase; tumor microenvironment

DOI:  https://doi.org/10.2147/OTT.S382161
Amino Acids. 2023 Aug 30.

Participation of protein metabolism in cancer progression and its potential targeting for the management of cancer.

Dalong Liu, Yun Wang, Xiaojiang Li, Yan Wang, Zhiqiang Zhang, Zhifeng Wang, Xudong Zhang.

  Cancer malignancies may broadly be described as heterogeneous disorders manifested by uncontrolled cellular growth/division and proliferation. Tumor cells utilize metabolic reprogramming to accomplish the upregulated nutritional requirements for sustaining their uncontrolled growth, proliferation, and survival. Metabolic reprogramming also called altered or dysregulated metabolism undergoes modification in normal metabolic pathways for anabolic precursor's generation that serves to continue biomass formation that sustains the growth, proliferation, and survival of carcinogenic cells under a nutrition-deprived microenvironment. A wide range of dysregulated/altered metabolic pathways encompassing different metabolic regulators have been described; however, the current review is focused to explain deeply the metabolic pathways modifications inducing upregulation of proteins/amino acids metabolism. The essential modification of various metabolic cycles with their consequent outcomes meanwhile explored promising therapeutic targets playing a pivotal role in metabolic regulation and is successfully employed for effective target-specific cancer treatment. The current review is aimed to understand the metabolic reprogramming of different proteins/amino acids involved in tumor progression along with potential therapeutic perspective elucidating targeted cancer therapy via these targets.

Keywords:  Cancer treatment; Dysregulated metabolism; Metabolic reprogramming; Nutritional requirements; Protein metabolism; Therapeutic targets

DOI:  https://doi.org/10.1007/s00726-023-03316-y
Mol Cell. 2023 Aug 24. pii: S1097-2765(23)00640-8. [Epub ahead of print]

Lysosomal cystine governs ferroptosis sensitivity in cancer via cysteine stress response.

Robert V Swanda, Quanquan Ji, Xincheng Wu, Jingyue Yan, Leiming Dong, Yuanhui Mao, Saori Uematsu, Yizhou Dong, Shu-Bing Qian.

  The amino acid cysteine and its oxidized dimeric form cystine are commonly believed to be synonymous in metabolic functions. Cyst(e)ine depletion not only induces amino acid response but also triggers ferroptosis, a non-apoptotic cell death. Here, we report that unlike general amino acid starvation, cyst(e)ine deprivation triggers ATF4 induction at the transcriptional level. Unexpectedly, it is the shortage of lysosomal cystine, but not the cytosolic cysteine, that elicits the adaptative ATF4 response. The lysosome-nucleus signaling pathway involves the aryl hydrocarbon receptor (AhR) that senses lysosomal cystine via the kynurenine pathway. A blockade of lysosomal cystine efflux attenuates ATF4 induction and sensitizes ferroptosis. To potentiate ferroptosis in cancer, we develop a synthetic mRNA reagent, CysRx, that converts cytosolic cysteine to lysosomal cystine. CysRx maximizes cancer cell ferroptosis and effectively suppresses tumor growth in vivo. Thus, intracellular nutrient reprogramming has the potential to induce selective ferroptosis in cancer without systematic starvation.

Keywords:  AhR; cancer therapy; cysteine; cystine; ferroptosis; lysosome; mRNA; nutrient stress

DOI:  https://doi.org/10.1016/j.molcel.2023.08.004
Mol Pharm. 2023 Aug 30.

Evaluation of (2S,4S)-4-[18F]FEBGln as a Positron Emission Tomography Tracer for Tumor Imaging.

Yong Huang, Yajing Liu, Chengze Li, Zhongjing Li, Hualong Chen, Lu Zhang, Ying Liang, Zehui Wu.

