bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2022–09–18
fiveteen papers selected by
Linda Chan, Yale University
  1. A happy cell stays home: When metabolic stress creates epigenetic advantages in the tumor microenvironment.
  2. Solute exchange through gap junctions lessens the adverse effects of inactivating mutations in metabolite-handling genes.
  3. Colorectal cancer: Metabolic interactions reshape the tumor microenvironment.
  4. ADSCs stimulated by resistin promote breast cancer cell malignancy via CXCL5 in a breast cancer coculture model.
  5. Sorting-free metabolic profiling uncovers the vulnerability of fatty acid β-oxidation in in vitro quiescence models.
  6. Warburg: father of the metabolic approach to cancer.
  7. Hypoxia promotes an inflammatory phenotype of fibroblasts in pancreatic cancer.
  8. Targeting Strategies for Aberrant Lipid Metabolism Reprogramming and the Immune Microenvironment in Esophageal Cancer: A Review.
  9. Metabolic reprogramming in the OPA1-deficient cells.
  10. Metabolic Tumor Imaging with Rapidly Signal-Enhanced 1-13C-Pyruvate-d3.
  11. Metabolic profiling of induced acute pancreatitis and pancreatic cancer progression in a mutant Kras mouse model.
  12. Spatial transcriptomics.
  13. The tumour microenvironment of clear cell ovarian cancer.
  14. NK cell immunometabolism as target for liver cancer therapy.
  15. Carboxylesterase 2 induces mitochondrial dysfunction via disrupting lipid homeostasis in oral squamous cell carcinoma.
  1. Front Oncol. 2022 ;12 962928
    A happy cell stays home: When metabolic stress creates epigenetic advantages in the tumor microenvironment.
    Eric A Hanse, Mei Kong.
      A paradox of fast-proliferating tumor cells is that they deplete extracellular nutrients that often results in a nutrient poor microenvironment in vivo. Having a better understanding of the adaptation mechanisms cells exhibit in response to metabolic stress will open new therapeutic windows targeting the tumor's extreme nutrient microenvironment. Glutamine is one of the most depleted amino acids in the tumor core and here, we provide insight into how important glutamine and its downstream by-product, α-ketoglutarate (αKG), are to communicating information about the nutrient environment. This communication is key in the cell's ability to foster adaptation. We highlight the epigenetic changes brought on when αKG concentrations are altered in cancer and discuss how depriving cells of glutamine may lead to cancer cell de-differentiation and the ability to grow and thrive in foreign environments. When we starve cells, they adapt to survive. Those survival "skills" allow them to go out looking for other places to live and metastasize. We further examine current challenges to modelling the metabolic tumor microenvironment in the laboratory and discuss strategies that consider current findings to target the tumor's poor nutrient microenvironment.
    Keywords:  alpha ketoglutarate; epigenetics; glutamine; glutaminolysis-inhibition; metabolism; tumor; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.962928
  2. Elife. 2022 Sep 15. pii: e78425. [Epub ahead of print]11
    Solute exchange through gap junctions lessens the adverse effects of inactivating mutations in metabolite-handling genes.
    Stefania Monterisi, Johanna Michl, Alzbeta Hulikova, Jana Koth, Esther M Bridges, Amaryllis E Hill, Gulnar Abdullayeva, Walter F Bodmer, Pawel Swietach.
      Growth of cancer cells in vitro can be attenuated by genetically inactivating selected metabolic pathways. However, loss-of-function mutations in metabolic pathways are not negatively selected in human cancers, indicating that these genes are not essential in vivo. We hypothesize that spontaneous mutations in 'metabolic genes' will not necessarily produce functional defects because mutation-bearing cells may be rescued by metabolite exchange with neighboring wild-type cells via gap junctions. Using fluorescent substances to probe inter-cellular diffusion, we show that colorectal cancer (CRC) cells are coupled by gap junctions assembled from connexins, particularly Cx26. Cells with genetically inactivated components of pH regulation (SLC9A1), glycolysis (ALDOA), or mitochondrial respiration (NDUFS1) could be rescued through access to functional proteins in co-cultured wild-type cells. The effect of diffusive coupling was also observed in co-culture xenografts. Rescue was largely dependent on solute exchange via Cx26 channels, a uniformly and constitutively expressed isoform in CRCs. Due to diffusive coupling, the emergent phenotype is less heterogenous than its genotype, and thus an individual cell should not be considered as the unit under selection, at least for metabolite-handling processes. Our findings can explain why certain loss-of-function mutations in genes ascribed as 'essential' do not influence the growth of human cancers.
