bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2022‒09‒04
seven papers selected by
Cristina Muñoz Pinedo
L’Institut d’Investigació Biomèdica de Bellvitge
  1. Metabolic reprogramming and crosstalk of cancer-related fibroblasts and immune cells in the tumor microenvironment.
  2. Bladder Cancer-Derived Small Extracellular Vesicles Promote Tumor Angiogenesis by Inducing HBP-Related Metabolic Reprogramming and SerRS O-GlcNAcylation in Endothelial Cells.
  3. Hypoxia-Driven M2-Polarized Macrophages Facilitate Cancer Aggressiveness and Temozolomide Resistance in Glioblastoma.
  4. IRE1α overexpression in malignant cells limits tumor progression by inducing an anti-cancer immune response.
  5. Lactate score predicts survival, immune cell infiltration and response to immunotherapy in breast cancer.
  6. Transcriptional regulation of Acsl1 by CHREBP and NF-kappa B in macrophages during hyperglycemia and inflammation.
  7. Impact of NSCLC metabolic remodeling on immunotherapy effectiveness.
  1. Front Endocrinol (Lausanne). 2022 ;13 988295
    Metabolic reprogramming and crosstalk of cancer-related fibroblasts and immune cells in the tumor microenvironment.
    Yifei Zhu, Xinyan Li, Lei Wang, Xiwei Hong, Jie Yang.
      It is notorious that cancer cells alter their metabolism to adjust to harsh environments of hypoxia and nutritional starvation. Metabolic reprogramming most often occurs in the tumor microenvironment (TME). TME is defined as the cellular environment in which the tumor resides. This includes surrounding blood vessels, fibroblasts, immune cells, signaling molecules and the extracellular matrix (ECM). It is increasingly recognized that cancer cells, fibroblasts and immune cells within TME can regulate tumor progression through metabolic reprogramming. As the most significant proportion of cells among all the stromal cells that constitute TME, cancer-associated fibroblasts (CAFs) are closely associated with tumorigenesis and progression. Multitudinous studies have shown that CAFs participate in and promote tumor metabolic reprogramming and exert regulatory effects via the dysregulation of metabolic pathways. Previous studies have demonstrated that curbing the substance exchange between CAFs and tumor cells can dramatically restrain tumor growth. Emerging studies suggest that CAFs within the TME have emerged as important determinants of metabolic reprogramming. Metabolic reprogramming also occurs in the metabolic pattern of immune cells. In the meanwhile, immune cell phenotype and functions are metabolically regulated. Notably, immune cell functions influenced by metabolic programs may ultimately lead to alterations in tumor immunity. Despite the fact that multiple previous researches have been devoted to studying the interplays between different cells in the tumor microenvironment, the complicated relationship between CAFs and immune cells and implications of metabolic reprogramming remains unknown and requires further investigation. In this review, we discuss our current comprehension of metabolic reprogramming of CAFs and immune cells (mainly glucose, amino acid, and lipid metabolism) and crosstalk between them that induces immune responses, and we also highlight their contributions to tumorigenesis and progression. Furthermore, we underscore potential therapeutic opportunities arising from metabolism dysregulation and metabolic crosstalk, focusing on strategies targeting CAFs and immune cell metabolic crosstalk in cancer immunotherapy.
    Keywords:  Tumor microenvironment; cancer-associated fibroblasts; immune cells; immunotherapy; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fendo.2022.988295
  2. Adv Sci (Weinh). 2022 Aug 31. e2202993
    Bladder Cancer-Derived Small Extracellular Vesicles Promote Tumor Angiogenesis by Inducing HBP-Related Metabolic Reprogramming and SerRS O-GlcNAcylation in Endothelial Cells.
    Xinyuan Li, Xiang Peng, Chunlin Zhang, Xuesong Bai, Yang Li, Guo Chen, Huixia Guo, Weiyang He, Xiang Zhou, Xin Gou.
      A malformed tumour vascular network provokes the nutrient-deprived tumour microenvironment (TME), which conversely activates endothelial cell (EC) functions and stimulates neovascularization. Emerging evidence suggests that the flexible metabolic adaptability of tumour cells helps to establish a metabolic symbiosis among various cell subpopulations in the fluctuating TME. In this study, the authors propose a novel metabolic link between bladder cancer (BCa) cells and ECs in the nutrient-scarce TME, in which BCa-secreted glutamine-fructose-6-phosphate aminotransferase 1 (GFAT1) via small extracellular vesicles (sEVs) reprograms glucose metabolism by increasing hexosamine biosynthesis pathway flux in ECs and thus enhances O-GlcNAcylation. Moreover, seryl-tRNA synthetase (SerRS) O-GlcNAcylation at serine 101 in ECs promotes its degradation by ubiquitination and impeded importin α5-mediated nuclear translocation. Intranuclear SerRS attenuates vascular endothelial growth factor transcription by competitively binding to the GC-rich region of the proximal promotor. Additionally, GFAT1 knockout in tumour cells blocks SerRS O-GlcNAcylation in ECs and attenuates angiogenesis both in vitro and in vivo. However, administration of GFAT1-overexpressing BCa cells-derived sEVs increase the angiogenetic activity in the ECs of GFAT1-knockout mice. In summary, this study suggests that inhibiting sEV-mediated GFAT1 secretion from BCa cells and targeting SerRS O-GlcNAcylation in ECs may serve as novel strategies for BCa antiangiogenetic therapy.
