bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2024–09–15
seven papers selected by
Oltea Sampetrean, Keio University
  1. PAF1/HIF1α axis rewires the glycolytic metabolism to fuel aggressiveness of pancreatic cancer.
  2. Naive primary neutrophils play a dual role in the tumor microenvironment.
  3. Cancer knocks you out by fasting: Cachexia as a consequence of metabolic alterations in cancer.
  4. A pinch of salt boosts T cell function.
  5. CAF-induced physical constraints controlling T cell state and localization in solid tumours.
  6. Hypoxia-induced BNIP3 facilitates the progression and metastasis of uveal melanoma by driving metabolic reprogramming.
  7. Spatial single-cell isotope tracing reveals heterogeneity of de novo fatty acid synthesis in cancer.
  1. Cancer Metab. 2024 Sep 06. 12(1): 26
    PAF1/HIF1α axis rewires the glycolytic metabolism to fuel aggressiveness of pancreatic cancer.
    Ayoola O Ogunleye, Neelanjana Gayen, Sanchita Rauth, Saravanakumar Marimuthu, Rama Krishna Nimmakayala, Zahraa W Alsafwani, Jesse L Cox, Surinder K Batra, Moorthy P Ponnusamy.
       BACKGROUND: PAF1/PD2 deregulation contributes to tumorigenesis, drug resistance, and cancer stem cell maintenance in Pancreatic Cancer (PC). Recent studies demonstrate that metabolic reprogramming plays a role in PC progression, but the mechanism is poorly understood. Here, we focused on examining the role of PAF1/PD2 in the metabolic rewiring of PC.
    METHODS: Cell lines were transfected with shRNAs to knockdown PAF1/PD2. Metabolic genes regulated by PAF1/PD2 were identified by qPCR/western blot, and metabolic assays were performed. Immunoprecipitations/ChIP were performed to identify PAF1/PD2 protein partners and confirm PAF1/HIF1α sub-complex binding to LDHA.
    RESULTS: PAF1 and LDHA showed progressively increased expression in human pancreatic tumor sections. Aerobic glycolysis genes were downregulated in PAF1-depleted PC cells. Metabolic assays indicated a decreased lactate production and glucose uptake in knockdown cells. Furthermore, PAF1/PD2 depletion showed a reduced glycolytic rate and increased oxidative phosphorylation by ECAR and OCR analysis. Interestingly, we identified that HIF1α interacts and co-localizes with PAF1, specifically in PC cells. We also observed that the PAF1/PD2-HIF1α complex binds to the LDHA promoter to regulate its expression, reprogramming the metabolism to utilize the aerobic glycolysis pathway preferentially.
    CONCLUSION: Overall, the results indicate that PAF1/PD2 rewires PC metabolism by interacting with HIF1α to regulate the expression of LDHA.
    Keywords:  Aerobic glycolysis; Metabolism; Pancreatic cancer
    DOI:  https://doi.org/10.1186/s40170-024-00354-2
  2. iScience. 2024 Sep 20. 27(9): 110632
    Naive primary neutrophils play a dual role in the tumor microenvironment.
    Kehinde Adebayo Babatunde, Rupsa Datta, Nathan W Hendrikse, Jose M Ayuso, Anna Huttenlocher, Melissa C Skala, David J Beebe, Sheena C Kerr.
      The tumor microenvironment (TME) is characterized by a network of cancer cells, recruited immune cells, and extracellular matrix (ECM). However, the specific role of neutrophils during tumor development, and their interactions with other immune cells is still not well understood. Here, we use both standard well plate culture and an under oil microfluidic (UOM) assay with an integrated ECM bridge to elucidate how naive primary neutrophils respond to tumor cells. Our data demonstrated that tumor cells trigger cluster formation in neutrophils accompanied with the generation of reactive oxygen species (ROS) and neutrophil extracellular trap (NET) release. Using label-free optical metabolic imaging (OMI), we observed changes in the metabolic activities of primary neutrophils during the different clustering phases when challenged with tumor cells. Finally, our data demonstrates that neutrophils in direct contact, or in close proximity, with tumor cells exhibit greater metabolic activities compared to non-contact neutrophils.
    Keywords:  Cancer; Cell biology; Immunology; Microenvironment
    DOI:  https://doi.org/10.1016/j.isci.2024.110632
  3. J Cell Physiol. 2024 Sep 08. e31417
    Cancer knocks you out by fasting: Cachexia as a consequence of metabolic alterations in cancer.
    Salvatore Cortellino, Margherita D'Angelo, Massimiliano Quintiliani, Antonio Giordano.
      Neoplastic transformation reprograms tumor and surrounding host cell metabolism, increasing nutrient consumption and depletion in the tumor microenvironment. Tumors uptake nutrients from neighboring normal tissues or the bloodstream to meet energy and anabolic demands. Tumor-induced chronic inflammation, a high-energy process, also consumes nutrients to sustain its dysfunctional activities. These tumor-related metabolic and physiological changes, including chronic inflammation, negatively impact systemic metabolism and physiology. Furthermore, the adverse effects of antitumor therapy and tumor obstruction impair the endocrine, neural, and gastrointestinal systems, thereby confounding the systemic status of patients. These alterations result in decreased appetite, impaired nutrient absorption, inflammation, and shift from anabolic to catabolic metabolism. Consequently, cancer patients often suffer from malnutrition, which worsens prognosis and increases susceptibility to secondary adverse events. This review explores how neoplastic transformation affects tumor and microenvironment metabolism and inflammation, leading to poor prognosis, and discusses potential strategies and clinical interventions to improve patient outcomes.