  Glutamine metabolism-related tracers have the potential to visualize numerous tumors because glutamine is the second largest source of energy for tumors. (2S,4S)-4-[18F]FEBGln was designed by introducing [18F]fluoroethoxy benzyl on carbon-4 of glutamine. The aim of this study was to investigate the pharmacokinetic properties and tumor positron emission tomography (PET) imaging characteristics of (2S,4S)-4-[18F]FEBGln in detail. The biodistribution results of nude mice bearing MCF-7 tumor showed that (2S,4S)-4-[18F]FEBGln had high initial tumor uptake, and a fast clearance rate, resulting in a high tumor-to-muscle ratio at 30 min postinjection. There was no obvious defluorination in vivo. The micro-PET-CT imaging results of (2S,4S)-4-[18F]FEBGln orthotopic MCF-7 tumor-bearing nude mice were consistent with the biological distribution results. Compared with (2S,4R)-4-[18F]FGln, (2S,4S)-4-[18F]FEBGln showed poor tumor retention, but its clearance in normal tissues was also fast, so it had better PET image contrast than the former. Unlike poor retention in MCF-7-bearing nude mice, (2S,4S)-4-[18F]FEBGln has good retention in NCI-h1975 and 22Rv1 tumor models. Since (2S,4S)-4-[18F]FEBGln has low uptake in normal lungs and high uptake in the bladder, it is expected to be used in the accurate diagnosis of lung cancer but cannot accurately determine prostate cancer. Consistent with the advantages of radiolabeled amino acids in the application of brain tumors, (2S,4S)-4-[18F]FEBGln accurately diagnoses U87MG glioma with higher contrast than [18F]FET and [18F]FDG, and there is a correlation between (2S,4S)-4-[18F]FEBGln uptake and tumor growth cycle. Further kinetic model analysis showed that (2S,4S)-4-[18F]FEBGln was similar to (2S,4R)-4-[18F]FGln, conforming to the one-compartment model and the Logan graphical model, and was expected to assess the size of the glutamine pool of the tumor. Therefore, (2S,4S)-4-[18F]FEBGln is expected to provide a strong imaging basis for the diagnosis, formulation of personalized plans, and efficacy evaluation of glioma, lung cancer, and breast cancer.

Keywords:  (2S,4S)-4-[18F]FEBGln; glutamine; positron emission tomography; tracer; tumor imaging

DOI:  https://doi.org/10.1021/acs.molpharmaceut.3c00544
J Nanobiotechnology. 2023 Aug 26. 21(1): 299

Biomimetic nanovesicle co-delivery system impairs energy metabolism for cancer treatment.

Yongmei Zhao, Yan Zhu, Kai Ding, Shanshan Li, Tianqing Liu.

  Metabolic reprogramming in cancer cells plays a crucial role in cancer development, metastasis and invasion. Cancer cells have a unique metabolism profile that could switch between glycolysis and oxidative phosphorylation (OXPHOS) in order to satisfy a higher proliferative rate and enable survival in tumor microenvironment. Although dietary-based cancer starvation therapy has shown some positive outcomes for cancer treatment, it is difficult for patients to persist for a long time due to the adverse effects. Here in this study, we developed a specific M1 macrophage-derived membrane-based drug delivery system for breast cancer treatment. Both metformin and 3-Bromopyruvate were loaded into the engineered cell membrane-based biomimetic carriers (Met-3BP-Lip@M1) for the shutdown of energy metabolism in cancer cells via simultaneous inhibition of both glycolysis and oxygen consumption. The in vitro studies showed that Met-3BP-Lip@M1 had excellent cancer cell uptake and enhanced cancer cell apoptosis via cell cycle arrest. Our results also demonstrated that this novel biomimetic nanomedicine-based cancer starvation therapy synergistically improved the therapeutic efficiency against breast cancer cells by blocking energy metabolic pathways, which resulted in a significant reduction of cancer cell proliferation, 3D tumor spheroid growth as well as in vivo tumor growth.