    Keywords:  biochemistry; cancer biology; chemical biology
    DOI:  https://doi.org/10.7554/eLife.78425
  3. Biochim Biophys Acta Rev Cancer. 2022 Sep 10. pii: S0304-419X(22)00122-6. [Epub ahead of print] 188797
    Colorectal cancer: Metabolic interactions reshape the tumor microenvironment.
    Jiawei Chen, Haodong Zhu, Yuhang Yin, Siyuan Jia, Xiangjian Luo.
      Colorectal cancer (CRC) is one of the most common cancers worldwide, which ranks third in terms of incidence and the second leading cause of cancer-related mortality. Metabolic reprogramming within the tumor microenvironment (TME) has been proved intimately involved in the initiation and malignant progression of CRC. Signal messengers, including cytokines, metabolites, and exosomes among others, derived from cancer cells can be utilized by the surrounding cells within the TME to induce metabolic alteration and cancer-associated transformation. In turn, the cargos secreted from cancer-associate cells further provide the nutrition and energy supply for cancer cells, supporting their metabolic reprogramming to promote proliferation, migration, metastasis, and radiochemoresistance. In this review, we focus on the main cellular components in the TME: CAFs, TAMs, lymphocytes and neutrophils, and enumerate and integrate how the metabolic interactions between these components and cancer cells reshape TME to foster CRC malignancy.
    Keywords:  Colorectal cancer; Metabolic reprogramming; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2022.188797
  4. Sci Rep. 2022 Sep 14. 12(1): 15437
    ADSCs stimulated by resistin promote breast cancer cell malignancy via CXCL5 in a breast cancer coculture model.
    Yen-Yun Wang, Amos C Hung, Yi-Chia Wu, Steven Lo, Huan-Da Chen, Yuk-Kwan Chen, Ya-Ching Hsieh, Stephen Chu-Sung Hu, Ming-Feng Hou, Shyng-Shiou F Yuan.
      The tumor microenvironment represents one of the main obstacles in breast cancer treatment owing to the presence of heterogeneous stromal cells, such as adipose-derived stem cells (ADSCs), that may interact with breast cancer cells and promote cancer development. Resistin is an adipocytokine associated with adverse breast cancer progression; however, its underlying mechanisms in the context of the breast tumor microenvironment remain largely unidentified. Here, we utilized a transwell co-culture model containing patient-derived ADSCs and breast cancer cell lines to investigate their potential interaction, and observed that breast cancer cells co-cultured with resistin-treated ADSCs (R-ADSCs) showed enhanced cancer cell growth and metastatic ability. Screening by proteome arrays revealed that C-X-C motif chemokine ligand 5 (CXCL5) was released in the conditioned medium of the co-culture system, and phosphorylated ERK was increased in breast cancer cells after co-culture with R-ADSCs. Breast cancer cells treated with the recombinant proteins of CXCL5 showed similarly enhanced cell migration and invasion ability as occurred in the co-culture model, whereas application of neutralizing antibodies against CXCL5 reversed these phenomena. The orthotopic xenograft in mice by breast cancer cells after co-culture with R-ADSCs had a larger tumor growth and more CXCL5 expression than control. In addition, clinical analysis revealed a positive correlation between the expression of resistin and CXCL5 in both tumor tissues and serum specimens of breast cancer patients. The current study suggests that resistin-stimulated ADSCs may interact with breast cancer cells in the tumor microenvironment via CXCL5 secretion, leading to breast cancer cell malignancy.
    DOI:  https://doi.org/10.1038/s41598-022-19290-6
  5. Mol Syst Biol. 2022 Sep;18(9): e10716
    Sorting-free metabolic profiling uncovers the vulnerability of fatty acid β-oxidation in in vitro quiescence models.
    Karin Ortmayr, Mattia Zampieri.
