bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2022‒11‒13
twelve papers selected by
Linda Chan
Yale University
  1. Metabolite activation of tumorigenic signaling pathways in the tumor microenvironment.
  2. Ferroptosis: a double-edged sword mediating immune tolerance of cancer.
  3. Probabilistic model checking of cancer metabolism.
  4. CD1d-dependent rewiring of lipid metabolism in macrophages regulates innate immune responses.
  5. The cross talk between cancer cells and their microenvironments.
  6. Keratinocyte-induced costimulation of human T cells through CD6 - but not CD2 - activates mTOR and prevents oxidative stress.
  7. Single cell sequencing reveals that CD39 inhibition mediates changes to the tumor microenvironment.
  8. Anti-neoplastic sulfonamides alter the metabolic homeostasis and disrupt the suppressor activity of regulatory T cells.
  9. Fatty acid metabolism predicts prognosis and NK cell immunosurveillance of acute myeloid leukemia patients.
  10. Secreted immune metabolites that mediate immune cell communication and function.
  11. Combining bulk RNA-sequencing and single-cell RNA-sequencing data to reveal the immune microenvironment and metabolic pattern of osteosarcoma.
  12. SLC7A8 is a key amino acids supplier for the metabolic programs that sustain homeostasis and activation of type 2 innate lymphoid cells.
  1. Sci Signal. 2022 Nov 08. 15(759): eabj4220
    Metabolite activation of tumorigenic signaling pathways in the tumor microenvironment.
    Vivien Low, Zhongchi Li, John Blenis.
      The role of metabolites exchanged in the tumor microenvironment is largely thought of as fuels to drive the increased biosynthetic and bioenergetic demands of growing tumors. However, this view is shifting as metabolites are increasingly shown to function as signaling molecules that directly regulate oncogenic pathways. Combined with our growing understanding of the essential role of stromal cells, this shift has led to increased interest in how the collective and interconnected metabolome of the tumor microenvironment can drive malignant transformation, epithelial-to-mesenchymal transition, drug resistance, immune evasion, and metastasis. In this review, we discuss how metabolite exchange between tumors and various cell types in the tumor microenvironment-such as fibroblasts, adipocytes, and immune cells-can activate signaling pathways that drive cancer progression.
    DOI:  https://doi.org/10.1126/scisignal.abj4220
  2. Cell Death Dis. 2022 Nov 05. 13(11): 925
    Ferroptosis: a double-edged sword mediating immune tolerance of cancer.
    Qin Dang, Ziqi Sun, Yang Wang, Libo Wang, Zaoqu Liu, Xinwei Han.
      The term ferroptosis was put forward in 2012 and has been researched exponentially over the past few years. Ferroptosis is an unconventional pattern of iron-dependent programmed cell death, which belongs to a type of necrosis and is distinguished from apoptosis and autophagy. Actuated by iron-dependent phospholipid peroxidation, ferroptosis is modulated by various cellular metabolic and signaling pathways, including amino acid, lipid, iron, and mitochondrial metabolism. Notably, ferroptosis is associated with numerous diseases and plays a double-edged sword role. Particularly, metastasis-prone or highly-mutated tumor cells are sensitive to ferroptosis. Hence, inducing or prohibiting ferroptosis in tumor cells has vastly promising potential in treating drug-resistant cancers. Immunotolerant cancer cells are not sensitive to the traditional cell death pathway such as apoptosis and necroptosis, while ferroptosis plays a crucial role in mediating tumor and immune cells to antagonize immune tolerance, which has broad prospects in the clinical setting. Herein, we summarized the mechanisms and delineated the regulatory network of ferroptosis, emphasized its dual role in mediating immune tolerance, proposed its significant clinical benefits in the tumor immune microenvironment, and ultimately presented some provocative doubts. This review aims to provide practical guidelines and research directions for the clinical practice of ferroptosis in treating immune-resistant tumors.
    DOI:  https://doi.org/10.1038/s41419-022-05384-6
  3. Sci Rep. 2022 Nov 07. 12(1): 18870
    Probabilistic model checking of cancer metabolism.
