bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2024–12–29
ten papers selected by
Oltea Sampetrean, Keio University
  1. Oncometabolites in pancreatic cancer: Strategies and its implications.
  2. Deciphering Colorectal Cancer-Hepatocyte Interactions: A Multiomic Platform for Interrogation of Metabolic Crosstalk in the Liver-Tumor Microenvironment.
  3. Regulation of Oxygen in the Tumor Microenvironment Synergizes with Immunotherapy to Suppress Tumor Progression.
  4. A Collection of Novel Antitumor Agents That Regulate Lipid Metabolism in the Tumor Microenvironment.
  5. Integrative systems-level analysis reveals a contextual crosstalk between hypoxia and global metabolism in human breast tumors.
  6. Limiting serine availability during tumor progression promotes muscle wasting in cancer cachexia.
  7. Genome-scale modeling identifies dynamic metabolic vulnerabilities during the epithelial to mesenchymal transition.
  8. Activated kynurenine pathway metabolism by YKL-40 establishes an inhibitory immune microenvironment and drives glioblastoma development.
  9. NGF-mediated crosstalk: unraveling the influence of metabolic deregulation on the interplay between neural and pancreatic cancer cells and its impact on patient outcomes.
  10. Distinct microbes, metabolites, and the host genome define the multi-omics profiles in right-sided and left-sided colon cancer.
  1. World J Exp Med. 2024 Dec 20. 14(4): 96005
    Oncometabolites in pancreatic cancer: Strategies and its implications.
    Arunima Maiti, Susmita Mondal, Sounetra Choudhury, Arnab Bandopadhyay, Sanghamitra Mukherjee, Nilabja Sikdar.
      Pancreatic cancer (PanCa) is a catastrophic disease, being third lethal in both the genders around the globe. The possible reasons are extreme disease invasiveness, highly fibrotic and desmoplastic stroma, dearth of confirmatory diagnostic approaches and resistance to chemotherapeutics. This inimitable tumor microenvironment (TME) or desmoplasia with excessive extracellular matrix accumulation, create an extremely hypovascular, hypoxic and nutrient-deficient zone inside the tumor. To survive, grow and proliferate in such tough TME, pancreatic tumor and stromal cells transform their metabolism. Transformed glucose, glutamine, fat, nucleotide metabolism and inter-metabolite communication between tumor and TME in synergism, impart therapy resistance, and immunosuppression in PanCa. Thus, a finer knowledge of altered metabolism would uncover its metabolic susceptibilities. These unique metabolic targets may help to device novel diagnostic/prognostic markers and therapeutic strategies for better management of PanCa. In this review, we sum up reshaped metabolic pathways in PanCa to formulate detection and remedial strategies of this devastating disease.
    Keywords:  Anti-pancreatic cancer therapy; Metabolic reprogramming; Metabolic symbiosis; Pancreatic cancer; Therapy resistance
    DOI:  https://doi.org/10.5493/wjem.v14.i4.96005
  2. bioRxiv. 2024 Dec 14. pii: 2024.12.06.627264. [Epub ahead of print]
    Deciphering Colorectal Cancer-Hepatocyte Interactions: A Multiomic Platform for Interrogation of Metabolic Crosstalk in the Liver-Tumor Microenvironment.
    Alisa B Nelson, Lyndsay E Reese, Elizabeth Rono, Eric D Queathem, Yinjie Qiu, Braedan M McCluskey, Alexandra Crampton, Eric Conniff, Katherine Cummins, Ella Boytim, Senali Dansou, Justin Hwang, Sandra Safo, Patrycja Puchalska, David K Wood, Kathryn L Schwertfeger, Peter A Crawford.
      Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to adapt to and exploit their microenvironment for sustained growth. The liver is a common site of metastasis, but the interactions between tumor cells and hepatocytes remain poorly understood. In the context of liver metastasis, these interactions play a crucial role in promoting tumor survival and progression. This study leverages multiomics coverage of the microenvironment via liquid chromatography and high-resolution, high-mass accuracy mass spectrometry-based untargeted metabolomics, 13 C-stable isotope tracing, and RNA sequencing to uncover the metabolic impact of co-localized primary hepatocytes and a colon adenocarcinoma cell line, SW480, using a 2D co-culture model. Metabolic profiling revealed disrupted Warburg metabolism with an 80% decrease in glucose consumption and 94% decrease in lactate production by hepatocyte-SW480 co-cultures relative to SW480 control cultures. Decreased glucose consumption was coupled with alterations in glutamine and ketone body metabolism, suggesting a possible fuel switch upon co-culturing. Further, integrated multiomic analysis indicates that disruptions in metabolic pathways, including nucleoside biosynthesis, amino acids, and TCA cycle, correlate with altered SW480 transcriptional profiles and highlight the importance of redox homeostasis in tumor adaptation. Finally, these findings were replicated in 3-dimensional microtissue organoids. Taken together, these studies support a bioinformatic approach to study metabolic crosstalk and discovery of potential therapeutic targets in preclinical models of the tumor microenvironment.
    DOI:  https://doi.org/10.1101/2024.12.06.627264
  3. J Funct Biomater. 2024 Nov 25. pii: 357. [Epub ahead of print]15(12):
    Regulation of Oxygen in the Tumor Microenvironment Synergizes with Immunotherapy to Suppress Tumor Progression.
    Shoucheng Wang, Yongjie Chi, Danyang Wang, Kai Zhao, Lianyan Wang.
      Hypoxia represents a crucial characteristic of the tumor microenvironment, which is closely related to cell proliferation, angiogenesis, and metabolic responses. These factors will further promote tumor progression, increase tumor invasion, and enhance tumor metastasis potential. A hypoxic microenvironment will also inhibit the activity of infiltrated immune cells in the tumor microenvironment, leading to the failure of cancer immunotherapy. Additionally, the hypoxic tumor microenvironment contributes to resistance to conventional therapies and leads to unfavorable prognoses. This review discusses advancements in strategies aimed at ameliorating tumor hypoxia within the microenvironment and modulating immune cell responses against tumors.
    Keywords:  hypoxia; immunosuppression; tumor microenvironment
    DOI:  https://doi.org/10.3390/jfb15120357
  4. J Med Chem. 2024 Dec 27.
    A Collection of Novel Antitumor Agents That Regulate Lipid Metabolism in the Tumor Microenvironment.
    Jiahao Zhang, Sha Xu, Lingfeng Yue, Hongrui Lei, Xin Zhai.
      Lipid metabolism disorder is the cause of one of the most significant metabolic changes in tumors. In the process of tumor occurrence and development, tumor cells choose a continuous metabolic adaptation to accommodate the changing environment to the maximum extent possible. In a variety of tumors, the uptake, production, and storage of lipids are generally upregulated. Tumor cells take advantage of lipid metabolism to access basic energy, biofilm components, and signal molecules of the tumor microenvironment required for proliferation, survival, invasion, and metastasis. This Perspective briefly uncovers the main metabolic processes and key factors involved in lipid metabolism reprogramming, mainly related to lipid uptake, de novo synthesis and storage of fatty acids, oxidation of fatty acids, cholesterol synthesis, and related regulatory factors. From a medicinal chemistry perspective, agents against related key targets are reviewed, expecting to pave the way for promising antitumor drugs with prospects for application through lipid metabolism reprogramming.
    DOI:  https://doi.org/10.1021/acs.jmedchem.4c02809
  5. Mol Oncol. 2024 Dec 27.
    Integrative systems-level analysis reveals a contextual crosstalk between hypoxia and global metabolism in human breast tumors.
    Raefa Abou Khouzam, Salem Chouaib, Mohammad Askandar Iqbal.