      Quiescent cancer cells are rare nondiving cells with the unique ability to evade chemotherapies and resume cell division after treatment. Despite the associated risk of cancer recurrence, how cells can reversibly switch between rapid proliferation and quiescence remains a long-standing open question. By developing a unique methodology for the cell sorting-free separation of metabolic profiles in cell subpopulations in vitro, we unraveled metabolic characteristics of quiescent cells that are largely invariant to basal differences in cell types and quiescence-inducing stimuli. Consistent with our metabolome-based analysis, we show that impairing mitochondrial fatty acid β-oxidation (FAO) can induce apoptosis in quiescence-induced cells and hamper their return to proliferation. Our findings suggest that in addition to mediating energy and redox balance, FAO can play a role in preventing the buildup of toxic intermediates during transitioning to quiescence. Uncovering metabolic strategies to enter, maintain, and exit quiescence can reveal fundamental principles in cell plasticity and new potential therapeutic targets beyond cancer.
    Keywords:  cellular quiescence; fatty acid oxidation; metabolic adaptation; quiescence-proliferation transition; trimetazidine
    DOI:  https://doi.org/10.15252/msb.202110716
  6. Lancet Gastroenterol Hepatol. 2022 Oct;pii: S2468-1253(22)00282-5. [Epub ahead of print]7(10): 911
    Warburg: father of the metabolic approach to cancer.
    Chris Wortley.
      
    DOI:  https://doi.org/10.1016/S2468-1253(22)00282-5
  7. Oncogenesis. 2022 Sep 15. 11(1): 56
    Hypoxia promotes an inflammatory phenotype of fibroblasts in pancreatic cancer.
    Ashley M Mello, Tenzin Ngodup, Yusoo Lee, Katelyn L Donahue, Jinju Li, Arvind Rao, Eileen S Carpenter, Howard C Crawford, Marina Pasca di Magliano, Kyoung Eun Lee.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive fibroinflammatory stroma and often experiences conditions of insufficient oxygen availability or hypoxia. Cancer-associated fibroblasts (CAF) are a predominant and heterogeneous population of stromal cells within the pancreatic tumor microenvironment. Here, we uncover a previously unrecognized role for hypoxia in driving an inflammatory phenotype in PDAC CAFs. We identify hypoxia as a strong inducer of tumor IL1ɑ expression, which is required for inflammatory CAF (iCAF) formation. Notably, iCAFs preferentially reside in hypoxic regions of PDAC. Our data implicate hypoxia as a critical regulator of CAF heterogeneity in PDAC.
    DOI:  https://doi.org/10.1038/s41389-022-00434-2
  8. J Oncol. 2022 ;2022 4257359
    Targeting Strategies for Aberrant Lipid Metabolism Reprogramming and the Immune Microenvironment in Esophageal Cancer: A Review.
    Meng-Ying Cui, Xing Yi, Zhen-Zhen Cao, Dan-Xia Zhu, Jun Wu.
      Esophageal cancer is of high importance to occurrence, development, and treatment resistance. As evidenced by recent studies, pathways (e.g., Wnt/β-catenin, AMPK, and Hippo) are critical to the proliferation, differentiation, and self-renewal of esophageal cancer. In addition, the above pathways play a certain role in regulating esophageal cancer and act as potential therapeutic targets. Over the past few years, the function of lipid metabolism in controlling tumor cells and immune cells has aroused extensive attention. It has been reported that there are intricate interactions between lipid metabolism reprogramming between immune and esophageal cancer cells, whereas molecular mechanisms should be studied in depth. Immune cells have been commonly recognized as a vital player in the esophageal cancer microenvironment, having complex crosstalk with cancer cells. It is increasingly evidenced that the function of immune cells in the tumor microenvironment (TME) is significantly correlated with abnormal lipid metabolism. In this review, the latest findings in lipid metabolism reprogramming in TME are summarized, and the above findings are linked to esophageal cancer progression. Aberrant lipid metabolism and associated signaling pathways are likely to serve as a novel strategy to treat esophageal cancer through lipid metabolism reprogramming.
    DOI:  https://doi.org/10.1155/2022/4257359
  9. Cell Mol Life Sci. 2022 Sep 14. 79(10): 517
    Metabolic reprogramming in the OPA1-deficient cells.