    Keywords:  cachexia; cancer metabolism; detary interventions; inflammation; malnutrition
    DOI:  https://doi.org/10.1002/jcp.31417
  4. Nat Immunol. 2024 Sep 09.
    A pinch of salt boosts T cell function.
    Karina L Hajdu, Lorène Rousseau, Ping-Chih Ho.
      
    DOI:  https://doi.org/10.1038/s41590-024-01946-2
  5. Nat Rev Cancer. 2024 Sep 09.
    CAF-induced physical constraints controlling T cell state and localization in solid tumours.
    Ludovica Arpinati, Giulia Carradori, Ruth Scherz-Shouval.
      Solid tumours comprise cancer cells that engage in continuous interactions with non-malignant cells and with acellular components, forming the tumour microenvironment (TME). The TME has crucial and diverse roles in tumour progression and metastasis, and substantial efforts have been dedicated into understanding the functions of different cell types within the TME. These efforts highlighted the importance of non-cell-autonomous signalling in cancer, mediating interactions between the cancer cells, the immune microenvironment and the non-immune stroma. Much of this non-cell-autonomous signalling is mediated through acellular components of the TME, known as the extracellular matrix (ECM), and controlled by the cells that secrete and remodel the ECM - the cancer-associated fibroblasts (CAFs). In this Review, we delve into the complex crosstalk among cancer cells, CAFs and immune cells, highlighting the effects of CAF-induced ECM remodelling on T cell functions and offering insights into the potential of targeting ECM components to improve cancer therapies.
    DOI:  https://doi.org/10.1038/s41568-024-00740-4
  6. Autophagy. 2024 Sep 12. 1-19
    Hypoxia-induced BNIP3 facilitates the progression and metastasis of uveal melanoma by driving metabolic reprogramming.
    Jie Sun, Jie Ding, Han Yue, Binbin Xu, Akrit Sodhi, Kang Xue, Hui Ren, Jiang Qian.
      Uveal melanoma (UM) is an aggressive intraocular malignancy derived from melanocytes in the uvea tract of the eye. Up to 50% of patients with UM develop distant metastases which is usually fatal within one year; preventing metastases is therefore essential. Metabolic reprogramming plays a critical role in UM progression and metastasis. However, the metabolic phenotype of UM cells in the hypoxic tumor is not well understood. Here, we report that hypoxia-induced BNIP3 reprograms tumor cell metabolism, promoting their survival and metastasis. In response to hypoxia, BNIP3-mediated mitophagy alleviates mitochondrial dysfunction and enhances mitochondrial oxidative phosphorylation (OXPHOS) while simultaneously reducing mitochondrial reactive oxygen species (mtROS) production. This, in turn, impairs HIF1A/HIF-1α protein stability and inhibits glycolysis. Inhibition of mitophagy significantly suppresses BNIP3-induced UM progression and metastasis in vitro and in vivo. Collectively, these observations demonstrate a novel mechanism whereby BNIP3 promotes UM metabolic reprogramming and malignant progression by mediating hypoxia-induced mitophagy and suggest that BNIP3 could be an important therapeutic target to prevent metastasis in patients with UM.Abbreviations: AOD: average optical density; BNIP3: BCL2/adenovirus E1B interacting protein 3; CQ: chloroquine; CoCl2: cobalt chloride; GEPIA: Gene Expression Profiling Interactive Analysis; HIF1A: hypoxia inducible factor 1, alpha subunit; IHC: immunohistochemistry; mtROS: mitochondrial reactive oxygen species; NAC: N-acetylcysteine; OCR: oxygen consumption rate; OXPHOS: oxidative phosphorylation; ROS: reactive oxygen species; TCGA: The Cancer Genome Atlas; UM: uveal melanoma.
    Keywords:  BNIP3; HIF1A; glycolysis; mitophagy; oxidative phosphorylation; uveal melanoma
    DOI:  https://doi.org/10.1080/15548627.2024.2395142
  7. Nat Metab. 2024 Sep 09.
    Spatial single-cell isotope tracing reveals heterogeneity of de novo fatty acid synthesis in cancer.
    Elena Buglakova, Måns Ekelöf, Michaela Schwaiger-Haber, Lisa Schlicker, Martijn R Molenaar, Mohammed Shahraz, Lachlan Stuart, Andreas Eisenbarth, Volker Hilsenstein, Gary J Patti, Almut Schulze, Marteinn T Snaebjornsson, Theodore Alexandrov.
      While heterogeneity is a key feature of cancer, understanding metabolic heterogeneity at the single-cell level remains a challenge. Here we present 13C-SpaceM, a method for spatial single-cell isotope tracing that extends the previously published SpaceM method with detection of 13C6-glucose-derived carbons in esterified fatty acids. We validated 13C-SpaceM on spatially heterogeneous models using liver cancer cells subjected to either normoxia-hypoxia or ATP citrate lyase depletion. This revealed substantial single-cell heterogeneity in labelling of the lipogenic acetyl-CoA pool and in relative fatty acid uptake versus synthesis hidden in bulk analyses. Analysing tumour-bearing brain tissue from mice fed a 13C6-glucose-containing diet, we found higher glucose-dependent synthesis of saturated fatty acids and increased elongation of essential fatty acids in tumours compared with healthy brains. Furthermore, our analysis uncovered spatial heterogeneity in lipogenic acetyl-CoA pool labelling in tumours. Our method enhances spatial probing of metabolic activities in single cells and tissues, providing insights into fatty acid metabolism in homoeostasis and disease.
    DOI:  https://doi.org/10.1038/s42255-024-01118-4
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