      Hypoxia is known to induce reprogramming of glucose metabolism in cancer. However, the impact of hypoxia on global metabolism remains poorly understood. Here, using the systems approach, we evaluated the potential crosstalk between hypoxia and global metabolism using data from > 2000 breast tumors. Tumor samples were scored for hypoxia and 90 metabolic pathways, and these metrics were subjected to an analysis pipeline. Hypoxia showed a very strong association with metabolic aggression and an overall contextual relationship with metabolism. Out of three (M1, M2, and M3) metabolic types in breast cancer, M3 exhibited the strongest relationship with hypoxia; that is, high hypoxic tumors were also metabolically deregulated. Further, the overall correlation pattern between hypoxia and metabolic pathway scores was specific to each type, with M1 showing maximal sensitivity to hypoxia, followed by M2 and then M3. Experimental validation using metabolic inhibitors on cell lines with high or low hypoxia scores further confirmed the metabolic type-dependence of hypoxia. In addition, evaluation of the impact of hypoxia on cancer pathways other than metabolic ones revealed a potential role of hypoxia in immune evasive characteristic of M3 tumors. Overall, the results suggest a complex interplay between hypoxia and metabolism in the context of human breast tumors, with potential implications for both basic cancer biology and breast cancer therapy.
    Keywords:  Warburg effect; breast cancer; cancer metabolism; hypoxia; systems biology
    DOI:  https://doi.org/10.1002/1878-0261.13762
  6. Cell Death Discov. 2024 Dec 21. 10(1): 510
    Limiting serine availability during tumor progression promotes muscle wasting in cancer cachexia.
    Erica Pranzini, Livio Muccillo, Ilaria Nesi, Alice Santi, Caterina Mancini, Giulia Lori, Massimo Genovese, Tiziano Lottini, Giuseppina Comito, Anna Caselli, Annarosa Arcangeli, Lina Sabatino, Vittorio Colantuoni, Maria Letizia Taddei, Paolo Cirri, Paolo Paoli.
      Cancer cachexia is a multifactorial syndrome characterized by a progressive loss of body weight occurring in about 80% of cancer patients, frequently representing the leading cause of death. Dietary intervention is emerging as a promising therapeutic strategy to counteract cancer-induced wasting. Serine is the second most-consumed amino acid (AA) by cancer cells and has emerged to be strictly necessary to preserve skeletal muscle structure and functionality. Here, we demonstrate that decreased serine availability during tumor progression promotes myotubes diameter reduction in vitro and induces muscle wasting in in vivo mice models. By investigating the metabolic crosstalk between colorectal cancer cells and muscle cells, we found that incubating myotubes with conditioned media from tumor cells relying on exogenous serine consumption triggers pronounced myotubes diameter reduction. Accordingly, culturing myotubes in a serine-free medium induces fibers width reduction and suppresses the activation of the AKT-mTORC1 pathway with consequent impairment in protein synthesis, increased protein degradation, and enhanced expression of the muscle atrophy-related genes Atrogin1 and MuRF1. In addition, serine-starved conditions affect myoblast differentiation and mitochondrial oxidative metabolism, finally inducing oxidative stress in myotubes. Consistently, serine dietary deprivation strongly strengthens cancer-associated weight loss and muscle atrophy in mice models. These findings uncover serine consumption by tumor cells as a previously undisclosed driver in cancer cachexia, opening new routes for possible therapeutic approaches.
    DOI:  https://doi.org/10.1038/s41420-024-02271-1
  7. Commun Biol. 2024 Dec 27. 7(1): 1704
    Genome-scale modeling identifies dynamic metabolic vulnerabilities during the epithelial to mesenchymal transition.
    Rupa Bhowmick, Scott Campit, Shiva Krishna Katkam, Venkateshwar G Keshamouni, Sriram Chandrasekaran.