    Meir D Friedenberg, Adrian Lita, Mark R Gilbert, Mioara Larion, Orieta Celiku.
      Cancer cell metabolism is often deregulated as a result of adaption to meeting energy and biosynthesis demands of rapid growth or direct mutation of key metabolic enzymes. Better understanding of such deregulation can provide new insights on targetable vulnerabilities, but is complicated by the difficulty in probing cell metabolism at different levels of resolution and under different experimental conditions. We construct computational models of glucose and glutamine metabolism with focus on the effect of IDH1/2-mutations in cancer using a combination of experimental metabolic flux data and patient-derived gene expression data. Our models demonstrate the potential of computational exploration to reveal biologic behavior: they show that an exogenously-mutated IDH1 experimental model utilizes glutamine as an alternative carbon source for lactate production under hypoxia, but does not fully-recapitulate the patient phenotype under normoxia. We also demonstrate the utility of using gene expression data as a proxy for relative differences in metabolic activity. We use the approach of probabilistic model checking and the freely-available Probabilistic Symbolic Model Checker to construct and reason about model behavior.
    DOI:  https://doi.org/10.1038/s41598-022-21846-5
  4. Nat Commun. 2022 Nov 07. 13(1): 6723
    CD1d-dependent rewiring of lipid metabolism in macrophages regulates innate immune responses.
    Phillip M Brailey, Lauren Evans, Juan Carlos López-Rodríguez, Anthony Sinadinos, Victoria Tyrrel, Gavin Kelly, Valerie O'Donnell, Peter Ghazal, Susan John, Patricia Barral.
      Alterations in cellular metabolism underpin macrophage activation, yet little is known regarding how key immunological molecules regulate metabolic programs in macrophages. Here we uncover a function for the antigen presenting molecule CD1d in the control of lipid metabolism. We show that CD1d-deficient macrophages exhibit a metabolic reprogramming, with a downregulation of lipid metabolic pathways and an increase in exogenous lipid import. This metabolic rewiring primes macrophages for enhanced responses to innate signals, as CD1d-KO cells show higher signalling and cytokine secretion upon Toll-like receptor stimulation. Mechanistically, CD1d modulates lipid import by controlling the internalization of the lipid transporter CD36, while blocking lipid uptake through CD36 restores metabolic and immune responses in macrophages. Thus, our data reveal CD1d as a key regulator of an inflammatory-metabolic circuit in macrophages, independent of its function in the control of T cell responses.
    DOI:  https://doi.org/10.1038/s41467-022-34532-x
  5. Biochem Biophys Res Commun. 2022 Dec 10. pii: S0006-291X(22)01323-7. [Epub ahead of print]633 59-60
    The cross talk between cancer cells and their microenvironments.
    Isaac P Witz.
      
    DOI:  https://doi.org/10.1016/j.bbrc.2022.09.066
  6. Front Immunol. 2022 ;13 1016112
    Keratinocyte-induced costimulation of human T cells through CD6 - but not CD2 - activates mTOR and prevents oxidative stress.
    Christian Orlik, Karina M Berschneider, Beate Jahraus, Beate Niesler, Emre Balta, Knut Schäkel, Jutta Schröder-Braunstein, Maria Margarida Souto-Carneiro, Yvonne Samstag.
      In psoriasis and other inflammatory skin diseases, keratinocytes (KCs) secrete chemokines that attract T cells, which, in turn, cause epidermal hyperplasia by secreting proinflammatory cytokines. To date, it remains unclear whether skin-homing T cells, particularly memory T cells, can also be activated by direct cell contact with KCs. In this study, we demonstrated the ability of primary human KCs to activate human memory T cells directly by transmitting costimulatory signals through the CD6/CD166/CD318 axis. Interestingly, despite being negative for CD80/CD86, KCs initiate a metabolic shift within T cells. Blockade of the CD6/CD166/CD318 axis prevents mammalian target of rapamycin activation and T cell proliferation but promotes oxidative stress and aerobic glycolysis. In addition, it diminishes formation of central memory T cells. Importantly, although KC-mediated costimulation by CD2/CD58 also activates T cells, it cannot compensate for the lack of CD6 costimulation. Therefore, KCs likely differentially regulate T cell functions in the skin through two distinct costimulatory receptors: CD6 and CD2. This may at least in part explain the divergent effects observed when treating inflammatory skin diseases with antibodies to CD6 versus CD2. Moreover, our findings may provide a molecular basis for selective interference with either CD6/CD166/CD318, or CD2/CD58, or both to specifically treat different types of inflammatory skin diseases.
