bims-mepmim 2022-05-01 papers

bims-mepmim

Biomed News

on Metabolites in pathological microenvironments and immunometabolism

Issue of 2022‒05‒01
39 papers selected by
Erika Mariana Palmieri
NIH/NCI Laboratory of Cancer ImmunoMetabolism

Metabolism in tumor-associated macrophages.
Targeting cellular energy metabolism- mediated ferroptosis by small molecule compounds for colorectal cancer therapy.
The paradoxical role of inositol in cancer: a consequence of the metabolic state of a tumor.
Regulation of Intrinsic and Extrinsic Metabolic Pathways in Tumor-Associated Macrophages.
Characterization of metabolic alterations of Chronic Lymphocytic Leukemia in the lymph node microenvironment.
Metabolic cross-talk between ovarian cancer and the tumor microenvironment-providing potential targets for cancer therapy.
Tumor metabolism destruction via metformin-based glycolysis inhibition and glucose oxidase-mediated glucose deprivation for enhanced cancer therapy.
A Sub-6 nm MnFe2O4-dichloroacetic acid nanocomposite modulates tumor metabolism and catabolism for reversing tumor immunosuppressive microenvironment and boosting immunotherapy.
Aldh2 is a lineage-specific metabolic gatekeeper in melanocyte stem cells.
Dual Relationship Between Stromal Cells and Immune Cells in the Tumor Microenvironment.
Highly motile cells are metabolically responsive to collagen density.
Succinate dehydrogenase/complex II is critical for metabolic and epigenetic regulation of T cell proliferation and inflammation.
Loss of hydrogen voltage-gated channel-1 expression reveals heterogeneous metabolic adaptation to intracellular acidification by T-cells.
Matrix stiffness enhances cancer-macrophage interactions and M2-like macrophage accumulation in the breast tumor microenvironment.
Cancer Associated Fibroblasts - An Impediment to Effective Anti-Cancer T Cell Immunity.
Protein phosphatase 2Acα modulates fatty acid oxidation and glycolysis to determine tubular cell fate and kidney injury.
Untargeted metabolomics identifies the potential role of monocarboxylate transporter 6 (MCT6/SLC16A5) in lipid and amino acid metabolism pathways.
Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation.
Tumor-associated macrophages promote intratumoral conversion of conventional CD4+ T cells into regulatory T cells via PD-1 signalling.
The immune checkpoint B7-H3 (CD276) regulates adipocyte progenitor metabolism and obesity development.
Hyperpolarized [1-13C]Pyruvate Magnetic Resonance Spectroscopic Imaging for Evaluation of Early Response to Tyrosine Kinase Inhibition Therapy in Gastric Cancer.
β-Cell Succinate Dehydrogenase Deficiency Triggers Metabolic Dysfunction and Insulinopenic Diabetes.
Fatty Acid Uptake in Liver Hepatocytes Induces Relocalization and Sequestration of Intracellular Copper.
Ablation of H+/glucose Exporter SLC45A2 Enhances Melanosomal Glycolysis to Inhibit Melanin Biosynthesis and Promote Melanoma Metastasis.
Mitochondrial fission in macrophages fuels phagocytosis of tumor cells.
Hepatitis C Virus Alters Macrophage Cholesterol Metabolism Through Interaction with Scavenger Receptors.
Polyamines in cancer: integrating organismal metabolism and antitumour immunity.
MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis.
Identification of a Four-Gene Metabolic Signature to Evaluate the Prognosis of Colon Adenocarcinoma Patients.
Patterns of Alpha-Linolenic Acid Incorporation into Phospholipids in H4IIE Cells.
Untargeted metabolomic and lipid metabolism-related gene expression analyses of the effects and mechanism of aged Liupao tea treatment in HFD-induced obese mice.
Metal ions/nucleotide coordinated nanoparticles comprehensively suppress tumor by synergizing ferroptosis with energy metabolism interference.
Subtle changes in pH affect the packing and robustness of fatty acid bilayers.
Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel.
Macrophage-mediated delivery of Fe3O4-nanoparticles: a generalized strategy to deliver iron to Tumor Microenvironment.
Silencing alanine transaminase 2 in diabetic liver attenuates hyperglycemia by reducing gluconeogenesis from amino acids.
Lipidomic Analysis of Extracellular Vesicles Isolated from Human Plasma and Serum.
Endometrial macrophages in health and disease.
Crosstalk Between Metabolism and Immune Activity Reveals Four Subtypes With Therapeutic Implications in Clear Cell Renal Cell Carcinoma.

Int Rev Cell Mol Biol. 2022 ;pii: S1937-6448(22)00004-1. [Epub ahead of print]367 65-100

Metabolism in tumor-associated macrophages.

Jie Li, Gina M DeNicola, Brian Ruffell.

  Macrophages functionally adapt to a diverse set of signals, a process that is critical for their role in maintaining or restoring tissue homeostasis. This process extends to cancer, where macrophages respond to a series of inflammatory and metabolic cues that direct a maladaptive healing response. Tumor-associated macrophages (TAMs) have altered glucose, amino acid, and lipid metabolic profiles, and interfering with this metabolic shift can blunt the ability of macrophages to promote tumor growth, metastasis, and the creation of an immunosuppressive microenvironment. Here we will review changes in metabolites and metabolic pathways in TAMs and link these with the phenotypic and functional properties of the cells. We will also discuss current strategies targeting TAM metabolism as a therapeutic intervention in cancer.

Keywords:  Immunometabolism; Metabolic reprogramming; Metabolism; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/bs.ircmb.2022.01.004
J Drug Target. 2022 Apr 28. 1-28

Targeting cellular energy metabolism- mediated ferroptosis by small molecule compounds for colorectal cancer therapy.

Gang Wang, Wang Jun-Jie, Xiao-Na Xu, Feng Shi, Fu Xing-Li.

  Alterations in cellular energy metabolism, including glycolysis, glutamine and lipid metabolism that affects ferroptosis in the tumor microenvironment (TME), play a critical role in the development and progression of colorectal cancer (CRC) and offer evolutionary advantages to tumor cells and even enhance their aggressive phenotype. This review summarizes the findings on the dysregulated energy metabolism pathways, including lipid and fatty acid metabolism especially for regulating the ferroptosis in TME. Moreover, the cellular energy metabolism and tumor ferroptosis to be regulated by small molecule compounds, which targeting the different aspects of metabolic pathways of energy production as well as metabolic enzymes that connect with the tumor cell growth and ferroptosis in CRC are also discussed. In this review, we will provide a comprehensive summary on small molecule compounds regulatory function of different energy metabolic routes on ferroptosis in tumor cells and discuss those metabolic vulnerabilities for the development of potential ferroptosis-based tumor therapies for colorectal cancer.

Keywords:  Colorectal cancers; energy metabolism; small molecule compounds; tumor ferroptosis

DOI:  https://doi.org/10.1080/1061186X.2022.2071909
Cancer Metastasis Rev. 2022 Apr 25.

The paradoxical role of inositol in cancer: a consequence of the metabolic state of a tumor.

Kendall C Case, Michael W Schmidtke, Miriam L Greenberg.

  Inositol is an essential nutrient, obtained either by uptake from the environment or by de novo synthesis from glucose. Inositol and its derivatives exhibit tumor-suppressive effects, potentially mediated by inhibition of the ERK-MAPK or PI3K-Akt pathways. Accordingly, many cancers have been documented to silence expression of the ISYNA1 gene, which encodes the rate-limiting enzyme of inositol synthesis. Paradoxically, recent studies have also reported upregulation of ISYNA1 in some cancers. Upregulation may reflect a compensatory response brought about by defective inositol uptake or oncogenic mutations that preclude its tumor-suppressive effects. In these scenarios, de novo synthesis of inositol may be upregulated to promote cell proliferation. The role of inositol in cancer is further complicated by its ability to inhibit the master metabolic regulator AMPK, which upon activation can either decrease cell proliferation and metastasis or promote cell survival. Due to its potential dual role in cancer, inositol homeostasis must be tightly regulated in tumor cells. Thus, whether inositol acts to suppress or promote tumor progression is determined by the metabolic profile and oncogenic background of the cancer.

Keywords:  AMPK; Cancer; ISYNA1; Inositol; Metabolism; PI3K-Akt

DOI:  https://doi.org/10.1007/s10555-022-10032-8
FEBS J. 2022 Apr 29.

Regulation of Intrinsic and Extrinsic Metabolic Pathways in Tumor-Associated Macrophages.

Goutham Venkata Naga Davuluri, Chia-Hsin Chan.

