bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2022–11–06
ten papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Hypoxia-driven metabolic reprogramming of adipocytes fuels cancer cell proliferation.
  2. Branched-chain ketoacids derived from cancer cells modulate macrophage polarization and metabolic reprogramming.
  3. Lactic acid and lactate: revisiting the physiological roles in the tumor microenvironment.
  4. NetrinG1+ cancer-associated fibroblasts generate unique extracellular vesicles that support the survival of pancreatic cancer cells under nutritional stress.
  5. The emerging role for metabolism in fueling neutrophilic inflammation.
  6. Lactate from the tumor microenvironment - A key obstacle in NK cell-based immunotherapies.
  7. High tumor hexokinase-2 expression promotes a pro-tumorigenic immune microenvironment by modulating CD8+/regulatory T-cell infiltration.
  8. Spermidine Supplementation Enhances Immune Checkpoint Blockade Response.
  9. Translational alterations in pancreatic cancer: a central role for the integrated stress response.
  10. Stress response protein REDD1 promotes diabetes-induced retinal inflammation by sustaining canonical NF-κB signaling.
  1. Front Endocrinol (Lausanne). 2022 ;13 989523
    Hypoxia-driven metabolic reprogramming of adipocytes fuels cancer cell proliferation.
    R Aird, J Wills, K F Roby, C Bénézech, R H Stimson, M Wabitsch, J W Pollard, A Finch, Z Michailidou.
       Objective: Obesity increases the risk of certain cancers, especially tumours that reside close to adipose tissue (breast and ovarian metastasis in the omentum). The obesogenic and tumour micro-environment share a common pathogenic feature, oxygen deprivation (hypoxia). Here we test how hypoxia changes the metabolome of adipocytes to assist cancer cell growth.
    Methods: Human and mouse breast and ovarian cancer cell lines were co-cultured with human and mouse adipocytes respectively under normoxia or hypoxia. Proliferation and lipid uptake in cancer cells were measured by commercial assays. Metabolite changes under normoxia or hypoxia were measured in the media of human adipocytes by targeted LC/MS.
    Results: Hypoxic cancer-conditioned media increased lipolysis in both human and mouse adipocytes. This led to increased transfer of lipids to cancer cells and consequent increased proliferation under hypoxia. These effects were dependent on HIF1α expression in adipocytes, as mouse adipocytes lacking HIF1α showed blunted responses under hypoxic conditions. Targeted metabolomics of the human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes media revealed that culture with hypoxic-conditioned media from non-malignant mammary epithelial cells (MCF10A) can alter the adipocyte metabolome and drive proliferation of the non-malignant cells.
    Conclusion: Here, we show that hypoxia in the adipose-tumour microenvironment is the driving force of the lipid uptake in both mammary and ovarian cancer cells. Hypoxia can modify the adipocyte metabolome towards accelerated lipolysis, glucose deprivation and reduced ketosis. These metabolic shifts in adipocytes could assist both mammary epithelial and cancer cells to bypass the inhibitory effects of hypoxia on proliferation and thrive.
    Keywords:  adipocytes; cancer cells; hypoxia; lipids; metabolites; obesity
    DOI:  https://doi.org/10.3389/fendo.2022.989523
  2. Front Immunol. 2022 ;13 966158
    Branched-chain ketoacids derived from cancer cells modulate macrophage polarization and metabolic reprogramming.
    Zhengnan Cai, Wan Li, Martin Brenner, Sheyda Bahiraii, Elke H Heiss, Wolfram Weckwerth.
      Macrophages are prominent immune cells in the tumor microenvironment that can be educated into pro-tumoral phenotype by tumor cells to favor tumor growth and metastasis. The mechanisms that mediate a mutualistic relationship between tumor cells and macrophages remain poorly characterized. Here, we have shown in vitro that different human and murine cancer cell lines release branched-chain α-ketoacids (BCKAs) into the extracellular milieu, which influence macrophage polarization in an monocarboxylate transporter 1 (MCT1)-dependent manner. We found that α-ketoisocaproate (KIC) and α-keto-β-methylvalerate (KMV) induced a pro-tumoral macrophage state, whereas α-ketoisovalerate (KIV) exerted a pro-inflammatory effect on macrophages. This process was further investigated by a combined metabolomics/proteomics platform. Uptake of KMV and KIC fueled macrophage tricarboxylic acid (TCA) cycle intermediates and increased polyamine metabolism. Proteomic and pathway analyses revealed that the three BCKAs, especially KMV, exhibited divergent effects on the inflammatory signal pathways, phagocytosis, apoptosis and redox balance. These findings uncover cancer-derived BCKAs as novel determinants for macrophage polarization with potential to be selectively exploited for optimizing antitumor immune responses.