    Wenting Dai, Zhichao Wang, Qiong A Wang, David Chan, Lei Jiang.
      OPA1, a dynamin-related GTPase mutated in autosomal dominant optic atrophy, is essential for the fusion of the inner mitochondrial membrane. Although OPA1 deficiency leads to impaired mitochondrial morphology, the role of OPA1 in central carbon metabolism remains unclear. Here, we aim to explore the functional role and metabolic mechanism of OPA1 in cell fitness beyond the control of mitochondrial fusion. We applied [U-13C]glucose and [U-13C]glutamine isotope tracing techniques to OPA1-knockout (OPA1-KO) mouse embryonic fibroblasts (MEFs) compared to OPA1 wild-type (OPA1-WT) controls. Furthermore, the resulting tracing data were integrated by metabolic flux analysis to understand the underlying metabolic mechanism through which OPA1 deficiency reprograms cellular metabolism. OPA1-deficient MEFs were depleted of intracellular citrate, which was consistent with the decreased oxygen consumption rate in these cells with mitochondrial fission that is not balanced by mitochondrial fusion. Whereas oxidative glucose metabolism was impaired, OPA1-deficient cells activated glutamine-dependent reductive carboxylation and subsequently relied on this reductive metabolism to produce cytosolic citrate as a predominant acetyl-CoA source for de novo fatty acid synthesis. Prevention of cytosolic glutamine reductive carboxylation by GSK321, an inhibitor of isocitrate dehydrogenase 1 (IDH1), largely repressed lipid synthesis and blocked cell proliferation in OPA1-deficient MEFs. Our data support that, when glucose oxidation failed to support lipogenesis and proliferation in cells with unbalanced mitochondrial fission, OPA1 deficiency stimulated metabolic anaplerosis into glutamine-dependent reductive carboxylation in an IDH1-mediated manner.
    Keywords:  Cell growth; Citrate; De novo lipogenesis; OPA1 dysfunction; Oxidative metabolism; Reductive carboxylation
    DOI:  https://doi.org/10.1007/s00018-022-04542-5
  10. Chemphyschem. 2022 Sep 14.
    Metabolic Tumor Imaging with Rapidly Signal-Enhanced 1-13C-Pyruvate-d3.
    Theresa Hune, Salvatore Mamone, Henning Schroeder, Anil P Jagtap, Sonja Sternkopf, Gabriele Stevanato, Sergey Korchak, Claudia Fokken, Christoph A Müller, Andreas B Schmidt, Dorothea Becker, Stefan Glöggler.
      The metabolism of malignant cells differs significantly from that of healthy cells and thus, it is possible to perform metabolic imaging to reveal not only the exact location of a tumor, but also intratumoral areas of high metabolic activity. Herein, we demonstrate the feasibility of metabolic tumor imaging using signal-enhanced 1- 13 C-pyruvate-d 3 , which is rapidly enhanced via para-hydrogen, and thus, the signal is amplified by several orders of magnitudes in less than a minute. Using as a model, human melanoma xenografts injected with signal-enhanced 1- 13 C-pyruvate-d3, we show that the conversion of pyruvate into lactate can be monitored along with its kinetics, which could pave the way  for rapidly detecting and monitoring changes in tumor metabolism.
    Keywords:  MRI; NMR; Para-hydrogen; cancer; hyperpolarization
    DOI:  https://doi.org/10.1002/cphc.202200615
  11. Front Mol Biosci. 2022 ;9 937865
    Metabolic profiling of induced acute pancreatitis and pancreatic cancer progression in a mutant Kras mouse model.
    Tatiana J Carneiro, Joana Pinto, Eva M Serrao, António S Barros, Kevin M Brindle, Ana M Gil.
      Untargeted Nuclear Magnetic Resonance (NMR) metabolomics of polar extracts from the pancreata of a caerulin-induced mouse model of pancreatitis (Pt) and of a transgenic mouse model of pancreatic cancer (PCa) were used to find metabolic markers of Pt and to characterize the metabolic changes accompanying PCa progression. Using multivariate analysis a 10-metabolite metabolic signature specific to Pt tissue was found to distinguish the benign condition from both normal tissue and precancerous tissue (low grade pancreatic intraepithelial neoplasia, PanIN, lesions). The mice pancreata showed significant changes in the progression from normal tissue, through low-grade and high-grade PanIN lesions to pancreatic ductal adenocarcinoma (PDA). These included increased lactate production, amino acid changes consistent with enhanced anaplerosis, decreased concentrations of intermediates in membrane biosynthesis (phosphocholine and phosphoethanolamine) and decreased glycosylated uridine phosphates, reflecting activation of the hexosamine biosynthesis pathway and protein glycosylation.