    Keywords:  CD6/CD166/CD318; GvHD; T cell costimulation; T cell metabolism; inflammatory skin diseases; keratinocytes; non-professional antigen-presenting cells; psoriasis
    DOI:  https://doi.org/10.3389/fimmu.2022.1016112
  7. Nat Commun. 2022 Nov 08. 13(1): 6740
    Single cell sequencing reveals that CD39 inhibition mediates changes to the tumor microenvironment.
    Lilong Liu, Yaxin Hou, Changqi Deng, Zhen Tao, Zhaohui Chen, Junyi Hu, Ke Chen.
      Single-cell sequencing technologies have noteworthily improved our understanding of the genetic map and molecular characteristics of bladder cancer (BC). Here we identify CD39 as a potential therapeutic target for BC via single-cell transcriptome analysis. In a subcutaneous tumor model and orthotopic bladder cancer model, inhibition of CD39 (CD39i) by sodium polyoxotungstate is able to limit the growth of BC and improve the overall survival of tumor-bearing mice. Via single cell RNA sequencing, we find that CD39i increase the intratumor NK cells, conventional type 1 dendritic cells (cDC1) and CD8 + T cells and decrease the Treg abundance. The antitumor effect and reprogramming of the tumor microenvironment are blockaded in both the NK cells depletion model and the cDC1-deficient Batf3-/- model. In addition, a significant synergistic effect is observed between CD39i and cisplatin, but the CD39i + anti-PD-L1 (or anti-PD1) strategy does not show any synergistic effects in the BC model. Our results confirm that CD39 is a potential target for the immune therapy of BC.
    DOI:  https://doi.org/10.1038/s41467-022-34495-z
  8. Sci Rep. 2022 Nov 09. 12(1): 19112
    Anti-neoplastic sulfonamides alter the metabolic homeostasis and disrupt the suppressor activity of regulatory T cells.
    Roberto Gedaly, Virgilius Cornea, Lilia Turcios, Jacob S Edmisson, Dwight D Harris, David S Watt, Fanny Chapelin, Aman Khurana, Xiaonan Mei, Chunming Liu, Isaac Taylor, Juan Gonzalez-Valdivieso, Hunter Mitchel, Alexis Ruffing, Asir Chishti, Gabriel Orozco, Joseph Zwischenberger, B Mark Evers, Francesc Marti.
      Regulatory T cells (Tregs) are essential to maintain self-tolerance and immune homeostasis but, as components of the tumor microenvironment (TME), are also a major barrier to effective cancer immunosurveillance and immunotherapy. FH535 and its derivative Y3 are two N-aryl-benzene-sulfonamides (NABs) that inhibit HCC cell proliferation and tumor progression. However, the impact of NABs on the immune cells in the TME is not yet known. Analyses of explanted livers from patients with hepatocellular carcinoma (HCC) showed that high levels of tumor-infiltrating Tregs were associated with poor tumor differentiation. These results lead us to investigate the immunomodulatory effects of NABs in regulatory and effector T cells. Exposure of primary human Tregs to NABs induced a rapid but temporary increase of cell expansion, a gradual disruption of suppressor activity, and concomitant bioenergetics and autophagic flux dysregulations. In contrast to Tregs, no gross effects were observed in effector T cells. Addition of Rapamycin prevented the functional decay of Tregs and restored their metabolic profile, suggesting that NAB effects require the integrity of the mTOR pathway. This study revealed the immunomodulatory properties of NABs with a preferential impact on Treg activity and provided novel insights into the anti-tumor potential of sulfonamides.