    Keywords:  BCKAs Fc-gamma receptor (FCgR)-mediated phagocytosis; apoptosis; macrophage polarization; panomics; tumor necrosis factor alpha (TNFα)-nuclear factor kappa B (NFκB) -mediated inflammatory pathway; tumor-associated macrophages
    DOI:  https://doi.org/10.3389/fimmu.2022.966158
  3. Trends Immunol. 2022 Oct 29. pii: S1471-4906(22)00213-7. [Epub ahead of print]
    Lactic acid and lactate: revisiting the physiological roles in the tumor microenvironment.
    Petya Apostolova, Erika L Pearce.
      Lactic acid production has been regarded as a mechanism by which malignant cells escape immunosurveillance. Recent technological advances in mass spectrometry and the use of cell culture media with a physiological nutrient composition have shed new light on the role of lactic acid and its conjugate lactate in the tumor microenvironment. Here, we review novel work identifying lactate as a physiological carbon source for mammalian tumors and immune cells. We highlight evidence that its use as a substrate is distinct from the immunosuppressive acidification of the extracellular milieu by lactic acid protons. Together, data suggest that neutralizing the effects of intratumoral acidity while maintaining physiological lactate metabolism in cytotoxic CD8+ T cells should be pursued to boost anti-tumor immunity.
    DOI:  https://doi.org/10.1016/j.it.2022.10.005
  4. Cancer Res Commun. 2022 Sep;2(9): 1017-1036
    NetrinG1+ cancer-associated fibroblasts generate unique extracellular vesicles that support the survival of pancreatic cancer cells under nutritional stress.
    Kristopher S Raghavan, Ralph Francescone, Janusz Franco-Barraza, Jaye C Gardiner, Débora Barbosa Vendramini-Costa, Tiffany Luong, Narges Pourmandi, Anthony Andren, Alison Kurimchak, Charline Ogier, Paul M Campbell, James S Duncan, Costas A Lyssiotis, Lucia R Languino, Edna Cukierman.
      It is projected that in 5 years, pancreatic cancer will become the second deadliest cancer in the United States. A unique aspect of pancreatic ductal adenocarcinoma (PDAC) is its stroma; rich in cancer-associated fibroblasts (CAFs) and a dense CAF-generated extracellular matrix (ECM). These pathogenic stroma CAF/ECM units cause the collapse of local blood vessels rendering the tumor microenvironment nutrient-poor. PDAC cells are able to survive this state of nutrient stress via support from CAF-secreted material, which includes small extracellular vesicles (sEVs). The tumor-supportive CAFs possess a distinct phenotypic profile, compared to normal-like fibroblasts, expressing NetrinG1 (NetG1) at the plasma membrane, and active Integrin α5β1 localized to the multivesicular bodies; traits indicative of poor patient survival. We herein report that NetG1+ CAFs secrete sEVs that stimulate Akt-mediated survival in nutrient-deprived PDAC cells, protecting them from undergoing apoptosis. Further, we show that NetG1 expression in CAFs is required for the pro-survival properties of sEVs. Additionally, we report that the above-mentioned CAF markers are secreted in distinct subpopulations of EVs; with NetG1 being enriched in exomeres, and Integrin α5β1 being enriched in exosomes. Finally, we found that NetG1 and Integrin α5β1 were detected in sEVs collected from plasma of PDAC patients, while their levels were significantly lower in plasma-derived sEVs of sex/age-matched healthy donors. The discovery of these tumor-supporting CAF-EVs elucidates novel avenues in tumor-stroma interactions and pathogenic stroma detection.
    Keywords:  NetrinG1; cancer-associated fibroblasts; extracellular matrix; extracellular vesicles; pancreatic cancer; α5β1-integrin
    DOI:  https://doi.org/10.1158/2767-9764.crc-21-0147
  5. Immunol Rev. 2022 Nov 03.
    The emerging role for metabolism in fueling neutrophilic inflammation.
    Tyler Morrison, Emily R Watts, Pranvera Sadiku, Sarah R Walmsley.