  Tumor-associated macrophages (TAMs) are highly plastic and are broadly grouped into two major functional states, namely the pro-inflammatory M1-type and the pro-tumoral M2-type. Conversion of the functional states of TAMs is regulated by various cytokines, chemokines growth factors, and other secreted factors in the microenvironment. Dysregulated metabolism is a hallmark of cancer. Emerging evidence suggests that metabolism governs the TAM differentiation and functional conversation in support of tumor growth and metastasis. Aside from the altered metabolism reprogramming in TAMs, extracellular metabolites secreted by cancer, stromal, and/or other cells within the tumor microenvironment have been found to regulate TAMs through passive competition for metabolite availability and direct regulation via receptor/transporter-mediated signaling reaction. In this review, we focus on the regulatory roles of different metabolites and metabolic pathways in TAM conversion and function. We also discuss if the dysregulated metabolism in TAMs can be exploited for the development of new therapeutic strategies against cancer.

Keywords:  immunotherapy; macrophage polarization and conversion; metabolic pathways; tumor-associated macrophages

DOI:  https://doi.org/10.1111/febs.16465
Blood. 2022 Apr 29. pii: blood.2021013990. [Epub ahead of print]

Characterization of metabolic alterations of Chronic Lymphocytic Leukemia in the lymph node microenvironment.

Zhenghao Chen, Helga Simon-Molas, Gaspard Cretenet, Beatriz Valle-Argos, Lindsay D Smith, Francesco Forconi, Bauke V Schomakers, Michel van Weeghel, Dean Bryant, Jaco A C van Bruggen, F S Peters, Jeffrey C Rathmell, G J W van der Windt, Arnon P Kater, Graham Packham, Eric Eldering.

Altered metabolism is one of the hallmarks of cell division and of cancer. CLL cells circulate between peripheral blood (PB) and lymph nodes (LN), where they receive proliferative and pro-survival signals from surrounding cells. Yet insight into the metabolism of LN CLL and how this may relate to therapeutic responses is lacking. To obtain insight into CLL LN metabolism, we applied a two-tiered strategy. First, we sampled PB from 8 patients at baseline, and after 3-month ibrutinib (IBR) treatment, which forces egress of CLL cells from LNs. Second, we applied in vitro B-cell receptor (BCR) or CD40 stimulation to mimic the LN microenvironment, and performed metabolomics and transcriptomics. The combined analyses indicated prominent changes in purine, glucose and glutamate metabolism occurring in the LN. CD40 signaling mostly regulated amino acid metabolism, tricarboxylic acid cycle (TCA) and energy production. BCR signaling preferably engaged glucose and glycerol metabolism, and several biosynthesis routes. Pathway analyses demonstrated opposite effects of in vitro stimulation versus IBR treatment. In agreement, the metabolic regulator MYC and its target genes were induced after BCR/CD40 stimulation and suppressed by IBR. Next, 13C-fluxomics performed on CD40/BCR-stimulated cells confirmed a strong contribution of glutamine as fuel for the TCA cycle while glucose was mainly converted into lactate and ribose-5-phosphate. Finally, inhibition of glutamine import with V9302 attenuated CD40/BCR-induced resistance to venetoclax. Altogether, these data provide insight into crucial metabolic changes driven by CLL LN microenvironment. The prominent use of amino acids as fuel for the TCA cycle suggests new therapeutic vulnerabilities.

DOI: https://doi.org/10.1182/blood.2021013990
Front Biosci (Landmark Ed). 2022 Apr 20. 27(4): 139

Metabolic cross-talk between ovarian cancer and the tumor microenvironment-providing potential targets for cancer therapy.

Yi Lin, Xiao Liang, Xijie Zhang, Yanghong Ni, Xiaoting Zhou, Xia Zhao.

  Conventional treatments for ovarian cancer, including debulking cytoreductive surgery combined with carboplatin/paclitaxel-based chemotherapy, are insufficient, as evidenced by the high mortality rate, which ranks first among gynecological tumors. Therefore, there is an urgent need to develop new and effective treatment strategies. Recent evidence has shown that metabolic processes and cell behaviors in ovarian cancer are regulated by intracellular factors as well as metabolites in the tumor microenvironment (TME), which determine occurrence, proliferation, and metastasis. In this review, we describe the comprehensive landscape of metabolic cross-talk between ovarian cancer and its TME with a focus on the following four aspects: (1) intracellular metabolism based on the Warburg effect, (2) metabolism in non-tumor cells in the ovarian TME, (3) metabolic communication between tumor cells and non-tumor cells in the TME, and (4) metabolism-related therapeutic targets and agents for ovarian cancer. The metabolic cross-talk between ovarian cancer and its microenvironment involves a complex network of interactions, and interrupting these interactions by metabolic interventions is a promising therapeutic strategy.

Keywords:  cancer therapies; metabolites; ovarian cancer; review; tumor microenvironment

DOI:  https://doi.org/10.31083/j.fbl2704139
Acta Biomater. 2022 Apr 20. pii: S1742-7061(22)00231-8. [Epub ahead of print]

Tumor metabolism destruction via metformin-based glycolysis inhibition and glucose oxidase-mediated glucose deprivation for enhanced cancer therapy.

Xiangyu Meng, Zhuoxuan Lu, Qingyu Lv, Yongqiang Jiang, Liming Zhang, Zhifei Wang.

  Cancer cells rely on glycolysis to support a high proliferation rate. Metformin (Met) is a promising drug for tumor treatment that targets hexokinase 2 (HK2) to block the glycolytic process, thereby further disrupting the metabolism of cancer cells. Herein, an intelligent nanomedicine based on glucose deprivation and glycolysis inhibition is creatively constructed for enhanced cancer synergistic treatment. In brief, Met and glucose oxidase (GOx) was encapsulated into histidine/zeolitic imidazolate framework-8 (His/ZIF-8), which was followed by coating with Arg-Gly-Asp (RGD) peptides to obtain the desired nanomedicine (Met/GOx@His/ZIF-8∼RGD). This smart nanomedicine presents the controllable Met and GOx release behavior in an acidic responsive manner. The liberated Met blocks the glycolysis process via suppressing the activity of HK2 and impairing ATP production, which activates the AMP-activated protein kinase (AMPK) pathway and p53 pathway and damages the Warburg effect, eventually leading to cells apoptosis. And the GOx boosts the glucose shortage for starvation therapy by depleting accumulated glucose. According to in vitro and in vivo assays, the combination of glycolysis inhibition and starvation therapy demonstrates efficient cancer cells growth suppression and superior antitumor properties compared to the Met-based or GOx-mediated monotherapy. This work provides an advanced therapeutic strategy via disrupting cellular metabolism against cancer. STATEMENT OF SIGNIFICANCE: The obtained nanomedicine (Met/GOx@His/ZIF-8∼RGD) presents the controllable Met and glucose oxidase (GOx) release behavior in an acidic responsive manner. The liberated Met blocks the glycolysis process via suppressing the activity of HK2 and impairing ATP production, which activates the AMP-activated protein kinase (AMPK) pathway and p53 pathway and damages the Warburg effect, eventually leading to cells apoptosis. And the GOx boosts the glucose shortage for starvation therapy by depleting accumulated glucose. The combination of glycolysis inhibition and starvation therapy demonstrate the efficient suppression of cancer cells growth and the superior antitumor properties when compared to the Met-based or GOx-mediated monotherapy.

Keywords:  Metformin; glycolysis inhibition; modified zeolitic imidazolate framework-8; starvation therapy; tumor metabolism

DOI:  https://doi.org/10.1016/j.actbio.2022.04.022
Biomaterials. 2022 Apr 18. pii: S0142-9612(22)00173-9. [Epub ahead of print]284 121533

A Sub-6 nm MnFe2O4-dichloroacetic acid nanocomposite modulates tumor metabolism and catabolism for reversing tumor immunosuppressive microenvironment and boosting immunotherapy.

Zan Dai, Qiaoyun Wang, Jie Tang, Rui Qu, Min Wu, Haoze Li, Yannan Yang, Xu Zhen, Chengzhong Yu.

  Adenosine and lactate accumulated in tumor microenvironment are two major causes of immunosuppression, their concurrent downregulation holds promise in effective cancer immunotherapy, but remains challenging. Here, a sub-6 nm MnFe2O4 conjugated with dichloroacetic acid (DCA) nanoparticle is developed to modulate tumor glucose metabolism and ATP catabolism for reversing the tumor immunosuppressive microenvironment. The ultrasmall MnFe2O4-DCA nanoparticle can efficiently enter mitochondria and supply oxygen, improving the bioactivity of DCA to regulate glucose metabolism and reduce lactate production ca. 100 times higher than free DCA itself. Moreover, this design significantly downregulates CD39 and CD73 expression than DCA or MnFe2O4 alone, which consequently decreases the extracellular ATP catabolism. The concurrent regulation of glucose metabolism and ATP catabolism leads to increased immunostimulatory ATP level and decreased immunosuppressive adenosine and lactate levels in tumor microenvironment, eventually amplified dendritic cells maturation, enhanced cytotoxic T lymphocyte response, and improved cancer immunotherapy efficacy.