      Epithelial-to-mesenchymal transition (EMT) is a conserved cellular process critical for embryogenesis, wound healing, and cancer metastasis. During EMT, cells undergo large-scale metabolic reprogramming that supports multiple functional phenotypes including migration, invasion, survival, chemo-resistance and stemness. However, the extent of metabolic network rewiring during EMT is unclear. In this work, using genome-scale metabolic modeling, we perform a meta-analysis of time-course transcriptomics, time-course proteomics, and single-cell transcriptomics EMT datasets from cell culture models stimulated with TGF-β. We uncovered temporal metabolic dependencies in glycolysis and glutamine metabolism, and experimentally validated isoform-specific dependency on Enolase3 for cell survival during EMT. We derived a prioritized list of metabolic dependencies based on model predictions, literature mining, and CRISPR-Cas9 essentiality screens. Notably, enolase and triose phosphate isomerase reaction fluxes significantly correlate with survival of lung adenocarcinoma patients. Our study illustrates how integration of heterogeneous datasets using a mechanistic computational model can uncover temporal and cell-state-specific metabolic dependencies.
    DOI:  https://doi.org/10.1038/s42003-024-07408-7
  8. Cell Mol Life Sci. 2024 Dec 24. 82(1): 11
    Activated kynurenine pathway metabolism by YKL-40 establishes an inhibitory immune microenvironment and drives glioblastoma development.
    Hui Chen, Xuemei Zhang, Ziyi Wang, Jing Luo, Yingbin Liu, Rong Shao.
       BACKGROUND: Glioblastoma (GB) is the stage IV of glioma and mesenchymal GB represents the most common and malignant subtype characterized with elevated expression of a mesenchymal marker YKL-40 and resistance to immune drug therapy. Here, we determined if YKL-40 regulates kynurenine (Kyn) pathway (KP) metabolism that contributes to establishing an immune suppressive microenvironment in GB.
    METHODS: Tumor cells expressing YKL-40 from GB patients were isolated and activated cellular metabolisms were identified via gene microarray analysis. KP metabolism was determined by LC/MS/MS system. Indoleamine 2,3-dioxygenase 1 (IDO1), tryptophan 2,3-dioxygenase (TDO2), their regulatory transcription factors AhR and SRF were evaluated using WB. AhR and SRF transactivity was measured by luciferase reporter gene assays with binding motif mutation, while m6A-mediated AhR and SRF mRNA stability was determined in the presence of an METTL3inhibitor. YKL-40 and Kyn-induced tumor cell migration and CD8+ cytotoxic T cell (CTL) apoptosis were measured in cultured cells. Tumors cells expressing YKL-40 were injected to mouse brains to establish orthotpic tumor models. In GB, YKL-40, IDO1 and TDO2 expression was analyzed for correlation with patient survival.
    RESULTS: KP metabolism was activated in YKL-40-expressing tumor cells. YKL-40 divergently regulated IDO1 and TDO2 via induction of AhR and SRF, respectively. mRNA levels of AhR and SRF were stabilized by decreased METTL3 and YTHDF2. YKL-40 and Kyn secreted from tumor cells and infiltrating M2 macrophages cooperated to enhance tumor cell migration and inhibit CTL immunity. In xenografts, tumors expressing YKL-40 displayed the elevated KP metabolism and macrophage infiltration, but decreased CTLs. Treatment with an anti-PD-1 antibody Tislelizumab significantly increased YKL-40+ mouse survival. In GB, YKL-40 was positively correlated with IDO1 expression and both were associated with decreased survival, whereas IDO1 was negatively correlated with TDO2.
    CONCLUSION: YKL-40 upregulates IDO1 or TDO2 to activate KP metabolism, and coordinates with Kyn to establish an inhibitory tumor immune microenvironment, leading to tumor immune evasion.
    Keywords:  Glioblastoma (GB); Immune evasion; Indoleamine 2,3-dioxygenase 1 (IDO1); METTL3; Tryptophan 2,3-dioxygenase (TDO2); YKL-40 (CHI3L1)
    DOI:  https://doi.org/10.1007/s00018-024-05497-5
  9. Front Pharmacol. 2024 ;15 1499414
    NGF-mediated crosstalk: unraveling the influence of metabolic deregulation on the interplay between neural and pancreatic cancer cells and its impact on patient outcomes.