      Neutrophils are a critical element of host defense and are rapidly recruited to inflammatory sites. Such sites are frequently limited in oxygen and/or nutrient availability, presenting a metabolic challenge for infiltrating cells. Long believed to be uniquely dependent on glycolysis, it is now clear that neutrophils possess far greater metabolic plasticity than previously thought, with the capacity to generate energy stores and utilize extracellular proteins to fuel central carbon metabolism and biosynthetic activity. Out-with cellular energetics, metabolic programs have also been implicated in the production of neutrophils and their progenitors in the bone marrow compartment, activation of neutrophil antimicrobial responses, inflammatory and cell survival signaling cascades, and training of the innate immune response. Thus, understanding the mechanisms by which metabolic processes sustain changes in neutrophil effector functions and how these are subverted in disease states provides exciting new avenues for the treatment of dysfunctional neutrophilic inflammation which are lacking in clinical practice to date.
    Keywords:  immunometabolism; inflammation; neutrophil; trained immunity
    DOI:  https://doi.org/10.1111/imr.13157
  6. Front Immunol. 2022 ;13 932055
    Lactate from the tumor microenvironment - A key obstacle in NK cell-based immunotherapies.
    Marek Jedlička, Tereza Feglarová, Lucie Janstová, Marcela Hortová-Kohoutková, Jan Frič.
      Recent findings about the new roles of lactate have changed our understanding of this end product of glycolysis or fermentation that was once considered only a waste product. It is now well accepted that lactate acts as a signaling molecule and fuel source for cancer cells in a glucose-restricted environment. Moreover, lactate and lactate dehydrogenase are markers of poor prognosis of many cancers and regulate many functions of immune cells. The presence of lactate in the tumor microenvironment (TME) leads to polarization of the immunosuppressive phenotypes of dendritic cells and impairs the cytotoxic abilities of T cells and NK cells, and as such lactate is a major obstacle to immune-cell effector functions and the efficacy of cell-based immunotherapies. Emerging evidence suggests that lactate in the TME might be a novel therapeutic target to enhance the immunotherapeutic potential of cell-based therapies. This review describes our current understanding of the role of lactate in tumor biology, including its detrimental effects on cell-based immunotherapy in cancer. We also highlight how the role of lactate in the TME must be considered when producing cell therapies designed for adoptive transfer and describe how targeted modulation of lactate in the TME might boost immune-cell functions and positively impact cellular immunotherapy, with a focus on NK cell.
    Keywords:  NK cell; T cell; cytotoxicity; immunometabolism; immunosuppression,; immunotherapy; lactate
    DOI:  https://doi.org/10.3389/fimmu.2022.932055
  7. BMC Cancer. 2022 Nov 01. 22(1): 1120
    High tumor hexokinase-2 expression promotes a pro-tumorigenic immune microenvironment by modulating CD8+/regulatory T-cell infiltration.
    Sehui Kim, Jaemoon Koh, Seung Geun Song, Jeemin Yim, Miso Kim, Bhumsuk Keam, Young Tae Kim, Jihun Kim, Doo Hyun Chung, Yoon Kyung Jeon.
       BACKGROUND: Relationship between cancer cell glycolysis and the landscape of tumor immune microenvironment in human cancers was investigated.
    METHODS: Forty-one fresh lung adenocarcinoma (ADC) tissues were analyzed using flow cytometry for comprehensive immunoprofiling. Formalin-fixed tissues were immunostained for hexokinase-2 (HK2) to assess cancer cell glycolysis. For validation, formalin-fixed tissues from 375 lung ADC, 118 lung squamous cell carcinoma (SqCC), 338 colon ADC, and 78 lung cancer patients treated with anti-PD-1/PD-L1 immunotherapy were immunostained for HK2, CD8, and FOXP3.
    RESULTS: Based on immunoprofiling of lung ADC, HK2 tumor expression was associated with the composition of lymphoid cells rather than myeloid cells. High HK2 tumor expression was associated with immunosuppressive/pro-tumorigenic features, especially decreased ratio of CD8 + T-cells to Tregs (rho = -0.415, P = 0.012). This correlation was also confirmed in four different cohorts including lung ADC and SqCC, colon ADC, and the immunotherapy cohort (rho = -0.175~-0.335, all P < 0.05). A low CD8 + T-cell to Treg ratio was associated with poor progression-free survival and overall survival in lung SqCC patients, and a shorter overall survival in the immunotherapy cohort (all, P < 0.05).