    DOI:  https://doi.org/10.1038/s41598-022-23601-2
  9. Front Oncol. 2022 ;12 1018154
    Fatty acid metabolism predicts prognosis and NK cell immunosurveillance of acute myeloid leukemia patients.
    Zhitao Ye, Yishan Li, Xiaobin Tian, Yan Wei, Yanhui Yu, Kaibin Lai, Keyue Yang, Zixuan Qiu, Jianqing Lin, Meng Zhao, Dongjun Lin, Xiaojun Xu.
      Background: Cell metabolic reprogramming is a hallmark of tumor prognosis, and fatty acid metabolism (FAM) plays a crucial role in the tumor microenvironment (TME). However, the relationship between FAM, TME, and prognosis of acute myeloid leukemia (AML) patients remains elusive.Methods: We extracted the single-cell RNA sequencing (scRNA-Seq) and bulk transcriptome data of AML patients from the TCGA and GEO databases and assessed the relationship between FAM, TME, and AML patient prognosis. We also performed functional enrichment (FE) assay to evaluate the significance of FAM in anti-AML immunosurveillance.
    Results: Our scRNA-Seq analysis revealed that the leukemic stem cell (LSC)-enriched population exhibited elevated levels of FAM-related genes. Using these FAM-related genes, we developed a prognostic model that accurately estimated AML patient outcome. FE analysis showed that FAM was strongly related to alterations of TME-based immunosurveillance in AML patients. More importantly, we demonstrated that FAM inhibition via pharmaceutical targeting of PLA2G4A, a highly expressed FAM gene in AML patients with poor prognosis, enhanced the NK cell-mediated immunosurveillance in leukemia cells.
    Conclusions: Leukemic stem cell (LSC)-enriched population exhibited elevated levels of FAM-related genes. We have successfully established the FAM formula that predicts AML patient prognosis and alterations in the TME-based immunosurveillance. We also found that PLA2G4A was a highly expressed FAM gene in AML patients with poor prognoses. Pharmaceutical targeting of PLA2G4A increased the expression of NKG2DL in leukemia cells in vitro and thus enhanced the NK cell-mediated immunosurveillance.
    Keywords:  NK cells; acute myeloid leukemia; fatty acid metabolism; prognostic model; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.1018154
  10. Trends Immunol. 2022 Nov 05. pii: S1471-4906(22)00214-9. [Epub ahead of print]
    Secreted immune metabolites that mediate immune cell communication and function.
    Baihao Zhang, Alexis Vogelzang, Sidonia Fagarasan.
      Metabolites are emerging as essential factors for the immune system that are involved in both metabolic circuits and signaling cascades. Accumulated evidence suggests that altered metabolic programs initiated by the activation and maturation of immune cell types are accompanied by the delivery of various metabolites into the local environment. We propose that, in addition to protein/peptide ligands, secreted immune metabolites (SIMets) are essential components of immune communication networks that fine-tune immune responses under homeostatic and pathological conditions. We summarize recent advances in our understanding of SIMets and discuss the potential mechanisms by which some metabolites engage in immunological responses through receptor-, transporter-, and post-translational-mediated regulation. These insights may contribute to understanding physiology and developing effective therapeutics for inflammatory and immune-mediated diseases.
    Keywords:  flux of metabolites; immune cell subsets; modification; receptor; transporter
    DOI:  https://doi.org/10.1016/j.it.2022.10.006
  11. Front Genet. 2022 ;13 976990
    Combining bulk RNA-sequencing and single-cell RNA-sequencing data to reveal the immune microenvironment and metabolic pattern of osteosarcoma.
    Ruichao Huang, Xiaohu Wang, Xiangyun Yin, Yaqi Zhou, Jiansheng Sun, Zhongxiu Yin, Zhi Zhu.