Keywords:  ATP catabolism; Glucose metabolism; Mitochondrial entry; Tumor immunosuppressive microenvironment; Ultrasmall nanocomposite

DOI:  https://doi.org/10.1016/j.biomaterials.2022.121533
Development. 2022 Apr 29. pii: dev.200277. [Epub ahead of print]

Aldh2 is a lineage-specific metabolic gatekeeper in melanocyte stem cells.

Hannah Brunsdon, Alessandro Brombin, Samuel Peterson, John H Postlethwait, E Elizabeth Patton.

  Melanocyte stem cells (McSCs) in zebrafish serve as an on-demand source of melanocytes during growth and regeneration, but metabolic programs associated with their activation and regenerative processes are not well known. Here, using live imaging coupled with scRNA-sequencing, we discovered that during regeneration quiescent McSCs activate a dormant embryonic neural crest transcriptional program followed by an aldehyde dehydrogenase (Aldh) 2 metabolic switch to generate progeny. Unexpectedly, while ALDH2 is well known for its aldehyde clearing mechanisms, we find that in regenerating McSCs Aldh2 activity is required to generate formate - the one-carbon (1C) building block for nucleotide biosynthesis - through formaldehyde metabolism. Consequently, we find that disrupting the 1C cycle with low doses of methotrexate causes melanocyte regeneration defects. In the absence of Aldh2, we find that purines are the metabolic end product sufficient for activated McSCs to generate progeny. Together, our work reveals McSCs undergo a two-step cell state transition during regeneration, and that the reaction products of Aldh2 enzymes have tissue-specific stem cell functions that meet metabolic demands in regeneration.

Keywords:  Aldh2; Formaldehyde; Melanocyte stem cell; Metabolism; Purines; Regeneration

DOI:  https://doi.org/10.1242/dev.200277
Front Immunol. 2022 ;13 864739

Dual Relationship Between Stromal Cells and Immune Cells in the Tumor Microenvironment.

Jeong-Yeon Mun, Sun-Hee Leem, Jun Ho Lee, Hyuk Soon Kim.

  The tumor microenvironment (TME) plays a critical role in tumorigenesis and is comprised of different components, including tumor cells, stromal cells, and immune cells. Among them, the relationship between each mediator involved in the construction of the TME can be understood by focusing on the secreting or expressing factors from each cells. Therefore, understanding the various interactions between each cellular component of the TME is necessary for precise therapeutic approaches. In carcinoma, stromal cells are well known to influence extracellular matrix (ECM) formation and tumor progression through multiple mediators. Immune cells respond to tumor cells by causing cytotoxicity or inflammatory responses. However, they are involved in tumor escape through immunoregulatory mechanisms. In general, anti-cancer therapy has mainly been focused on cancer cells themselves or the interactions between cancer cells and specific cell components. However, cancer cells directly or indirectly influence other TME partners, and members such as stromal cells and immune cells also participate in TME organization through their mutual communication. In this review, we summarized the relationship between stromal cells and immune cells in the TME and discussed the positive and negative relationships from the point of view of tumor development for use in research applications and therapeutic strategies.

Keywords:  NK cell; T cell; cancer-associated adipocyte; cancer-associated fibroblast (CAF); immune cells; stromal cells; tumor endothelial cell; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2022.864739
Proc Natl Acad Sci U S A. 2022 May 03. 119(18): e2114672119

Highly motile cells are metabolically responsive to collagen density.

Matthew R Zanotelli, Jian Zhang, Ismael Ortiz, Wenjun Wang, Neil C Chada, Cynthia A Reinhart-King.

  Altered tissue mechanics and metabolism have gained significant attention as drivers of tumorigenesis, and mechanoresponsive metabolism has been implicated in migration and metastasis. However, heterogeneity in cell populations makes it difficult to link changes in behavior with metabolism, as individual cell behaviors are not necessarily reflected in population-based measurements. As such, the impact of increased collagen deposition, a tumor-associated collagen signature, on metabolism remains ambiguous. Here, we utilize a wide range of collagen densities to alter migration ability and study the bioenergetics of individual cells over time. Sorting cells based on their level of motility revealed energetics are a function of collagen density only for highly motile cells, not the entire population or cells with low motility. Changes in migration with increasing collagen density were correlated with cellular energetics, where matrix conditions most permissive to migration required less energy usage during movement and migrated more efficiently. These findings reveal a link between matrix mechanics, migratory phenotype, and bioenergetics and suggest that energetic costs are determined by the extracellular matrix and influence cell motility.

Keywords:  cell migration; extracellular matrix; heterogeneity; mechanobiology; metabolism

DOI:  https://doi.org/10.1073/pnas.2114672119
Sci Immunol. 2022 Apr 29. 7(70): eabm8161

Succinate dehydrogenase/complex II is critical for metabolic and epigenetic regulation of T cell proliferation and inflammation.

Xuyong Chen, Benjamin Sunkel, Meng Wang, Siwen Kang, Tingting Wang, J N Rashida Gnanaprakasam, Lingling Liu, Teresa A Cassel, David A Scott, Ana M Muñoz-Cabello, Jose Lopez-Barneo, Jun Yang, Andrew N Lane, Gang Xin, Benjamin Z Stanton, Teresa W-M Fan, Ruoning Wang.

Effective T cell-mediated immune responses require the proper allocation of metabolic resources to sustain growth, proliferation, and cytokine production. Epigenetic control of the genome also governs T cell transcriptome and T cell lineage commitment and maintenance. Cellular metabolic programs interact with epigenetic regulation by providing substrates for covalent modifications of chromatin. By using complementary genetic, epigenetic, and metabolic approaches, we revealed that tricarboxylic acid (TCA) cycle flux fueled biosynthetic processes while controlling the ratio of succinate/α-ketoglutarate (α-KG) to modulate the activities of dioxygenases that are critical for driving T cell inflammation. In contrast to cancer cells, where succinate dehydrogenase (SDH)/complex II inactivation drives cell transformation and growth, SDH/complex II deficiency in T cells caused proliferation and survival defects when the TCA cycle was truncated, blocking carbon flux to support nucleoside biosynthesis. Replenishing the intracellular nucleoside pool partially relieved the dependence of T cells on SDH/complex II for proliferation and survival. SDH deficiency induced a proinflammatory gene signature in T cells and promoted T helper 1 and T helper 17 lineage differentiation. An increasing succinate/α-KG ratio in SDH-deficient T cells promoted inflammation by changing the pattern of the transcriptional and chromatin accessibility signatures and consequentially increasing the expression of the transcription factor, PR domain zinc finger protein 1. Collectively, our studies revealed a role of SDH/complex II in allocating carbon resources for anabolic processes and epigenetic regulation in T cell proliferation and inflammation.

DOI: https://doi.org/10.1126/sciimmunol.abm8161
JCI Insight. 2022 Apr 26. pii: e147814. [Epub ahead of print]

Loss of hydrogen voltage-gated channel-1 expression reveals heterogeneous metabolic adaptation to intracellular acidification by T-cells.

David Coe, Thanushiyan Poobalasingam, Hongmei Fu, Fabrizia Bonacina, Guosu Wang, Valle Morales, Annalisa Moregola, Nico Mitro, Kenneth Cp Cheung, Eleanor J Ward, Suchita Nadkarni, Dunja Aksentijevic, Katiuscia Bianchi, Giuseppe Danilo Norata, Melania Capasso, Federica M Marelli-Berg.

  Hvcn1 is a voltage-gated proton channel, which reduces cytosol acidification and facilitates the production of reactive oxygen species (ROS). The increased expression of this channel in some cancers, has led to proposing Hvcn1 antagonists as potential therapeutics.While its role in most leukocytes has been studied in-depth, the function of Hvcn1 in T-cells remains poorly defined. We show that HVCN1 plays a non-redundant role in protecting naïve T-cells from intracellular acidification during priming. Despite sharing overall functional impairment in vivo and in vitro, Hvcn1-deficient CD4+ and CD8+ T-cells display profound differences during the transition from naïve to primed T-cells, including in the preservation of TCR signaling, cellular division and death. These selective features result, at least in part, from a substantially different metabolic response to intracellular acidification associated with priming. While Hvcn1-deficient naïve CD4+ T-cells reprogram to rescue the glycolytic pathway, naïve CD8+ T-cells, which express high levels of this channel in the mitochondria, respond by metabolically compensating mitochondrial dysfunction, at least in part via AMPK activation.These observations imply heterogeneity between adaptation of naïve CD4+ and CD8+ T-cells to intracellular acidification during activation.

Keywords:  Adaptive immunity; Immunology

DOI:  https://doi.org/10.1172/jci.insight.147814
Acta Biomater. 2022 Apr 25. pii: S1742-7061(22)00240-9. [Epub ahead of print]

Matrix stiffness enhances cancer-macrophage interactions and M2-like macrophage accumulation in the breast tumor microenvironment.

Paul V Taufalele, Wenjun Wang, Alan J Simmons, Austin N Southard-Smith, Bob Chen, Joshua D Greenlee, Michael R King, Ken S Lau, Duane C Hassane, François Bordeleau, Cynthia A Reinhart-King.