    CONCLUSION: An increase in HK2 expression may contribute to shaping the immunosuppressive/pro-tumorigenic tumor microenvironment by modulating the CD8 + T-cell to Treg ratio. Targeting tumor HK2 expression might be a potential strategy for enhancing anti-tumor immunity.
    Keywords:  CD8 + T-cell to Treg ratio; Glycolysis; Hexokinase-2; Immunotherapy; Tumor microenvironment; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1186/s12885-022-10239-6
  8. Cancer Discov. 2022 Nov 04. OF1
    Spermidine Supplementation Enhances Immune Checkpoint Blockade Response.
      Spermidine enhances T-cell mitochondrial metabolism and the antitumor response to anti-PD-L1.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-196
  9. NAR Cancer. 2022 Dec;4(4): zcac031
    Translational alterations in pancreatic cancer: a central role for the integrated stress response.
    Sauyeun Shin, Jacobo Solorzano, Mehdi Liauzun, Stéphane Pyronnet, Corinne Bousquet, Yvan Martineau.
      mRNA translation is a key mechanism for cancer cell proliferation and stress adaptation. Regulation of this machinery implicates upstream pathways such as PI3K/AKT/mTOR, RAS/MEK/ERK and the integrated stress response (ISR), principally coordinating the translation initiation step. During the last decade, dysregulation of the mRNA translation process in pancreatic cancer has been widely reported, and shown to critically impact on cancer initiation, development and survival. This includes translation dysregulation of mRNAs encoding oncogenes and tumor suppressors. Hence, cancer cells survive a stressful microenvironment through a flexible regulation of translation initiation for rapid adaptation. The ISR pathway has an important role in chemoresistance and shows high potential therapeutic interest. Despite the numerous translational alterations reported in pancreatic cancer, their consequences are greatly underestimated. In this review, we summarize the different translation dysregulations described in pancreatic cancer, which make it invulnerable, as well as the latest drug discoveries bringing a glimmer of hope.
    DOI:  https://doi.org/10.1093/narcan/zcac031
  10. J Biol Chem. 2022 Oct 26. pii: S0021-9258(22)01081-X. [Epub ahead of print] 102638
    Stress response protein REDD1 promotes diabetes-induced retinal inflammation by sustaining canonical NF-κB signaling.
    Siddharth Sunilkumar, Allyson L Toro, Christopher F McCurry, Ashley M VanCleave, Shaunaci A Stevens, William P Miller, Scot R Kimball, Michael D Dennis.
      Inflammation contributes to the progression of retinal pathology caused by diabetes. Here, we investigated a role for the stress response protein regulated in development and DNA damage response 1 (REDD1) in the development of retinal inflammation. Increased REDD1 expression was observed in the retina of mice after 16-weeks of streptozotocin (STZ)-induced diabetes, and REDD1 was essential for diabetes-induced pro-inflammatory cytokine expression. In human retinal MIO-M1 Müller cell cultures, REDD1 deletion prevented increased pro-inflammatory cytokine expression in response to hyperglycemic conditions. REDD1 deletion promoted nuclear factor erythroid-2-related factor 2 (Nrf2) hyperactivation; however, Nrf2 was not required for reduced inflammatory cytokine expression in REDD1-deficient cells. Rather, REDD1 enhanced inflammatory cytokine expression by promoting activation of nuclear transcription factor κB (NF-κB). In wild-type cells exposed to tumor necrosis factor α (TNFα), inflammatory cytokine expression was increased in coordination with activating transcription factor 4 (ATF4)-dependent REDD1 expression and sustained activation of NF-κB. In both Müller cell cultures exposed to TNFα and in the retina of STZ-diabetic mice, REDD1 deletion promoted inhibitor of κB (I-κB) expression and reduced NF-κB DNA-binding activity. We found that REDD1 acted upstream of I-κB by enhancing both K63-ubiquitination and auto-phosphorylation of I-κB kinase (IKK) complex. In contrast with STZ-diabetic REDD1+/+ mice, IKK complex autophosphorylation and macrophage infiltration were not observed in the retina of STZ-diabetic REDD1-/- mice. The findings provide new insight into how diabetes promotes retinal inflammation and support a model wherein REDD1 sustains activation of canonical NF-κB signaling.
    Keywords:  DDIT4 (REDD1); Diabetes; NF‐kappa B (NF‐KB); inflammation; retina
    DOI:  https://doi.org/10.1016/j.jbc.2022.102638
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