      Background: Osteosarcoma (OS) is a kind of solid tumor with high heterogeneity at tumor microenvironment (TME), genome and transcriptome level. In view of the regulatory effect of metabolism on TME, this study was based on four metabolic models to explore the intertumoral heterogeneity of OS at the RNA sequencing (RNA-seq) level and the intratumoral heterogeneity of OS at the bulk RNA-seq and single cell RNA-seq (scRNA-seq) level. Methods: The GSVA package was used for single-sample gene set enrichment analysis (ssGSEA) analysis to obtain a glycolysis, pentose phosphate pathway (PPP), fatty acid oxidation (FAO) and glutaminolysis gene sets score. ConsensusClusterPlus was employed to cluster OS samples downloaded from the Target database. The scRNA-seq and bulk RNA-seq data of immune cells from GSE162454 dataset were analyzed to identify the subsets and types of immune cells in OS. Malignant cells and non-malignant cells were distinguished by large-scale chromosomal copy number variation. The correlations of metabolic molecular subtypes and immune cell types with four metabolic patterns, hypoxia and angiogenesis were determined by Pearson correlation analysis. Results: Two metabolism-related molecular subtypes of OS, cluster 1 and cluster 2, were identified. Cluster 2 was associated with poor prognosis of OS, active glycolysis, FAO, glutaminolysis, and bad TME. The identified 28608 immune cells were divided into 15 separate clusters covering 6 types of immune cells. The enrichment scores of 5 kinds of immune cells in cluster-1 and cluster-2 were significantly different. And five kinds of immune cells were significantly correlated with four metabolic modes, hypoxia and angiogenesis. Of the 28,608 immune cells, 7617 were malignant cells. The four metabolic patterns of malignant cells were significantly positively correlated with hypoxia and negatively correlated with angiogenesis. Conclusion: We used RNA-seq to reveal two molecular subtypes of OS with prognosis, metabolic pattern and TME, and determined the composition and metabolic heterogeneity of immune cells in OS tumor by bulk RNA-seq and single-cell RNA-seq.
    Keywords:  bulk RNA sequencing; metabolism; osteosarcoma; single cell RNA sequencing; tumor microenvironment
    DOI:  https://doi.org/10.3389/fgene.2022.976990
  12. Proc Natl Acad Sci U S A. 2022 11 16. 119(46): e2215528119
    SLC7A8 is a key amino acids supplier for the metabolic programs that sustain homeostasis and activation of type 2 innate lymphoid cells.
    Santosh K Panda, Do-Hyun Kim, Pritesh Desai, Patrick F Rodrigues, Raki Sudan, Susan Gilfillan, Marina Cella, Steven J Van Dyken, Marco Colonna.
      Group 2 innate lymphoid cells (ILC2) are innate counterparts of T helper 2 (Th2) cells that maintain tissue homeostasis and respond to injuries through rapid interleukin (IL)-5 and IL-13 secretion. ILC2s depend on availability of arginine and branched-chain amino acids for sustaining cellular fitness, proliferation, and cytokine secretion in both steady state and upon activation. However, the contribution of amino acid transporters to ILC2 functions is not known. Here, we found that ILC2s selectively express <i>Slc7a8</i>, encoding a transporter for arginine and large amino acids. <i>Slc7a8</i> was expressed in ILC2s in a tissue-specific manner in steady state and was further increased upon activation. Genetic ablation of <i>Slc7a8</i> in lymphocytes reduced the frequency of ILC2s, suppressed IL-5 and IL-13 production upon stimulation, and impaired type 2 immune responses to helminth infection. Consistent with this, <i>Slc7a8-</i>deficient ILC2s also failed to induce cytokine production and recruit eosinophils in a model of allergic lung inflammation. Mechanistically, reduced amino acid availability due to <i>Slc7a8</i> deficiency led to compromised mitochondrial oxidative phosphorylation, as well as impaired activation of mammalian target of rapamycin and c-Myc signaling pathways. These findings identify <i>Slc7a8</i> as a key supplier of amino acids for the metabolic programs underpinning fitness and activation of ILC2s.
    Keywords:  allergy; amino acid; asthma; innate lymphoid cells; transporter
    DOI:  https://doi.org/10.1073/pnas.2215528119
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