  The role of intratumor heterogeneity is becoming increasingly apparent in part due to expansion in single cell technologies. Clinically, tumor heterogeneity poses several obstacles to effective cancer therapy dealing with biomarker variability and treatment responses. Matrix stiffening is known to occur during tumor progression and contribute to pathogenesis in several cancer hallmarks, including tumor angiogenesis and metastasis. However, the effects of matrix stiffening on intratumor heterogeneity have not been thoroughly studied. In this study, we applied single-cell RNA sequencing to investigate the differences in the transcriptional landscapes between stiff and compliant MMTV-PyMT mouse mammary tumors. We found similar compositions of cancer and stromal subpopulations in compliant and stiff tumors but differential intercellular communication and a significantly higher concentration of tumor-promoting, M2-like macrophages in the stiffer tumor microenvironments. Interestingly, we found that cancer cells seeded on stiffer substrates recruited more macrophages. Furthermore, elevated matrix stiffness increased Colony Stimulating Factor 1 (CSF-1) expression in breast cancer cells and reduction of CSF-1 expression on stiffer substrates reduced macrophage recruitment. Thus, our results demonstrate that tissue phenotypes were conserved between stiff and compliant tumors but matrix stiffening altered cell-cell interactions which may be responsible for shifting the phenotypic balance of macrophages residing in the tumor microenvironment towards a pro-tumor progression M2 phenotype. STATEMENT OF SIGNIFICANCE: Cells within tumors are highly heterogeneous, posing challenges with treatment and recurrence. While increased tissue stiffness can promote several hallmarks of cancer, its effects on tumor heterogeneity are unclear. We used single-cell RNA sequencing to investigate the differences in the transcriptional landscapes between stiff and compliant MMTV-PyMT mouse mammary tumors. We found similar compositions of cancer and stromal subpopulations in compliant and stiff tumors but differential intercellular communication and a significantly higher concentration of tumor-promoting, M2-like macrophages in the stiffer tumor microenvironments. Using a biomaterial-based platform, we found that cancer cells seeded on stiffer substrates recruited more macrophages, supporting our in vivo findings. Together, our results demonstrate a key role of matrix stiffness in affecting cell-cell communication and macrophage recruitment.

Keywords:  CSF-1; Matrix stiffness; breast cancer; macrophage

DOI:  https://doi.org/10.1016/j.actbio.2022.04.031
Front Immunol. 2022 ;13 887380

Cancer Associated Fibroblasts - An Impediment to Effective Anti-Cancer T Cell Immunity.

Lilian Koppensteiner, Layla Mathieson, Richard A O'Connor, Ahsan R Akram.

  The presence of functionally efficient cytotoxic T lymphocytes (CTL) in the Tumour nest is crucial in mediating a successful immune response to cancer. The detection and elimination of cancer cells by CTL can be impaired by cancer-mediated immune evasion. In recent years, it has become increasingly clear that not only neoplastic cells themselves, but also cells of the tumour microenvironment (TME) exert immunosuppressive functions and thereby play an integral part in the immune escape of cancer. The most abundant stromal cells of the TME, cancer associated fibroblasts (CAFs), promote tumour progression via multiple pathways and play a role in dampening the immune response to cancer. Recent research indicates that T cells react to CAF signalling and establish bidirectional crosstalk that plays a significant role in the tumour immune response. This review discusses the various mechanisms by which the CAF/T cell crosstalk may impede anti-cancer immunity.

Keywords:  T cell exhaustion; cancer-associated fibroblast (CAF); mechanisms of immune evasion; targeting CAFs; tumour microenvironment

DOI:  https://doi.org/10.3389/fimmu.2022.887380
Kidney Int. 2022 Apr 25. pii: S0085-2538(22)00343-X. [Epub ahead of print]

Protein phosphatase 2Acα modulates fatty acid oxidation and glycolysis to determine tubular cell fate and kidney injury.

Mengru Gu, Mengzhu Tan, Lu Zhou, Xiaoli Sun, Qingmiao Lu, Mingjie Wang, Hanlu Jiang, Yan Liang, Qing Hou, Xian Xue, Zhuo Xu, Chunsun Dai.

  Energy metabolism is crucial in maintaining cellular homeostasis and adapting to stimuli for tubular cells. However, the underlying mechanisms remain largely unknown. Here, we report that PP2Acα was upregulated in damaged tubular cells from patients and animal models with acute or chronic kidney injury. Using in vitro and in vivo model, we demonstrated that PP2Acα induction in damaged tubular cells suppresses fatty acid oxidation and promotes glycolysis, leading to cell death and fibrosis. Mechanistically, we revealed that PP2Acα dephosphorylates ACC through interaction with B56δ, leading to the regulation of fatty acid oxidation. Furthermore, PP2Acα also dephosphorylates p-Glut1 (Thr478) and suppresses Trim21-mediated Glut1 ubiquitination and degradation, leading to the promotion of glucose intake and glycolysis. Thus, this study adds new insight into the tubular cell metabolic alterations in kidney diseases. PP2Acα may be a promising therapeutic target for kidney injury.

Keywords:  PP2Aca; acute kidney injury; chronic kidney disease; tubular cells

DOI:  https://doi.org/10.1016/j.kint.2022.03.024
Pharmacol Res Perspect. 2022 Jun;10(3): e00944

Untargeted metabolomics identifies the potential role of monocarboxylate transporter 6 (MCT6/SLC16A5) in lipid and amino acid metabolism pathways.

Tianjing Ren, Robert S Jones, Marilyn E Morris.

  Monocarboxylate transporter 6 (MCT6; SLC16A5) is an orphan transporter protein with expression in multiple tissues. The endogenous function of MCT6 related to human health and disease remains unknown. Our previous transcriptomic and proteomic analyses in Mct6 knockout (KO) mice suggested that MCT6 may play a role in lipid and glucose homeostasis, but additional evidence is required. Thus, the objective of this study was to further explore the impact of MCT6 on metabolic function using untargeted metabolomic analysis in Mct6 KO mice. The plasma from male and female mice and livers from male mice were submitted for global metabolomics analysis to assess the relative changes in endogenous small molecules across the liver and systemic circulation associated with absence of Mct6. More than 782 compounds were detected with 101 and 51 metabolites significantly changed in plasma of male and female mice, respectively, and 100 metabolites significantly changed in the livers of male mice (p < .05). Significant perturbations in lipid metabolism were annotated in the plasma and liver metabolome, with additional alterations in the amino acid metabolism pathway in plasma samples from male and female mice. Elevated lipid diacylglycerol and altered fatty acid metabolite concentrations were found in liver and plasma samples of male Mct6 KO mice. Significant reduction of N-terminal acetylated amino acids was found in plasma samples of male and female Mct6 KO mice. In summary, the present study confirmed the significant role of MCT6 in lipid and amino acid homeostasis, suggesting its contribution in metabolic diseases.

Keywords:  MCT6; PPAR-alpha; SLC16A5; amino acid homeostasis; lipid metabolism; metabolomics

DOI:  https://doi.org/10.1002/prp2.944
Nat Immunol. 2022 Apr 28.

Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation.

Leah K Billingham, Joshua S Stoolman, Karthik Vasan, Arianne E Rodriguez, Taylor A Poor, Marten Szibor, Howard T Jacobs, Colleen R Reczek, Aida Rashidi, Peng Zhang, Jason Miska, Navdeep S Chandel.

The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, and its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of the NLRP3 inflammasome through several mechanisms including generation of mitochondrial reactive oxygen species (ROS). Here, we report that mitochondrial electron transport chain (ETC) complex I, II, III and V inhibitors all prevent NLRP3 inflammasome activation. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase, which can complement the functional loss of mitochondrial complex I or III, respectively, without generation of ROS, rescued NLRP3 inflammasome activation in the absence of endogenous mitochondrial complex I or complex III function. Metabolomics revealed phosphocreatine (PCr), which can sustain ATP levels, as a common metabolite that is diminished by mitochondrial ETC inhibitors. PCr depletion decreased ATP levels and NLRP3 inflammasome activation. Thus, the mitochondrial ETC sustains NLRP3 inflammasome activation through PCr-dependent generation of ATP, but via a ROS-independent mechanism.

DOI: https://doi.org/10.1038/s41590-022-01185-3
Oncoimmunology. 2022 ;11(1): 2063225

Tumor-associated macrophages promote intratumoral conversion of conventional CD4+ T cells into regulatory T cells via PD-1 signalling.

Kevin Kos, Camilla Salvagno, Max D Wellenstein, Muhammad A Aslam, Denize A Meijer, Cheei-Sing Hau, Kim Vrijland, Daphne Kaldenbach, Elisabeth A M Raeven, Martina Schmittnaegel, Carola H Ries, Karin E de Visser.