    Keywords:  KRAS; PanIN; metabolomics; nuclear magnetic resonance (1H-NMR); pancreatic cancer; pancreatic ductal adenocarcinoma; pancreatitis
    DOI:  https://doi.org/10.3389/fmolb.2022.937865
  12. Cancer Cell. 2022 Sep 12. pii: S1535-6108(22)00385-3. [Epub ahead of print]40(9): 895-900
    Spatial transcriptomics.
    Ana C Anderson, Itai Yanai, Lucy R Yates, Linghua Wang, Alexander Swarbrick, Peter Sorger, Sandro Santagata, Wolf H Fridman, Qiang Gao, Livnat Jerby, Benjamin Izar, Lulu Shang, Xiang Zhou.
      Spatial transcriptomics, with other spatial technologies, has enabled scientists to dissect the organization and interaction of different cell types within the tumor microenvironment. We asked experts to discuss some aspects of this technology from revealing the tumor microenvironment and heterogeneity, to tracking tumor evolution, to guiding tumor therapy, to current technical challenges.
    DOI:  https://doi.org/10.1016/j.ccell.2022.08.021
  13. Cancer Immunol Res. 2022 Sep 12. pii: CIR-22-0407. [Epub ahead of print]
    The tumour microenvironment of clear cell ovarian cancer.
    Michael-John Devlin, Rowan Miller, Florian Laforets, Panoraia Kotantaki, Dale W Garsed, Rebecca Kristeleit, David D Bowtell, Jacqueline McDermott, Eleni Maniati, Frances R Balkwill.
      Some patients with advanced clear cell ovarian cancer (CCOC) respond to immunotherapy; however, little is known about the tumor microenvironment (TME) of this relatively rare disease. Here, we describe a comprehensive quantitative and topographical analysis of biopsies from forty-five patients, nine with FIGO stage I/II (early CCOC) and thirty-six with FIGO stage III/IV (advanced CCOC). We investigated fourteen immune cell phenotype markers, PD-1 and ligands, and collagen structure and texture. We interrogated a microarray dataset from a second cohort of twenty-nine patients and compared the TMEs of ARID1A-wildtype (ARID1Awt) versus ARID1A-mutant (ARID1Amut) disease. We found significant variations in immune cell frequency and phenotype, checkpoint expression, and collagen matrix between the malignant cell area (MCA), leading edge (LE), and stroma. The MCA had the largest population of CD138+ plasma cells, the LE had more CD20+ B cells and T cells, whereas the stroma had more mast cells and αSMA+ fibroblasts. PD-L2 was expressed predominantly on malignant cells and was the dominant PD-1 ligand. Compared to early-CCOC, advanced-stage disease had significantly more fibroblasts and a more complex collagen matrix, with microarray analysis indicating "TGFβ remodeling of the extracellular matrix" as the most significantly enriched pathway. Data showed significant differences in immune cell populations, collagen matrix, and cytokine expression between ARID1Awt and ARID1Amut CCOC, which may reflect different paths of tumorigenesis and the relationship to endometriosis. Increased infiltration of CD8+ T cells within the MCA and CD4+ T cells at the LE and stroma significantly associated with decreased overall survival.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-22-0407
  14. Int Immunopharmacol. 2022 Sep 07. pii: S1567-5769(22)00677-4. [Epub ahead of print]112 109193
    NK cell immunometabolism as target for liver cancer therapy.
    Junqi Wang, Xiaolin Liu, Tianqiang Jin, Yuqing Cao, Yu Tian, Feng Xu.