    Francesca Trentini, Virginia Agnetti, Martina Manini, Elisa Giovannetti, Ingrid Garajová.
      Neural invasion is one of the most common routes of invasion in pancreatic cancer and it is responsible for the high rate of tumor recurrence after surgery and the pain generation associated with pancreatic cancer. Several molecules implicated in neural invasion are also responsible for pain onset including NGF belonging to the family of neutrophins. NGF released by cancer cells can sensitize sensory nerves which in turn results in severe pain. NGF receptors, TrkA and P75NTR, are expressed on both PDAC cells and nerves, strongly suggesting their role in neural invasion. The crosstalk between the nervous system and cancer cells has emerged as an important regulator of pancreatic cancer and its microenvironment. Nerve cells influence the pancreatic tumor microenvironment and these interactions are important for cancer metabolism reprogramming and tumor progression. In this review, we summarized the current knowledge on the interaction between nerves and pancreatic cancer cells and its impact on cancer metabolism.
    Keywords:  NGF; metabolism; neural invasion; pain; pancreatic cancer
    DOI:  https://doi.org/10.3389/fphar.2024.1499414
  10. Microbiome. 2024 Dec 28. 12(1): 274
    Distinct microbes, metabolites, and the host genome define the multi-omics profiles in right-sided and left-sided colon cancer.
    Lei Liang, Cheng Kong, Jinming Li, Guang Liu, Jinwang Wei, Guan Wang, Qinying Wang, Yongzhi Yang, Debing Shi, Xinxiang Li, Yanlei Ma.
       BACKGROUND: Studies have reported clinical heterogeneity between right-sided colon cancer (RCC) and left-sided colon cancer (LCC). However, none of these studies used multi-omics analysis combining genetic regulation, microbiota, and metabolites to explain the site-specific difference.
    METHODS: Here, 494 participants from a 16S rRNA gene sequencing cohort (50 RCC, 114 LCC, and 100 healthy controls) and a multi-omics cohort (63 RCC, 79 LCC, and 88 healthy controls) were analyzed. 16S rRNA gene, metagenomic sequencing, and metabolomics analyses of fecal samples were evaluated to identify tumor location-related bacteria and metabolites. Whole-exome sequencing (WES) and transcriptome sequencing (RNA-seq) were conducted to obtain the mutation burden and genomic expression pattern.
    RESULTS: We found unique profiles of the intestinal microbiome, metabolome, and host genome between RCC and LCC. The bacteria Flavonifractor plautii (Fp) and Fusobacterium nucleatum, the metabolites L-phenylalanine, and the host genes PHLDA1 and WBP1 were the key omics features of RCC; whereas the bacteria Bacteroides sp. A1C1 (B.A1C1) and Parvimonas micra, the metabolites L-citrulline and D-ornithine, and the host genes TCF25 and HLA-DRB5 were considered the dominant omics features in LCC. Multi-omics correlation analysis indicated that RCC-enriched Fp was related to the accumulation of the metabolite L-phenylalanine and the suppressed WBP1 signal in RCC patients. In addition, LCC-enriched B.A1C1 was associated with the accumulation of the metabolites D-ornithine and L-citrulline as well as activation of the genes TCF25, HLA-DRB5, and AC079354.1.
    CONCLUSION: Our findings identify previously unknown links between intestinal microbiota alterations, metabolites, and host genomics in RCC vs. LCC, suggesting that it may be possible to treat colorectal cancer (CRC) by targeting the gut microbiota-host interaction. Video Abstract.
    Keywords:  Host genomics; Left-sided colon cancer; Metabolomics; Metagenomics; Multi-omics analysis; Right-sided colon cancer
    DOI:  https://doi.org/10.1186/s40168-024-01987-7
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