  While regulatory T cells (Tregs) and macrophages have been recognized as key orchestrators of cancer-associated immunosuppression, their cellular crosstalk within tumors has been poorly characterized. Here, using spontaneous models for breast cancer, we demonstrate that tumor-associated macrophages (TAMs) contribute to the intratumoral accumulation of Tregs by promoting the conversion of conventional CD4+ T cells (Tconvs) into Tregs. Mechanistically, two processes were identified that independently contribute to this process. While TAM-derived TGF-β directly promotes the conversion of CD4+ Tconvs into Tregs in vitro, we additionally show that TAMs enhance PD-1 expression on CD4+ T cells. This indirectly contributes to the intratumoral accumulation of Tregs, as loss of PD-1 on CD4+ Tconvs abrogates intratumoral conversion of adoptively transferred CD4+ Tconvs into Tregs. Combined, this study provides insights into the complex immune cell crosstalk between CD4+ T cells and TAMs in the tumor microenvironment of breast cancer, and further highlights that therapeutic exploitation of macrophages may be an attractive immune intervention to limit the accumulation of Tregs in breast tumors.

Keywords:  Breast cancer immunology; T cell plasticity; regulatory T cells; tumor-associated macrophages

DOI:  https://doi.org/10.1080/2162402X.2022.2063225
Sci Adv. 2022 Apr 29. 8(17): eabm7012

The immune checkpoint B7-H3 (CD276) regulates adipocyte progenitor metabolism and obesity development.

Elodie Picarda, Phillip M Galbo, Haihong Zong, Meenu Rohini Rajan, Ville Wallenius, Deyou Zheng, Emma Börgeson, Rajat Singh, Jeffrey Pessin, Xingxing Zang.

The immune checkpoint B7-H3 (CD276) is a member of the B7 family that has been studied in the tumor microenvironment and immunotherapy, but its potential role in metabolism remains largely unknown. Here, we show that B7-H3 is highly expressed in mouse and human adipose tissue at steady state, with the highest levels in adipocyte progenitor cells. B7-H3 is rapidly down-regulated upon the initiation of adipocyte differentiation. Combined RNA sequencing and metabolic studies reveal that B7-H3 stimulates glycolytic and mitochondrial activity of adipocyte progenitors. Loss of B7-H3 in progenitors results in impaired oxidative metabolism program and increased lipid accumulation in derived adipocytes. Consistent with these observations, mice knocked out for B7-H3 develop spontaneous obesity, metabolic dysfunction, and adipose tissue inflammation. Our results reveal an unexpected metabolic role for B7-H3 in adipose tissue and open potential new avenues for the treatment of metabolic diseases by targeting the B7-H3 pathway.

DOI: https://doi.org/10.1126/sciadv.abm7012
Mol Imaging Biol. 2022 Apr 25.

Hyperpolarized [1-13C]Pyruvate Magnetic Resonance Spectroscopic Imaging for Evaluation of Early Response to Tyrosine Kinase Inhibition Therapy in Gastric Cancer.

Shadi A Esfahani, Cody Callahan, Nicholas J Rotile, Pedram Heidari, Umar Mahmood, Peter D Caravan, Aaron K Grant, Yi-Fen Yen.

  PURPOSE: To evaluate the use of hyperpolarized [1-13C]pyruvate magnetic resonance spectroscopic imaging (HP-13C MRSI) for quantitative measurement of early changes in glycolytic metabolism and its ability to predict response to pan-tyrosine kinase inhibitor (Pan-TKI) therapy in gastric cancer (GCa).PROCEDURES: Pan-TKI afatinib-sensitive NCI-N87 and resistant SNU16 human GCa cells were assessed for GLUT1, hexokinase-II (HKII), lactate dehydrogenase (LDHA), phosphorylated AKT (pAKT), and phosphorylated MAPK (pMAPK) at 0-72 h of treatment with 0.1 μM afatinib. Subcutaneous NCI-N87 tumor-bearing nude mice underwent [18F]FDG PET/MRI and HP-13C MRSI at baseline and 4 days after treatment with afatinib 10 mg/kg/day or vehicle (n = 10/group). Changes in PET and HP-13C MRSI metabolic parameters were compared between the two groups. Imaging findings were correlated with tumor growth and histopathology over 3 weeks of treatment.
RESULTS: In vitro analysis showed a continuous decrease in LDHA, pAKT, and pMAPK in NCI-N87 compared to SNU16 cells within 72 h of treatment with afatinib, without a significant change in GLUT1 and HKII in either cell type. [18F]FDG PET of NCI-N87 tumors showed no significant change in PET measures at baseline and day 4 of treatment in either treatment group (SUVmean day 4/day 0: 2.7 ± 0.42/2.34 ± 0.38, p = 0.57 in the treated group vs. 1.73 ± 0.66/2.24 ± 0.43, p = 0.4 in the control group). HP-13C MRSI demonstrated significantly decreased lactate-to-pyruvate ratio (L/P) in treated tumors (L/P day 4/day 0: 0.83 ± 0.30/1.10 ± 0.20, p = 0.012 vs. 0.94 ± 0.20/0.98 ± 0.30, p = 0.75, in the treated vs. control group, respectively). Response to afatinib was confirmed with decreased tumor size over 3 weeks (11.10 ± 16.50 vs. 293.00 ± 79.30 mm3, p < 0.001, treated group vs. control group, respectively) and histopathologic evaluation.
CONCLUSIONS: HP-13C MRSI is a more representative biomarker of early metabolic changes in response to pan-TKI in GCa than [18F]FDG PET and could be used for early prediction of response to targeted therapies.

Keywords:  Gastric cancer; Glycolysis; Hyperpolarized [1-13C]pyruvate; Magnetic resonance spectroscopic imaging; PET; PET/MRI; Tyrosine kinase inhibitor; [18F]FDG

DOI:  https://doi.org/10.1007/s11307-022-01727-z
Diabetes. 2022 Apr 26. pii: db210834. [Epub ahead of print]

β-Cell Succinate Dehydrogenase Deficiency Triggers Metabolic Dysfunction and Insulinopenic Diabetes.

Sooyeon Lee, Haixia Xu, Aidan Van Vleck, Alex M Mawla, Albert Mao Li, Jiangbin Ye, Mark O Huising, Justin P Annes.

Mitochondrial dysfunction plays a central role in Type 2 Diabetes (T2D); however, the pathogenic mechanisms in pancreatic β-cells are incompletely elucidated. Succinate dehydrogenase (SDH) is a key mitochondrial enzyme with dual functions in the TCA cycle and electron transport chain (ETC). Using human diabetic samples and a mouse model of β-cell-specific SDH ablation (SDHBβKO), we define SDH deficiency as a driver of mitochondrial dysfunction in β-cell failure and insulinopenic diabetes. β-Cell SDH deficiency impairs glucose-induced respiratory oxidative phosphorylation and mitochondrial membrane potential (ΔΨm) collapse, thereby compromising glucose-stimulated ATP production, insulin secretion and β-cell growth. Mechanistically, metabolomic and transcriptomic studies reveal that the loss of SDH causes excess succinate accumulation, which inappropriately activates mTORC1-regulated metabolic anabolism, including increased SREBP-regulated lipid synthesis. These alterations, which mirror diabetes-associated human β-cell dysfunction, are partially reversed by acute mTOR inhibition with rapamycin. We propose SDH deficiency as a contributing mechanism to the progressive β-cell failure of diabetes and identify mTORC1 inhibition as a potential mitigation strategy.

DOI: https://doi.org/10.2337/db21-0834
Front Mol Biosci. 2022 ;9 863296

Fatty Acid Uptake in Liver Hepatocytes Induces Relocalization and Sequestration of Intracellular Copper.

Nathaniel H O Harder, Hannah P Lee, Valerie J Flood, Jessica A San Juan, Skyler K Gillette, Marie C Heffern.

  Copper is an essential metal micronutrient with biological roles ranging from energy metabolism to cell signaling. Recent studies have shown that copper regulation is altered by fat accumulation in both rodent and cell models with phenotypes consistent with copper deficiency, including the elevated expression of the copper transporter, ATP7B. This study examines the changes in the copper trafficking mechanisms of liver cells exposed to excess fatty acids. Fatty acid uptake was induced in liver hepatocarcinoma cells, HepG2, by treatment with the saturated fatty acid, palmitic acid. Changes in chaperones, transporters, and chelators demonstrate an initial state of copper overload in the cell that over time shifts to a state of copper deficiency. This deficiency is due to sequestration of copper both into the membrane-bound copper protein, hephaestin, and lysosomal units. These changes are independent of changes in copper concentration, supporting perturbations in copper localization at the subcellular level. We hypothesize that fat accumulation triggers an initial copper miscompartmentalization within the cell, due to disruptions in mitochondrial copper balance, which induces a homeostatic response to cytosolic copper overload. This leads the cell to activate copper export and sequestering mechanisms that in turn induces a condition of cytosolic copper deficiency. Taken together, this work provides molecular insights into the previously observed phenotypes in clinical and rodent models linking copper-deficient states to obesity-associated disorders.