      Natural killer (NK) cells are being used effectively as a potential candidate in tumor immunotherapy. However, the migration and transport of NK cells to solid tumors is inadequate. NK cell dysfunction, tumor invasiveness, and metastasis are associated with altered metabolism of NK cells in the liver cancer microenvironment. However, in liver cancers, metabolic impairment of NK cells is still not understood fully. Evidence from various sources has shown that the interaction of NK cell's immune checkpoints with its metabolic checkpoints is responsible for the regulation of the development and function of these cells. How immune checkpoints contribute to metabolic programming is still not fully understood, and how this can be beneficial needs a better understanding, but they are emerging to be incredibly compelling to rebuilding the function of NK cells in the tumor. It is expected to represent a potential aim that focuses on improving the efficacy of therapies based on NK cells for treating liver cancer. Here, the recent advancements made to understand the NK cell's metabolic reprogramming in liver cancer have been summarized, along with the possible interplay between the immune and the metabolic checkpoints in NK cell function. Finally, an overview of some potential metabolic-related targets that can be used for liver cancer therapy treatment has been presented.
    Keywords:  Immune checkpoints; Immunometabolism; Liver cancer; Natural killer cells
    DOI:  https://doi.org/10.1016/j.intimp.2022.109193
  15. Mol Metab. 2022 Sep 13. pii: S2212-8778(22)00169-7. [Epub ahead of print] 101600
    Carboxylesterase 2 induces mitochondrial dysfunction via disrupting lipid homeostasis in oral squamous cell carcinoma.
    Xijuan Chen, Qin Liu, Yingyao Chen, Lixuan Wang, Rongchun Yang, Weilin Zhang, Xue Pan, Siyuan Zhang, Chuwen Chen, Tong Wu, Juan Xia, Bin Cheng, Xiaobing Chen, Xianyue Ren.
       INTRODUCTION: Oral squamous cell carcinoma (OSCC) is characterized by high recurrence and metastasis and places a heavy burden on societies worldwide. Cancer cells thrive in a changing microenvironment by reprogramming lipidomic metabolic processes to provide nutrients and energy, activate oncogenic signaling pathways, and manage redox homeostasis to avoid lipotoxicity. The mechanism by which OSCC cells maintain lipid homeostasis during malignant progression is unclear.
    METHODS: The altered expression of fatty acid (FA) metabolism genes in OSCC, compared with that in normal tissues, and in OSCC patients with or without recurrence or metastasis were determined using public data from the TCGA and GEO databases. Immunohistochemistry was performed to examine the carboxylesterase 2 (CES2) protein level in our own cohort. CCK-8 and Transwell assays and an in vivo xenograft model were used to evaluate the biological functions of CES2. Mass spectrometry and RNA sequencing were performed to determine the lipidome and transcriptome alterations induced by CES2. Mitochondrial mass, mtDNA content, mitochondrial membrane potential, ROS levels, and oxygen consumption and apoptosis rates were evaluated to determine the effects of CES2 on mitochondrial function in OSCC.
    RESULTS: CES2 was downregulated in OSCC patients, especially those with recurrence or metastasis. CES2high OSCC patients showed better overall survival than CES2low OSCC patients. Restoring CES2 expression reduced OSCC cell viability and suppressed their migration and invasion in vitro, and it inhibited OSCC tumor growth in vivo. CES2 reprogrammed lipid metabolism in OSCC cells by hydrolyzing neutral lipid diacylglycerols (DGs) to release free fatty acids and reduce the membrane structure lipid phospholipids (PLs) synthesis. Free FAs were converted to acyl-carnitines (CARs) and transferred to mitochondria for oxidation, which induced reactive oxygen species (ROS) accumulation, mitochondrial damage, and apoptosis activation. Furthermore, the reduction in signaling lipids, e.g., DGs, PLs and substrates, suppressed PI3K/AKT/MYC signaling pathways. Restoring MYC rescued the diminished cell viability, suppressed migratory and invasive abilities, damaged mitochondria and reduced apoptosis rate induced by CES2.
    CONCLUSIONS: We demonstrated that CES2 downregulation plays an important role in OSCC by maintaining lipid homeostasis and reducing lipotoxicity during tumor progression and may provide a potential therapeutic target for OSCC.
    Keywords:  CES2; Oral squamous cell carcinoma; diacylglycerols; lipotoxicity; mitochondrial damage
    DOI:  https://doi.org/10.1016/j.molmet.2022.101600
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