bims-mecami 2024-02-11 papers

bims-mecami

Biomed News

on Metabolic interactions between cancer cells and their microenvironment

Issue of 2024–02–11
eight papers selected by
Oltea Sampetrean, Keio University

Metabolomic Investigations into Hypoxia-Mediated Metabolic Reprogramming of Pancreatic Cancer Cells.
Polyphenol nanocomplex modulates lactate metabolic reprogramming and elicits immune responses to enhance cancer therapeutic effect.
Measurement of Metabolic Alteration in Immune Cells Under Hypoxia.
Metabolic Signature of Warburg Effect in Cancer: An Effective and Obligatory Interplay between Nutrient Transporters and Catabolic/Anabolic Pathways to Promote Tumor Growth.
Tumor-secreted FGF21 acts as an immune suppressor by rewiring cholesterol metabolism of CD8+T cells.
Lipid droplets provide metabolic flexibility for cancer progression.
pH regulators and their inhibitors in tumor microenvironment.
Tumor cell senescence-induced macrophage CD73 expression is a critical metabolic immune checkpoint in the aging tumor microenvironment.

Methods Mol Biol. 2024 ;2755 191-200

Metabolomic Investigations into Hypoxia-Mediated Metabolic Reprogramming of Pancreatic Cancer Cells.

Vira Chumak, Girish H Rajacharya, Pankaj K Singh.

  Hypoxia is a crucial microenvironmental factor that defines tumor cell growth and aggressiveness. Cancer cells adapt to hypoxia by altering their metabolism. These alterations impact various cellular and physiological functions, including energy metabolism, vascularization, invasion and metastasis, genetic instability, cell immortalization, stem cell maintenance, and resistance to chemotherapy (Li et al. Technol Cancer Res Treat 20:15330338211036304, 2021). Hypoxia-inducible factor-1α (HIF-1α) is known to be a critical regulator of glycolysis that directly regulates the transcription of multiple key enzymes of the glycolysis pathway. Moreover, HIF-1α stabilization can be directly modulated by TCA-derived metabolites, including 2-ketoglutarate and succinate (Infantino et al, Int J Mol Sci 22(22), https://doi.org/10.3390/ijms22115703 , 2021). Overall, the molecular mechanisms underlying the adaptation of cellular metabolism to hypoxia impact the metabolic phenotype of cancer cells. Such adaptations include increased glucose uptake, increased lactate production, and increased levels of other metabolites that stabilize HIF-1α, leading to a vicious circle of hypoxia-induced tumor growth.

Keywords:  HIF; Hypoxia; Metabolomics; Pancreatic cancer; Tandem mass spectrometry

DOI:  https://doi.org/10.1007/978-1-0716-3633-6_14
Drug Resist Updat. 2024 Jan 20. pii: S1368-7646(24)00018-9. [Epub ahead of print]73 101060

Polyphenol nanocomplex modulates lactate metabolic reprogramming and elicits immune responses to enhance cancer therapeutic effect.

Zhan Zhang, Xinnan Li, Weiqiang Liu, Guanglei Chen, Jinchi Liu, Qingtian Ma, Pengjie Hou, Lu Liang, Caigang Liu.

  Cancer lactate metabolic reprogramming induces an elevated level of extracellular lactate and H+, leading to an acidic immunosuppressive tumor microenvironment (TEM). High lactic acid level may affect the metabolic programs of various cells that comprise an antitumor immune response, therefore, restricting immune-mediated tumor destruction, and leading to therapeutic resistance and unsatisfactory prognosis. Here, we report a metal-phenolic coordination-based nanocomplex loaded with a natural polyphenol galloflavin, which inhibits the function of lactate dehydrogenase, reducing the production of lactic acid, and alleviating the acidic immunosuppressive TME. Besides, the co-entrapped natural polyphenol carnosic acid and the synthetic PEG-Ce6 polyphenol derivative (serving as a photosensitizer) could induce immunogenic cancer cell death upon laser irradiation, which further activates immune system and promotes immune cell recruitment and infiltration in tumor tissues. We demonstrated that this nanocomplex-based combinational therapy could reshape the TME and elicit immune responses in a murine breast cancer model, which provides a promising strategy to enhance the therapeutic efficiency of drug-resistant breast cancer.

Keywords:  Acidic tumor microenvironment; Antitumor therapy; Drug resistance; Lactate metabolic reprogramming; Metal-phenolic network

DOI:  https://doi.org/10.1016/j.drup.2024.101060
Methods Mol Biol. 2024 ;2755 201-212

Measurement of Metabolic Alteration in Immune Cells Under Hypoxia.

Yuki Fujii, Kamiya Mehla.