Keywords:  copper; fatty acid metabolism and signaling; homeostasis; metabolic disease; metal homeostasis

DOI:  https://doi.org/10.3389/fmolb.2022.863296
J Invest Dermatol. 2022 Apr 22. pii: S0022-202X(22)00301-3. [Epub ahead of print]

Ablation of H+/glucose Exporter SLC45A2 Enhances Melanosomal Glycolysis to Inhibit Melanin Biosynthesis and Promote Melanoma Metastasis.

Ye Liu, Wenna Chi, Lei Tao, Guoqiang Wang, R N V Krishna Deepak, Linlin Sheng, Taiqi Chen, Yaqian Feng, Xizhi Cao, Lili Cheng, Xinbin Zhao, Xiaohui Liu, Haiteng Deng, Hao Fan, Peng Jiang, Ligong Chen.

  Mutations in SLC45A2 are responsible for oculocutaneous albinism type 4 in many species and associated with melanoma susceptibility, but the molecular mechanism is unclear. Here, we used Slc45a2-deficient melanocyte and mouse models to elucidate the roles of Slc45a2 in melanogenesis and melanoma metastasis. We find that the acidified cellular environment impairs the activity of key melanogenic enzyme tyrosinase in Slc45a2-deficient melanocytes. Slc45a2 is identified as a proton/glucose exporter in melanosomes, and its ablation increases acidification of melanosomal pH through enhanced glycolysis. Intriguingly, 13C-glucose labeled metabolic flux and biochemical assays show that melanosomes are active glucose-metabolizing organelles, indicating that elevated glycolysis mainly occurs in melanosomes due to Slc45a2-deficiency. Moreover, Slc45a2-deficiency significantly up-regulates the activities of glycolytic enzymes and PI3K/Akt signaling to promote glycolysis-dependent survival and metastasis of melanoma cells. Collectively, our study reveals that the H+/glucose exporter Slc45a2 mediates melanin synthesis and melanoma metastasis primarily via modulating melanosomal glucose metabolism.

Keywords:  Slc45a2; glucose uptake; melanoma metastasis; melanosomal glycolysis

DOI:  https://doi.org/10.1016/j.jid.2022.04.008
Nat Cancer. 2022 Apr;3(4): 384-385

Mitochondrial fission in macrophages fuels phagocytosis of tumor cells.

DOI: https://doi.org/10.1038/s43018-022-00350-9
Viral Immunol. 2022 Apr;35(3): 223-235

Hepatitis C Virus Alters Macrophage Cholesterol Metabolism Through Interaction with Scavenger Receptors.

Lucas T Jennelle, Tshifhiwa Magoro, Angelina R Angelucci, Aditya Dandekar, Young S Hahn.

  Lipid accumulation and inflammation act together to induce, sustain, and further development of chronic liver disease. Hepatitis C virus (HCV) infection induces metabolic and immune changes in liver macrophages, promoting lipid accumulation and inflammation that synergize and culminate in the development of steatohepatitis and fibrogenesis. Chronic HCV patients have increased liver macrophages with disruptions in cholesterol metabolism and alterations in inflammatory mediators. While HCV-induced changes in inflammatory mediators are well documented, how HCV triggers metabolic change in macrophages is unknown. In this report, we examined the mechanism of macrophage sensing of HCV to cause metabolic impairment and subsequent immune dysfunction. We demonstrate that HCV protein and RNA kinetics in macrophages are distinct from hepatocytes. In macrophages, HCV RNAs and protein accumulate rapidly after exposure but internalized RNAs quickly decline to a low-level set point. Notably, exposure of macrophages to HCV resulted in increased lipids and cholesterol and activation of cholesterol-sensing, immunomodulatory liver X receptors (LXRs). Furthermore, we provide evidence that HCV RNA accumulation in macrophages occurs through scavenging receptors. These results suggest that HCV released from infected hepatocytes stimulates accumulation of lipids and activation of LXR in macrophages contributing to metabolic changes involved in HCV-induced chronic liver disease. Our results provide novel insight into mechanisms through which impaired lipid metabolism in macrophages associated with HCV infection promotes development of liver steatohepatitis and fibrosis.

Keywords:  LXR; SR-B1; cholesterol; hepatitis C virus; macrophages; scavenger receptor

DOI:  https://doi.org/10.1089/vim.2021.0101
Nat Rev Cancer. 2022 Apr 27.

Polyamines in cancer: integrating organismal metabolism and antitumour immunity.

Cassandra E Holbert, Michael T Cullen, Robert A Casero, Tracy Murray Stewart.

The natural mammalian polyamines putrescine, spermidine and spermine are essential for both normal and neoplastic cell function and replication. Dysregulation of metabolism of polyamines and their requirements is common in many cancers. Both clinical and experimental depletion of polyamines have demonstrated their metabolism to be a rational target for therapy; however, the mechanisms through which polyamines can establish a tumour-permissive microenvironment are only now emerging. Recent data indicate that polyamines can play a major role in regulating the antitumour immune response, thus likely contributing to the existence of immunologically 'cold' tumours that do not respond to immune checkpoint blockade. Additionally, the interplay between the microbiota and associated tissues creates a tumour microenvironment in which polyamine metabolism, content and function can all be dramatically altered on the basis of microbiota composition, dietary polyamine availability and tissue response to its surrounding microenvironment. The goal of this Perspective is to introduce the reader to the many ways in which polyamines, polyamine metabolism, the microbiota and the diet interconnect to establish a tumour microenvironment that facilitates the initiation and progression of cancer. It also details ways in which polyamine metabolism and function can be successfully targeted for therapeutic benefit, including specifically enhancing the antitumour immune response.

DOI: https://doi.org/10.1038/s41568-022-00473-2
Nat Cancer. 2022 Apr;3(4): 471-485

MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis.

Hamed Alborzinia, Andrés F Flórez, Sina Kreth, Lena M Brückner, Umut Yildiz, Moritz Gartlgruber, Dorett I Odoni, Gernot Poschet, Karolina Garbowicz, Chunxuan Shao, Corinna Klein, Jasmin Meier, Petra Zeisberger, Michal Nadler-Holly, Matthias Ziehm, Franziska Paul, Jürgen Burhenne, Emma Bell, Marjan Shaikhkarami, Roberto Würth, Sabine A Stainczyk, Elisa M Wecht, Jochen Kreth, Michael Büttner, Naveed Ishaque, Matthias Schlesner, Barbara Nicke, Carlo Stresemann, María Llamazares-Prada, Jan H Reiling, Matthias Fischer, Ido Amit, Matthias Selbach, Carl Herrmann, Stefan Wölfl, Kai-Oliver Henrich, Thomas Höfer, Andreas Trumpp, Frank Westermann.

Aberrant expression of MYC transcription factor family members predicts poor clinical outcome in many human cancers. Oncogenic MYC profoundly alters metabolism and mediates an antioxidant response to maintain redox balance. Here we show that MYCN induces massive lipid peroxidation on depletion of cysteine, the rate-limiting amino acid for glutathione (GSH) biosynthesis, and sensitizes cells to ferroptosis, an oxidative, non-apoptotic and iron-dependent type of cell death. The high cysteine demand of MYCN-amplified childhood neuroblastoma is met by uptake and transsulfuration. When uptake is limited, cysteine usage for protein synthesis is maintained at the expense of GSH triggering ferroptosis and potentially contributing to spontaneous tumor regression in low-risk neuroblastomas. Pharmacological inhibition of both cystine uptake and transsulfuration combined with GPX4 inactivation resulted in tumor remission in an orthotopic MYCN-amplified neuroblastoma model. These findings provide a proof of concept of combining multiple ferroptosis targets as a promising therapeutic strategy for aggressive MYCN-amplified tumors.

DOI: https://doi.org/10.1038/s43018-022-00355-4
Front Public Health. 2022 ;10 860381

Identification of a Four-Gene Metabolic Signature to Evaluate the Prognosis of Colon Adenocarcinoma Patients.

Yang Zheng, Rilige Wu, Ximo Wang, Chengliang Yin.

  Background: Colon adenocarcinoma (COAD) is a highly heterogeneous disease, thus making prognostic predictions uniquely challenging. Metabolic reprogramming is emerging as a novel cancer hallmark that may serve as the basis for more effective prognosis strategies.Methods: The mRNA expression profiles and relevant clinical information of COAD patients were downloaded from public resources. The least absolute shrinkage and selection operator (LASSO) Cox regression model was exploited to establish a prognostic model, which was performed to gain risk scores for multiple genes in The Cancer Genome Atlas (TCGA) COAD patients and validated in GSE39582 cohort. A forest plot and nomogram were constructed to visualize the data. The clinical nomogram was calibrated using a calibration curve coupled with decision curve analysis (DCA). The association between the model genes' expression and six types of infiltrating immunocytes was evaluated. Apoptosis, cell cycle assays and cell transfection experiments were performed.
Results: Univariate Cox regression analysis results indicated that ten differentially expressed genes (DEGs) were related with disease-free survival (DFS) (P-value< 0.01). A four-gene signature was developed to classify patients into high- and low-risk groups. And patients with high-risk exhibited obviously lower DFS in the training and validation cohorts (P < 0.05). The risk score was an independent parameter of the multivariate Cox regression analyses of DFS in the training cohort (HR > 1, P-value< 0.001). The same findings for overall survival (OS) were obtained GO enrichment analysis revealed several metabolic pathways with significant DEGs enrichment, G1/S transition of mitotic cell cycle, CD8+ T-cells and B-cells may be significantly associated with COAD in DFS and OS. These findings demonstrate that si-FUT1 inhibited cell migration and facilitated apoptosis in COAD.
Conclusion: This research reveals that a novel metabolic gene signature could be used to evaluate the prognosis of COAD, and targeting metabolic pathways may serve as a therapeutic alternative.