    Keywords:  O-GlcNAcylation; angiogenesis; glutamine-fructose-6-phosphate aminotransferase 1; metabolic reprogramming; small extracellular vesicles
    DOI:  https://doi.org/10.1002/advs.202202993
  3. Oxid Med Cell Longev. 2022 ;2022 1614336
    Hypoxia-Driven M2-Polarized Macrophages Facilitate Cancer Aggressiveness and Temozolomide Resistance in Glioblastoma.
    Ge Zhang, Xiang Tao, Baowei Ji, Jie Gong.
      Hypoxia-induced M2 phenotypes of tumor associated macrophages (TAMs) promote the development and chemoresistance of multiple types of cancers, including glioblastoma (GBM). However, the detailed molecular mechanisms have not been fully understood. In this study, we firstly reported that hypoxic pressure promoted M2 macrophage generation, which further promoted cancer progression and temozolomide (TMZ) resistance in GBM through secreting vascular endothelial growth factor (VEGF). Specifically, the clinical data suggested that M2 macrophages were significantly enriched in GBM tissues compared with the adjacent normal tissues, and the following in vitro experiments validated that hypoxic pressure promoted M2-polarized macrophages through upregulating hypoxia-inducible factor-1α (HIF-1α). In addition, hypoxic M2 macrophages VEGF-dependently promoted cell proliferation, epithelial-mesenchymal transition (EMT), glioblastoma stem cell (GSC) properties, and TMZ resistance in GBM cells through activating the PI3K/Akt/Nrf2 pathway. Also, M2 macrophages secreted VEGF to accelerate angiogenesis in human umbilical vein endothelial cells (HUVECs) through interacting with its receptor VEGFR. In general, we concluded that hypoxic M2 macrophages contributed to cancer progression, stemness, drug resistance, and angiogenesis in GBM through secreting VEGF, and our data supported the notion that targeting hypoxia-associated M2 macrophages might be an effective treatment strategy for GBM in clinical practices.
    DOI:  https://doi.org/10.1155/2022/1614336
  4. Oncoimmunology. 2022 ;11(1): 2116844
    IRE1α overexpression in malignant cells limits tumor progression by inducing an anti-cancer immune response.
    Adriana Martinez-Turtos, Rachel Paul, Manuel Grima-Reyes, Hussein Issaoui, Adrien Krug, Rana Mhaidly, Jozef P Bossowski, Johanna Chiche, Sandrine Marchetti, Els Verhoeyen, Eric Chevet, Jean-Ehrland Ricci.
      IRE1α is one of the three ER transmembrane transducers of the Unfolded Protein Response (UPR) activated under endoplasmic reticulum (ER) stress. IRE1α activation has a dual role in cancer as it may be either pro- or anti-tumoral depending on the studied models. Here, we describe the discovery that exogenous expression of IRE1α, resulting in IRE1α auto-activation, did not affect cancer cell proliferation in vitro but resulted in a tumor-suppressive phenotype in syngeneic immunocompetent mice. We found that exogenous expression of IRE1α in murine colorectal and Lewis lung carcinoma cells impaired tumor growth when syngeneic tumor cells were subcutaneously implanted in immunocompetent mice but not in immunodeficient mice. Mechanistically, the in vivo tumor-suppressive effect of overexpressing IRE1α in tumor cells was associated with IRE1α RNAse activity driving both XBP1 mRNA splicing and regulated IRE1-dependent decay of RNA (RIDD). We showed that the tumor-suppressive phenotype upon IRE1α overexpression was characterized by the induction of apoptosis in tumor cells along with an enhanced adaptive anti-cancer immunosurveillance. Hence, our work indicates that IRE1α overexpression and/or activation in tumor cells can limit tumor growth in immunocompetent mice. This finding might point toward the need of adjusting the use of IRE1α inhibitors in cancer treatments based on the predominant outcome of the RNAse activity of IRE1α.
    Keywords:  Cancer; IRE1α; RIDD; UPR; XBP1s; anti-cancer immunosurveillance; apoptosis
    DOI:  https://doi.org/10.1080/2162402X.2022.2116844
  5. Front Genet. 2022 ;13 943849
    Lactate score predicts survival, immune cell infiltration and response to immunotherapy in breast cancer.
    Ting-Ting Yin, Meng-Xing Huang, Fei Wang, Yi-Hua Jiang, Jie Long, Liang Li, Jie Cao.