  The hypoxic microenvironment in solid tumors affects the metabolism of tumor cells and infiltrating immune cells, which aids in robust tumor growth and expansion. Myeloid-derived suppressor cells (MDSCs) are heterogenous immature myeloid cells in the TME, which play an essential role in immune evasion by subverting T/NK cell-mediated killing. The immunosuppressive function of MDSCs is tightly regulated to the metabolic pathways, in which hypoxia plays a critical role. In this chapter, we describe the isolation of murine MDSCs from bone marrows and the measurement of the transcriptomic changes of essential metabolic enzymes under hypoxic conditions. This method can be applied to study MDSCs function, mimicking the hypoxic environment in vitro. This method can be utilized to investigate the critical metabolic alterations under a given tumor context and help evaluate the efficacy of metabolic-targeted therapies in the long run.

Keywords:  Cancer; Glycolysis; Hypoxia; Myeloid-derived suppressor cell; Tumor microenvironment

DOI:  https://doi.org/10.1007/978-1-0716-3633-6_15
Cancers (Basel). 2024 Jan 24. pii: 504. [Epub ahead of print]16(3):

Metabolic Signature of Warburg Effect in Cancer: An Effective and Obligatory Interplay between Nutrient Transporters and Catabolic/Anabolic Pathways to Promote Tumor Growth.

Marilyn Mathew, Nhi T Nguyen, Yangzom D Bhutia, Sathish Sivaprakasam, Vadivel Ganapathy.

  Aerobic glycolysis in cancer cells, originally observed by Warburg 100 years ago, which involves the production of lactate as the end product of glucose breakdown even in the presence of adequate oxygen, is the foundation for the current interest in the cancer-cell-specific reprograming of metabolic pathways. The renewed interest in cancer cell metabolism has now gone well beyond the original Warburg effect related to glycolysis to other metabolic pathways that include amino acid metabolism, one-carbon metabolism, the pentose phosphate pathway, nucleotide synthesis, antioxidant machinery, etc. Since glucose and amino acids constitute the primary nutrients that fuel the altered metabolic pathways in cancer cells, the transporters that mediate the transfer of these nutrients and their metabolites not only across the plasma membrane but also across the mitochondrial and lysosomal membranes have become an integral component of the expansion of the Warburg effect. In this review, we focus on the interplay between these transporters and metabolic pathways that facilitates metabolic reprogramming, which has become a hallmark of cancer cells. The beneficial outcome of this recent understanding of the unique metabolic signature surrounding the Warburg effect is the identification of novel drug targets for the development of a new generation of therapeutics to treat cancer.

Keywords:  aerobic glycolysis; glutamine addiction; glutaminolysis; lactate receptors; nutrient transporters; oncogenes; oncometabolites; one-carbon metabolism; reductive carboxylation; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers16030504
Cell Metab. 2024 Jan 23. pii: S1550-4131(24)00006-8. [Epub ahead of print]

Tumor-secreted FGF21 acts as an immune suppressor by rewiring cholesterol metabolism of CD8+T cells.

Cegui Hu, Wen Qiao, Xiang Li, Zhi-Kun Ning, Jiang Liu, Sumiya Dalangood, Hanjun Li, Xiang Yu, Zhen Zong, Zhenke Wen, Jun Gui.

  Tumors employ diverse strategies for immune evasion. Unraveling the mechanisms by which tumors suppress anti-tumor immunity facilitates the development of immunotherapies. Here, we have identified tumor-secreted fibroblast growth factor 21 (FGF21) as a pivotal immune suppressor. FGF21 is upregulated in multiple types of tumors and promotes tumor progression. Tumor-secreted FGF21 significantly disrupts anti-tumor immunity by rewiring cholesterol metabolism of CD8+T cells. Mechanistically, FGF21 sustains the hyperactivation of AKT-mTORC1-sterol regulatory-element-binding protein 1 (SREBP1) signal axis in the activated CD8+T cells, resulting in the augment of cholesterol biosynthesis and T cell exhaustion. FGF21 knockdown or blockade using a neutralizing antibody normalizes AKT-mTORC1 signaling and reduces excessive cholesterol accumulation in CD8+T cells, thus restoring CD8+T cytotoxic function and robustly suppressing tumor growth. Our findings reveal FGF21 as a "secreted immune checkpoint" that hampers anti-tumor immunity, suggesting that inhibiting FGF21 could be a valuable strategy to enhance the cancer immunotherapy efficacy.

Keywords:  CD8(+)T; FGF21; cancer immunotherapy; cholesterol; mTORC1; tumor immune evasion

DOI:  https://doi.org/10.1016/j.cmet.2024.01.005
FEBS Lett. 2024 Feb 07.

Lipid droplets provide metabolic flexibility for cancer progression.

Rémi Safi, Pablo Menéndez, Albert Pol.