Keywords:  3-Bromopyruvate; Biomimetic nanomedicines; Cancer therapy; Energy metabolism; M1 macrophage; Metformin

DOI:  https://doi.org/10.1186/s12951-023-02061-4
Int Immunopharmacol. 2023 Aug 25. pii: S1567-5769(23)01157-8. [Epub ahead of print]124(Pt A): 110832

Glutamine protects intestinal immunity through microbial metabolites rather than microbiota.

Shuai Li, Xiaolu Wen, Xuefen Yang, Li Wang, Kaiguo Gao, Xingwei Liang, Hao Xiao.

  Glutamine has anti-inflammatory properties as well as the ability to maintain the integrity of the intestinal barrier. In our previous study, we found that 1.0% glutamine promoted SIgA (secretory immunoglobulin A) synthesis in the gut via both T cell-dependent and non-dependent processes, as well as via the intestinal microbiota. The purpose of this study was to investigate whether the intestinal microbiota or microbial metabolites regulate SIgA synthesis. In the mouse model, supplementation with 1.0% glutamine had no significant effect on the intestinal microbiota, but KEGG function prediction showed the difference on microbiota metabolites. Therefore, in this study, untargeted metabolomics techniques were used to detect and analyze the metabolic changes of glutamine in intestinal luminal contents. Metabolomics showed that in the positive ion (POS) mode, a total of 1446 metabolic differentials (VIP ≥ 1, P < 0.05, FC ≥ 2 or FC ≤ 0.5) were annotated in samples treated with glutamine-supplemented group compared to control group, of which 922 were up-regulated and 524 down-regulated. In the negative ion (NEG) mode, 370 differential metabolites (VIP ≥ 1, P < 0.05, FC ≥ 2 or FC ≤ 0.5) were screened, of which 220 were up-regulated and 150 down-regulated. These differential metabolites mainly include bile secretion synthesis, ABC transporters, diterpenoids and other secondary metabolites. KEGG analysis showed that propionic acid metabolism, TCA cycle, endoplasmic reticulum protein processing, nitrogen metabolism and other metabolic pathways were active. The above metabolic pathways and differential metabolites have positive effects on intestinal development and intestinal immunity, and combined with our previous studies, we conclude that glutamine supplementation can may maintain intestinal homeostasis and improving intestinal immunity through intestinal microbial metabolites.

Keywords:  Glutamine; Intestinal immunity; Intestinal microbiota; Metabolomics profiling; Mice

DOI:  https://doi.org/10.1016/j.intimp.2023.110832
Nat Metab. 2023 Aug 31.

Adipocytes reprogram cancer cell metabolism by diverting glucose towards glycerol-3-phosphate thereby promoting metastasis.

Abir Mukherjee, Divya Bezwada, Francesco Greco, Malu Zandbergen, Tong Shen, Chun-Yi Chiang, Medine Tasdemir, Johannes Fahrmann, Dmitry Grapov, Michael R La Frano, Hieu S Vu, Brandon Faubert, John W Newman, Liam A McDonnell, Luigi Nezi, Oliver Fiehn, Ralph J DeBerardinis, Ernst Lengyel.

In the tumor microenvironment, adipocytes function as an alternate fuel source for cancer cells. However, whether adipocytes influence macromolecular biosynthesis in cancer cells is unknown. Here we systematically characterized the bidirectional interaction between primary human adipocytes and ovarian cancer (OvCa) cells using multi-platform metabolomics, imaging mass spectrometry, isotope tracing and gene expression analysis. We report that, in OvCa cells co-cultured with adipocytes and in metastatic tumors, a part of the glucose from glycolysis is utilized for the biosynthesis of glycerol-3-phosphate (G3P). Normoxic HIF1α protein regulates the altered flow of glucose-derived carbons in cancer cells, resulting in increased glycerophospholipids and triacylglycerol synthesis. The knockdown of HIF1α or G3P acyltransferase 3 (a regulatory enzyme of glycerophospholipid synthesis) reduced metastasis in xenograft models of OvCa. In summary, we show that, in an adipose-rich tumor microenvironment, cancer cells generate G3P as a precursor for critical membrane and signaling components, thereby promoting metastasis. Targeting biosynthetic processes specific to adipose-rich tumor microenvironments might be an effective strategy against metastasis.