Keywords:  COAD; Cox; LASSO; metabolic; prognostic prediction; signature

DOI:  https://doi.org/10.3389/fpubh.2022.860381
J Nutr Biochem. 2022 Apr 21. pii: S0955-2863(22)00085-7. [Epub ahead of print] 109014

Patterns of Alpha-Linolenic Acid Incorporation into Phospholipids in H4IIE Cells.

Danielle Defries, Kayla Curtis, Jay C Petkau, Shiva Shariati-Ievari, Heather Blewett, Michel Aliani.

  Alpha linolenic acid (ALA) is an 18-carbon essential fatty acid found in plant-based foods and oils. While much attention has been placed on conversion of ALA to long chain polyunsaturated fatty acids, alternative routes of ALA metabolism exist and may lead to formation of other bioactive metabolites of ALA. The current study employed a non-targeted metabolomics approach to profile ALA metabolites that are significantly upregulated by ALA treatment. H4IIE hepatoma cells (n=3 samples per time point) were treated with 60 μM ALA or vehicle for 0, 0.25, 0.5, 1, 2, 3, 4, 6, 8, and 12 hours. Samples were then extracted with methanol and analyzed using high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. We observed selective changes in ALA incorporation into phospholipid classes and subclasses over the 12 hours following ALA treatment. While levels of specific molecular species of ALA-containing phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and lysophospholipids were elevated with ALA treatment, others were not affected. Of the phospholipids that were increased, some [e.g. PC(18:3/18:1), PC(18:3/18:4), PE(18:3/18:2), PE(18:3/18:3)] were elevated almost immediately after exposure to ALA, while others (e.g. PE(18:1/18:3) PA(18:3/22:6), and PA(18:3/18:2)] were not elevated until several hours after ALA treatment. Overall, these results suggest that ALA incorporation into phospholipids is selective and support a metabolic hierarchy for ALA incorporation into specific phospholipids. Given the functionality of phospholipids based on their fatty acid composition, future studies will need to investigate the implications of ALA incorporation into specific phospholipids on cell function.

Keywords:  Alpha-linolenic acid; H4IIE cells; metabolomics; phosphatidylcholine; phosphatidylethanolamine; phospholipid metabolism

DOI:  https://doi.org/10.1016/j.jnutbio.2022.109014
RSC Adv. 2021 Jul 01. 11(38): 23791-23800

Untargeted metabolomic and lipid metabolism-related gene expression analyses of the effects and mechanism of aged Liupao tea treatment in HFD-induced obese mice.

Wenliang Wu, Yao Hu, Shuguang Zhang, Dongming Liu, Qing Li, Yong Lin, Zhonghua Liu.

Liupao tea (LPT) has been demonstrated to have beneficial effects on obesity induced by a high-fat diet (HFD); however, the effects and mechanism of aged Liupao tea (different storage years) treatment on obesity have not yet been reported. In this study, mice were divided into four groups as follows: the control group fed a normal diet; the model group fed an HFD; and the LPT aged 1 year (1Y) and LPT aged 10 years (10Y) groups receiving an HFD and water extractions from LPTs of different ages for 5 weeks. Our results revealed that aged LPT significantly alleviated HFD-induced obesity symptoms, especially in the 10Y group. Additionally, metabolomic analysis identified 11 common differential metabolites that were partly recovered to normal levels after aged LPT treatment, involved mainly in the metabolic pathways of the citrate cycle, purine metabolism, fatty acid metabolism, and amino acid metabolism. Aged LPT treatment also regulated lipid metabolism-related gene expression in the liver, which decreased the mRNA levels of SREBP-1C/HMGR/FAS involved in de novo lipogenesis and increased the mRNA levels of PPARα, LDLR and LCAT. Our study demonstrated that aged LPT may be used as a potential dietary supplement for improving obesity-related diseases caused by an HFD.

DOI: https://doi.org/10.1039/d1ra04438a
J Nanobiotechnology. 2022 Apr 26. 20(1): 199

Metal ions/nucleotide coordinated nanoparticles comprehensively suppress tumor by synergizing ferroptosis with energy metabolism interference.

Yanqiu Wang, Jie Chen, Jianxiu Lu, Juqun Xi, Zhilong Xu, Lei Fan, Hua Dai, Lizeng Gao.

  BACKGROUND: Ferroptosis holds promise as a potential tumor therapy by programming cell death with a hallmark of reactive oxygen species (ROS)-induced lipid peroxidation. However, vigorous energy metabolism may assist tumors to resist oxidative damage and thus weaken the effects of ferroptosis in tumor treatment.RESULTS: Herein, a bifunctional antitumor platform was constructed via coordinated interactions between metal ions and nucleotides to synergistically activate ferroptosis and interrupt energy metabolism for tumor therapy. The designed nanoparticles were composed of Fe2+/small interfering RNA (siRNA) as the core and polydopamine as the cloak, which responded to the tumor microenvironment with structural dissociation, thereby permitting tumor-specific Fe2+ and siRNA release. The over-loaded Fe2+ ions in the tumor cells then triggered ferroptosis, with hallmarks of lipid peroxidation and cellular glutathione peroxidase 4 (GPX4) down-regulation. Simultaneously, the released siRNA targeted and down-regulated glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression in the tumor to inhibit glycolytic pathway, which interfered with tumor energy metabolism and enhanced Fe2+-induced ferroptosis to kill tumor cells.
CONCLUSIONS: This study presents a concise fabrication of a metal ion/nucleotide-based platform to integrate ferroptosis and energy metabolism intervention in one vehicle, thereby providing a promising combination modality for anticancer therapy.

Keywords:  Cancer synergistic therapy; Energy metabolic interference; GAPDH siRNA; Metal ion–nucleotide interaction; Nano ferroptosis inducers

DOI:  https://doi.org/10.1186/s12951-022-01405-w
Soft Matter. 2022 Apr 27.

Subtle changes in pH affect the packing and robustness of fatty acid bilayers.

Lauren A Lowe, James T Kindt, Charles Cranfield, Bruce Cornell, Alexander Macmillan, Anna Wang.

Connecting molecular interactions to emergent properties is a goal of physical chemistry, self-assembly, and soft matter science. We show that for fatty acid bilayers, vesicle rupture tension, and permeability to water and ions are coupled to pH via alterations to lipid packing. A change in pH of one, for example, can halve the rupture tension of oleic acid membranes, an effect that is comparable to increasing lipid unsaturation in phospholipid systems. We use both experiments and molecular dynamics simulations to reveal that a subtle increase in pH can lead to increased water penetration, ion permeability, pore formation rates, and membrane disorder. For changes in membrane water content, oleic acid membranes appear to be more than a million times more sensitive to protons than to sodium ions. The work has implications for systems in which fatty acids are likely to be found, for example in the primitive cells on early Earth, biological membranes especially during digestion, and other biomaterials.

DOI: https://doi.org/10.1039/d2sm00272h
Nat Chem Biol. 2022 May;18(5): 461-469

Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel.

Michael P Murphy, Edward T Chouchani.

Metabolites once considered solely in catabolism or anabolism turn out to have key regulatory functions. Among these, the citric acid cycle intermediate succinate stands out owing to its multiple roles in disparate pathways, its dramatic concentration changes and its selective cell release. Here we propose that succinate has evolved as a signaling modality because its concentration reflects the coenzyme Q (CoQ) pool redox state, a central redox couple confined to the mitochondrial inner membrane. This connection is of general importance because CoQ redox state integrates three bioenergetic parameters: mitochondrial electron supply, oxygen tension and ATP demand. Succinate, by equilibrating with the CoQ pool, enables the status of this central bioenergetic parameter to be communicated from mitochondria to the rest of the cell, into the circulation and to other cells. The logic of this form of regulation explains many emerging roles of succinate in biology, and suggests future research questions.

DOI: https://doi.org/10.1038/s41589-022-01004-8
Curr Drug Deliv. 2022 Apr 26.

Macrophage-mediated delivery of Fe3O4-nanoparticles: a generalized strategy to deliver iron to Tumor Microenvironment.

Cong Wu, Guozhong Zhang, Zhihao Wang, Hongcan Shi.