      Background: Tumor-derived lactate can modulate the function of infiltrating immune cells to establish an immunosuppressive microenvironment that favors tumor progression. However, possible effects of lactate-related genes (LRGs) on the tumor microenvironment (TME) of breast cancer (BRCA) are still unknown. Methods: LRGs were comprehensively screened from lactate metabolism-related pathways. We correlated the expression of these LRGs with immune cell infiltrating characteristics in the TME and clinicopathological features of patients. We also established a lactate score for quantifying lactate metabolism patterns of cancers and to predict of recurrence-free survival (RFS). Results: We successfully constructed a lactate score that was an independent prognostic factor in BRCA. A low lactate score, which was associated with immune activation with increased CD8+ T cells infiltration levels, indicated an inflamed TME. Consistently, higher expression levels of inhibitory immune checkpoints, including PD-L1, LAG3, CTLA4, and TIM3, as observed from high lactate score subgroup, suggested an immune-desert phenotype as well as poor prognosis. Moreover, a low lactate score predicted the increased chemotherapeutic drug sensitivity and enhanced anti-PD-1 immunotherapy responses. Conclusion: The present study analyzed the potential roles of LRGs in the TME diversity and prognosis. These results will help to improve our understanding of the characteristics of TME immune cell infiltration and guide the development of more effective immunotherapy strategies.
    Keywords:  breast cancer; chemotherapy; immunotherapy; lactate score; tumor microenvironment
    DOI:  https://doi.org/10.3389/fgene.2022.943849
  6. PLoS One. 2022 ;17(9): e0272986
    Transcriptional regulation of Acsl1 by CHREBP and NF-kappa B in macrophages during hyperglycemia and inflammation.
    Prashanth Thevkar-Nagesh, Justine Habault, Maud Voisin, Sophie E Ruff, Susan Ha, Rachel Ruoff, Xi Chen, Shruti Rawal, Tarik Zahr, Gyongyi Szabo, Inez Rogatsky, Edward A Fisher, Michael J Garabedian.
      Acyl-CoA synthetase 1 (ACSL1) is an enzyme that converts fatty acids to acyl-CoA-derivatives for lipid catabolism and lipid synthesis in general and can provide substrates for the production of mediators of inflammation in monocytes and macrophages. Acsl1 expression is increased by hyperglycemia and inflammatory stimuli in monocytes and macrophages, and promotes the pro-atherosclerotic effects of diabetes in mice. Yet, surprisingly little is known about the mechanisms underlying Acsl1 transcriptional regulation. Here we demonstrate that the glucose-sensing transcription factor, Carbohydrate Response Element Binding Protein (CHREBP), is a regulator of the expression of Acsl1 mRNA by high glucose in mouse bone marrow-derived macrophages (BMDMs). In addition, we show that inflammatory stimulation of BMDMs with lipopolysaccharide (LPS) increases Acsl1 mRNA via the transcription factor, NF-kappa B. LPS treatment also increases ACSL1 protein abundance and localization to membranes where it can exert its activity. Using an Acsl1 reporter gene containing the promoter and an upstream regulatory region, which has multiple conserved CHREBP and NF-kappa B (p65/RELA) binding sites, we found increased Acsl1 promoter activity upon CHREBP and p65/RELA expression. We also show that CHREBP and p65/RELA occupy the Acsl1 promoter in BMDMs. In primary human monocytes cultured in high glucose versus normal glucose, ACSL1 mRNA expression was elevated by high glucose and further enhanced by LPS treatment. Our findings demonstrate that CHREBP and NF-kappa B control Acsl1 expression under hyperglycemic and inflammatory conditions.
    DOI:  https://doi.org/10.1371/journal.pone.0272986
  7. Biomark Res. 2022 Aug 29. 10(1): 66
    Impact of NSCLC metabolic remodeling on immunotherapy effectiveness.
    Lulu Lv, Ruo Han Huang, Jiale Li, Jing Xu, Wen Gao.
      It is known that metabolic reprogramming (MR) contributes to tumorigenesis through the activation of processes that support survival of cells, proliferation, and grow in the tumor microenvironment. In order to keep the tumor proliferating at a high rate, metabolic pathways must be upregulated, and tumor metabolism must be adapted to meet this requirement. Additionally, immune cells engage in metabolic remodeling to maintain body and self-health. With the advent of immunotherapy, the fate of individuals suffering from non-small cell lung cancer (NSCLC) has been transformed dramatically. MR may have a profound influence on their prognosis. The aim of this review is to summarize current research advancements in metabolic reprogramming and their impact on immunotherapy in NSCLC. Moreover, we talk about promising approaches targeting and manipulating metabolic pathways to improve cancer immunotherapy's effectiveness in NSCLC.
    Keywords:  Immunotherapy; Metabolic reprogramming; NSCLC; TME
    DOI:  https://doi.org/10.1186/s40364-022-00412-1
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