  A hallmark of cancer cells is their remarkable ability to efficiently adapt to favorable and hostile environments. Due to a unique metabolic flexibility, tumor cells can grow even in the absence of extracellular nutrients or in stressful scenarios. To achieve this, cancer cells need large amounts of lipids to build membranes, synthesize lipid-derived molecules, and generate metabolic energy in the absence of other nutrients. Tumor cells potentiate strategies to obtain lipids from other cells, metabolic pathways to synthesize new lipids, and mechanisms for efficient storage, mobilization, and utilization of these lipids. Lipid droplets (LDs) are the organelles that collect and supply lipids in eukaryotes and it is increasingly recognized that the accumulation of LDs is a new hallmark of cancer cells. Furthermore, an active role of LD proteins in processes underlying tumorigenesis has been proposed. Here, by focusing on three major classes of LD-resident proteins (perilipins, lipases, and acyl-CoA synthetases), we provide an overview of the contribution of LDs to cancer progression and discuss the role of LD proteins during the proliferation, invasion, metastasis, apoptosis, and stemness of cancer cells.

Keywords:  cancer; invasion; lipid droplets; lipids; metastasis; tumorigenesis

DOI:  https://doi.org/10.1002/1873-3468.14820
Eur J Med Chem. 2024 Feb 01. pii: S0223-5234(24)00050-3. [Epub ahead of print]267 116170

pH regulators and their inhibitors in tumor microenvironment.

Senyi Liao, Guang Wu, Zhizhong Xie, Xiaoyong Lei, Xiaoyan Yang, Sheng Huang, Xiangping Deng, Zhe Wang, Guotao Tang.

  As an important characteristic of tumor, acidic tumor microenvironment (TME) is closely related to immune escape, invasion, migration and drug resistance of tumor. The acidity of the TME mainly comes from the acidic products produced by the high level of tumor metabolism, such as lactic acid and carbon dioxide. pH regulators such as monocarboxylate transporters (MCTs), carbonic anhydrase IX (CA IX), and Na+/H+ exchange 1 (NHE1) expel protons directly or indirectly from the tumor to maintain the pH balance of tumor cells and create an acidic TME. We review the functions of several pH regulators involved in the construction of acidic TME, the structure and structure-activity relationship of pH regulator inhibitors, and provide strategies for the development of small-molecule antitumor inhibitors based on these targets.

Keywords:  Carbonic anhydrase IX; Monocarboxylate transportors; Na(+)/H(+) exchanger 1; Structure-activity relationship; Tumor microenvironment; pH regulators

DOI:  https://doi.org/10.1016/j.ejmech.2024.116170
Theranostics. 2024 ;14(3): 1224-1240

Tumor cell senescence-induced macrophage CD73 expression is a critical metabolic immune checkpoint in the aging tumor microenvironment.

Yue Deng, Qinyan Chen, Xiao Yang, Yajie Sun, Bin Zhang, Wenwen Wei, Suke Deng, Jingshu Meng, Yan Hu, Yijun Wang, Zhanjie Zhang, Lu Wen, Fang Huang, Chao Wan, Kunyu Yang.

  Background: The role of senescent cells in the tumor microenvironment (TME) is usually bilateral, and diverse therapeutic approaches, such as radiotherapy and chemotherapy, can induce cellular senescence. Cellular interactions are widespread in the TME, and tumor cells reprogram immune cells metabolically by producing metabolites. However, how senescent cells remodel the metabolism of TME remains unclear. This study aimed to explore precise targets to enhance senescent cells-induced anti-tumor immunity from a metabolic perspective. Methods: The in vivo senescence model was induced by 8 Gy×3 radiotherapy or cisplatin chemotherapy, and the in vitro model was induced by 10 Gy-irradiation or cisplatin treatment. Metabonomic analysis and ELISA assay on tumor interstitial fluid were performed for metabolites screening. Marker expression and immune cell infiltration in the TME were analyzed by flow cytometry. Cell co-culture system and senescence-conditioned medium were used for crosstalk validation in vitro. RNA sequencing and rescue experiments were conducted for mechanism excavation. Immunofluorescence staining and single-cell transcriptome profiling analysis were performed for clinical validation. Results: We innovatively reveal the metabolic landscape of the senescent TME, characterized with the elevation of adenosine. It is attributed to the senescent tumor cell-induced CD73 upregulation of tumor-associated macrophages (TAMs). CD73 expression in TAMs is evoked by SASP-related pro-inflammatory cytokines, especially IL-6, and regulated by JAK/STAT3 pathway. Consistently, a positive correlation between tumor cells senescence and TAMs CD73 expression is identified in lung cancer clinical specimens and databases. Lastly, blocking CD73 in a senescent background suppresses tumors and activates CD8+ T cell-mediated antitumor immunity. Conclusions: TAMs expressed CD73 contributes significantly to the adenosine accumulation in the senescent TME, suggesting targeting CD73 is a novel synergistic anti-tumor strategy in the aging microenvironment.

Keywords:  CD73; cancer immunotherapy; senescence; tumor microenvironment; tumor-associated macrophages

DOI:  https://doi.org/10.7150/thno.91119