  Background：Iron are used to alter macrophage phenotypes and induce tumor cell death. Iron oxide nanoparticles can induce macrophage polarization into the M1 phenotype, which inhibits tumor growth and can dissociate into iron ions in macrophages. Objective：In this study, we proposed to construct high expression of Ferroportin1 macrophages as carriers to deliver Fe3O4-nanoparticles and iron directly to tumor sites.METHODS: Three sizes of Fe3O4-nanoparticles with gradient concentrations were used. The migration ability of iron-carrying macrophages was confirmed by an in vitro migration experiment and monocyte chemoattractant protein-1 detection. The release of iron from macrophages was confirmed by determining their levels in the cell culture supernatant, and we constructed a high expression of ferroportin strain of macrophage lines to increase intracellular iron efflux by increasing membrane transferrin expression. Fe3O4-NPs in Ana-1 cells were degraded in lysosomes, and the amount of iron released was correlated with the expression of ferroportin1.
RESULTS: After Fe3O4-nanoparticles uptake by macrophages, not only polarized macrophages into M1 phenotype, but the nanoparticles also dissolved in the lysosome and iron were released out of the cell. FPN1 has known as the only known Fe transporter, we use Lentiviral vector carrying FPN1 gene transfected into macrophages, has successfully constructed Ana-1-FPN1 cells, and maintains high expression of FPN1. Ana-1-FPN1 cells increases intracellular iron release. Fe3O4-nanoparticles loaded engineered Ana-1 macrophages can act as a "reservoir" of iron.
CONCLUSION: Our study provides proof of strategy for Fe3O4-NPs target delivery to the tumor microenvironment. Moreover, increase of intracellular iron efflux by overexpression of FPN1, cell carriers can act as a reservoir for iron, providing the basis for targeted delivery of Fe3O4-NPs and iron ions in vivo.

Keywords:  Fe3O4-nanoparticles; cell carrier; ferroportin1; lentiviral transfection.; macrophage; polarization

DOI:  https://doi.org/10.2174/1567201819666220426085450
Cell Rep. 2022 Apr 26. pii: S2211-1247(22)00494-6. [Epub ahead of print]39(4): 110733

Silencing alanine transaminase 2 in diabetic liver attenuates hyperglycemia by reducing gluconeogenesis from amino acids.

Michael R Martino, Manuel Gutiérrez-Aguilar, Nicole K H Yiew, Andrew J Lutkewitte, Jason M Singer, Kyle S McCommis, Daniel Ferguson, Kim H H Liss, Jun Yoshino, M Katie Renkemeyer, Gordon I Smith, Kevin Cho, Justin A Fletcher, Samuel Klein, Gary J Patti, Shawn C Burgess, Brian N Finck.

  Hepatic gluconeogenesis from amino acids contributes significantly to diabetic hyperglycemia, but the molecular mechanisms involved are incompletely understood. Alanine transaminases (ALT1 and ALT2) catalyze the interconversion of alanine and pyruvate, which is required for gluconeogenesis from alanine. We find that ALT2 is overexpressed in the liver of diet-induced obese and db/db mice and that the expression of the gene encoding ALT2 (GPT2) is downregulated following bariatric surgery in people with obesity. The increased hepatic expression of Gpt2 in db/db liver is mediated by activating transcription factor 4, an endoplasmic reticulum stress-activated transcription factor. Hepatocyte-specific knockout of Gpt2 attenuates incorporation of 13C-alanine into newly synthesized glucose by hepatocytes. In vivo Gpt2 knockdown or knockout in liver has no effect on glucose concentrations in lean mice, but Gpt2 suppression alleviates hyperglycemia in db/db mice. These data suggest that ALT2 plays a significant role in hepatic gluconeogenesis from amino acids in diabetes.

Keywords:  ATF4; CP: Metabolism; GPT2; amino acids; gluconeogenesis; liver

DOI:  https://doi.org/10.1016/j.celrep.2022.110733
Methods Mol Biol. 2022 ;2504 157-173

Lipidomic Analysis of Extracellular Vesicles Isolated from Human Plasma and Serum.

Yuchen Sun, Kosuke Saito, Yoshiro Saito.

  Lipidomics is an omics approach to comprehensively study lipid profiles in biological samples, such as plasma, serum, urine, and tissue specimens. Moreover, lipidomic analyses are useful for identifying novel lipid biomarkers, especially for various metabolic and malignant diseases in humans. Extracellular vesicles (EVs) are lipid bilayer-encapsulated nanoparticles secreted from various cells into the extracellular space. In particular, circulating EVs in the blood stream have attracted considerable research interest as they are considered the fingerprint of the cells from which they are secreted and are a promising source for less-invasive biomarker screening. Here, we describe the entire workflow for the lipidomic analysis of circulating EVs, including the methods for their purification from human plasma and serum, liquid chromatography coupled with high-resolution mass spectrometry-based lipid measurement, and data analyses for profiling EV lipids. Using this methodological workflow, over 260 lipid molecules belonging to the glycerophospholipid and sphingolipid groups can be detected.

Keywords:  Extracellular vesicles; Lipid biomarkers; Lipidomics; Liquid biopsy; Liquid chromatography coupled with high-resolution mass spectrometry

DOI:  https://doi.org/10.1007/978-1-0716-2341-1_12
Int Rev Cell Mol Biol. 2022 ;pii: S1937-6448(22)00032-6. [Epub ahead of print]367 183-208

Endometrial macrophages in health and disease.

Erin Brown, Rocío Martínez-Aguilar, Jacqueline A Maybin, Douglas A Gibson.

  Macrophages are present in the endometrium throughout the menstrual cycle and are most abundant during menstruation. Endometrial macrophages contribute to tissue remodeling during establishment of pregnancy and are thought to play key roles in mediating tissue breakdown and repair during menstruation. Despite these important roles, the phenotype and function of endometrial macrophages remains poorly understood. In this review, we summarize approaches used to characterize endometrial macrophage phenotype, current understanding of the functional role of macrophages in normal endometrial physiology as well as the putative contribution of macrophage dysfunction to women's reproductive health disorders.

Keywords:  Abnormal uterine bleeding; Endometriosis; Endometrium; Heavy menstrual bleeding; Macrophage; Menstruation; Uterus

DOI:  https://doi.org/10.1016/bs.ircmb.2022.03.011
Front Immunol. 2022 ;13 861328

Crosstalk Between Metabolism and Immune Activity Reveals Four Subtypes With Therapeutic Implications in Clear Cell Renal Cell Carcinoma.

Yi Wang, Xin-De Zheng, Gui-Qi Zhu, Na Li, Chang-Wu Zhou, Chun Yang, Meng-Su Zeng.

  Clear cell renal cell carcinoma (ccRCC) is characterized by metabolic dysregulation and distinct immunological signatures. The interplay between metabolic and immune processes in the tumor microenvironment (TME) causes the complexity and heterogeneity of immunotherapy responses observed during ccRCC treatment. Herein, we initially identified two distinct metabolic subtypes (C1 and C2 subtypes) and immune subtypes (I1 and I2 subtypes) based on the occurrence of differentially expressed metabolism-related prognostic genes and immune-related components. Notably, we observed that immune regulators with upregulated expression actively participated in multiple metabolic pathways. Therefore, we further delineated four immunometabolism-based ccRCC subtypes (M1, M2, M3, and M4 subtypes) according to the results of the above classification. Generally, we found that high metabolic activity could suppress immune infiltration. Immunometabolism subtype classification was associated with immunotherapy response, with patients possessing the immune-inflamed, metabolic-desert subtype (M3 subtype) that benefits the most from immunotherapy. Moreover, differences in the shifts in the immunometabolism subtype after immunotherapy were observed in the responder and non-responder groups, with patients from the responder group transferring to subtypes with immune-inflamed characteristics and less active metabolic activity (M3 or M4 subtype). Immunometabolism subtypes could also serve as biomarkers for predicting immunotherapy response. To decipher the genomic and epigenomic features of the four subtypes, we analyzed multiomics data, including miRNA expression, DNA methylation status, copy number variations occurrence, and somatic mutation profiles. Patients with the M2 subtype possessed the highest VHL gene mutation rates and were more likely to be sensitive to sunitinib therapy. Moreover, we developed non-invasive radiomic models to reveal the status of immune activity and metabolism. In addition, we constructed a radiomic prognostic score (PRS) for predicting ccRCC survival based on the seven radiomic features. PRS was further demonstrated to be closely linked to immunometabolism subtype classification, immune score, and tumor mutation burden. The prognostic value of the PRS and the association of the PRS with immune activity and metabolism were validated in our cohort. Overall, our study established four immunometabolism subtypes, thereby revealing the crosstalk between immune and metabolic activities and providing new insights into personal therapy selection.

Keywords:  immune activity; immunotherapy; metabolism; muti-omics analysis; radiomic analysis

DOI:  https://doi.org/10.3389/fimmu.2022.861328