DOI: https://doi.org/10.1038/s42255-023-00879-8
bioRxiv. 2023 Aug 14. pii: 2023.08.11.552957. [Epub ahead of print]

Machine learning of cellular metabolic rewiring.

Joao B Xavier.

Metabolic rewiring allows cells to adapt their metabolism in response to evolving environmental conditions. Traditional metabolomics techniques, whether targeted or untargeted, often struggle to interpret these adaptive shifts. Here we introduce MetaboLiteLearner , a machine learning framework that harnesses the detailed fragmentation patterns from electron ionization (EI) collected in scan mode during gas chromatography/mass spectrometry (GC/MS) to predict abundance changes in metabolically adapted cells. When tested on breast cancer cells with different preferences to metastasize to specific organs, MetaboLiteLearner successfully predicted the impact of metabolic rewiring on metabolites withheld from the training dataset using only the EI spectra, without metabolite identification or pre-existing knowledge of metabolic networks. Our analysis highlights shared and unique metabolomic shifts between brain- and lung-homing metastatic lineages, suggesting potential organ-tailored cellular adaptations. MetaboLiteLearner 's integration of machine learning and metabolomics paves the way for new insights into complex cellular adaptations.
Significance: Metabolic rewiring-the cellular adaptation to shifts in environment and nutrients-plays key roles in many contexts, including cancer metastasis. Traditional metabolomics often falls short of capturing the nuances of these metabolic shifts. This work introduces MetaboliLiteLearner , a machine learning framework that harnesses the rich fragmentation patterns from electron ionization collected in scan mode during gas chromatography/mass spectrometry, paving the way for enhanced insights into metabolic adaptations. Demonstrating its robustness on a breast cancer model, we highlight MetaboliLiteLearner 's potential to reshape our understanding of metabolic rewiring, with implications in diagnostics, therapeutics, and basic cell biology.

DOI: https://doi.org/10.1101/2023.08.11.552957
Anal Bioanal Chem. 2023 Aug 30.

In situ and dynamic SERS monitoring of glutathione levels during cellular ferroptosis metabolism.

Lixing Xu, Xing Du, Tianqing Liu, Dan Sun.

  Ferroptosis is a non-apoptotic cell death regulated by iron-dependent lipid peroxidation. Glutathione (GSH), a key antioxidant against oxidative damage, is involved in one of the most important metabolic pathways of ferroptosis. Herein, an excellent plasmonic nanoprobe was developed for highly sensitive, in situ, dynamic real-time monitoring of intracellular GSH levels during ferroptosis. A nanoprobe was prepared by functionalizing gold nanoparticles (AuNPs) with the probe molecule crystal violet (CV). The fluctuation in the SERS signal intensity of CV via the competitive displacement reaction can be used to detect GSH. The advantages of the plasmonic nanoprobe including low-cost production techniques, outstanding stability and biocompatibility, high specificity and sensitivity towards GSH with a detection limit of 0.05 μM. It enables real-time dynamic monitoring of GSH levels in living cells during erastin-induced ferroptosis. This approach is expected to provide important theoretical support for elucidating the GSH-related ferroptosis metabolic mechanism and advancing our understanding of ferroptosis-based cancer therapy. Overview of the workflow of sensing principle for highly sensitive, in situ and dynamic tracking of intracellular GSH levels during drug-triggered ferroptosis process.

Keywords:  Ferroptosis; Glutathione; Nanoprobe; Surface-enhanced Raman scattering

DOI:  https://doi.org/10.1007/s00216-023-04909-y