bims-tumime Biomed News
on Tumor microenvironment and metabolism
Issue of 2024–03–03
eleven papers selected by
Alex Muir, University of Chicago
  1. Metabolic rewiring and communication in cancer immunity.
  2. Nutrients: Signal 4 in T cell immunity.
  3. From monocyte-derived macrophages to resident macrophages-how metabolism leads their way in cancer.
  4. β-catenin Activation Reprograms Ammonia Metabolism to Promote Senescence Resistance in Hepatocellular Carcinoma.
  5. Nucleosides are overlooked fuels in central carbon metabolism.
  6. IL-37 dampens immunosuppressive functions of MDSCs via metabolic reprogramming in the tumor microenvironment.
  7. Nutrient scavenging-fueled growth in pancreatic cancer depends on caveolae-mediated endocytosis under nutrient-deprived conditions.
  8. Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis.
  9. Lymphatic endothelial-like cells in the glioblastoma tumor niche drive metabolic alterations that promote stem cell proliferation and survival.
  10. The colibactin-producing Escherichia coli alters the tumor microenvironment to immunosuppressive lipid overload facilitating colorectal cancer progression and chemoresistance.
  11. Riboflavin-LSD1 axis participates in the in vivo tumor-associated macrophage morphology in human colorectal liver metastases.
  1. Cell Chem Biol. 2024 Feb 26. pii: S2451-9456(24)00075-8. [Epub ahead of print]
    Metabolic rewiring and communication in cancer immunity.
    Nicole M Chapman, Hongbo Chi.
      The immune system shapes tumor development and progression. Although immunotherapy has transformed cancer treatment, its overall efficacy remains limited, underscoring the need to uncover mechanisms to improve therapeutic effects. Metabolism-associated processes, including intracellular metabolic reprogramming and intercellular metabolic crosstalk, are emerging as instructive signals for anti-tumor immunity. Here, we first summarize the roles of intracellular metabolic pathways in controlling immune cell function in the tumor microenvironment. How intercellular metabolic communication regulates anti-tumor immunity, and the impact of metabolites or nutrients on signaling events, are also discussed. We then describe how targeting metabolic pathways in tumor cells or intratumoral immune cells or via nutrient-based interventions may boost cancer immunotherapies. Finally, we conclude with discussions on profiling and functional perturbation methods of metabolic activity in intratumoral immune cells, and perspectives on future directions. Uncovering the mechanisms for metabolic rewiring and communication in the tumor microenvironment may enable development of novel cancer immunotherapies.
    DOI:  https://doi.org/10.1016/j.chembiol.2024.02.001
  2. J Exp Med. 2024 Mar 04. pii: e20221839. [Epub ahead of print]221(3):
    Nutrients: Signal 4 in T cell immunity.
    Jana L Raynor, Hongbo Chi.
      T cells are integral in mediating adaptive immunity to infection, autoimmunity, and cancer. Upon immune challenge, T cells exit from a quiescent state, followed by clonal expansion and effector differentiation. These processes are shaped by three established immune signals, namely antigen stimulation (Signal 1), costimulation (Signal 2), and cytokines (Signal 3). Emerging findings reveal that nutrients, including glucose, amino acids, and lipids, are crucial regulators of T cell responses and interplay with Signals 1-3, highlighting nutrients as Signal 4 to license T cell immunity. Here, we first summarize the functional importance of Signal 4 and the underlying mechanisms of nutrient transport, sensing, and signaling in orchestrating T cell activation and quiescence exit. We also discuss the roles of nutrients in programming T cell differentiation and functional fitness and how nutrients can be targeted to improve disease therapy. Understanding how T cells respond to Signal 4 nutrients in microenvironments will provide insights into context-dependent functions of adaptive immunity and therapeutic interventions.
    DOI:  https://doi.org/10.1084/jem.20221839
  3. Mol Oncol. 2024 Feb 27.
    From monocyte-derived macrophages to resident macrophages-how metabolism leads their way in cancer.
    Ummi Ammarah, Andreia Pereira-Nunes, Marcello Delfini, Massimiliano Mazzone.
      Macrophages are innate immune cells that play key roles during both homeostasis and disease. Depending on the microenvironmental cues sensed in different tissues, macrophages are known to acquire specific phenotypes and exhibit unique features that, ultimately, orchestrate tissue homeostasis, defense, and repair. Within the tumor microenvironment, macrophages are referred to as tumor-associated macrophages (TAMs) and constitute a heterogeneous population. Like their tissue resident counterpart, TAMs are plastic and can switch function and phenotype according to the niche-derived stimuli sensed. While changes in TAM phenotype are known to be accompanied by adaptive alterations in their cell metabolism, it is reported that metabolic reprogramming of macrophages can dictate their activation state and function. In line with these observations, recent research efforts have been focused on defining the metabolic traits of TAM subsets in different tumor malignancies and understanding their role in cancer progression and metastasis formation. This knowledge will pave the way to novel therapeutic strategies tailored to cancer subtype-specific metabolic landscapes. This review outlines the metabolic characteristics of distinct TAM subsets and their implications in tumorigenesis across multiple cancer types.
    Keywords:  cancer metabolism; immunometabolism; monocyte-derived macrophages; tissue-resident macrophages; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.1002/1878-0261.13618
  4. Cancer Res. 2024 Feb 28.
    β-catenin Activation Reprograms Ammonia Metabolism to Promote Senescence Resistance in Hepatocellular Carcinoma.
    Ye Wang, Chunxiao Cheng, Yanjun Lu, Zhaowu Lian, Qi Liu, Yanchao Xu, Yunzheng Li, Huan Li, Laizhu Zhang, Xiang Jiang, Binghua Li, Decai Yu.
      Hepatocellular carcinoma (HCC) is a typical tumor that undergoes metabolic reprogramming, differing from normal liver tissue in glucose, lipid, nucleic acid, and amino acid metabolism. While ammonia is a toxic metabolic byproduct, it has also been recently recognized as a signaling molecule to activate lipid metabolism, and it can be a nitrogen source for biosynthesis to support tumorigenesis. In this study, we revealed that β-catenin activation increases ammonia production in HCC mainly by stimulating glutaminolysis. β-catenin/LEF1 activated the transcription of the glutamate dehydrogenase GLUD1, which then promoted ammonia utilization to enhance the production of glutamate, aspartate, and proline as evidenced by 15NH4Cl metabolic flux. β-catenin/TCF4 induced the transcription of SLC4A11, an ammonia transporter, to excrete excess ammonia. SLC4A11 was upregulated in HCC tumor tissues, and high SLC4A11 expression was associated with poor prognosis and advanced disease stages. Loss of SLC4A11 induced HCC cell senescence in vitro by blocking ammonia excretion and reduced β-catenin-driven tumor growth in vivo. Furthermore, elevated levels of plasma ammonia promoted the progression of β-catenin mutant HCC, which was impeded by SLC4A11 deficiency. Downregulation of SLC4A11 led to ammonia accumulation in tumor interstitial fluid (TIF) and decreased plasma ammonia levels in HCC with activated β-catenin. Altogether, this study indicates that β-catenin activation reprograms ammonia metabolism and that blocking ammonia excretion by targeting SLC4A11 could be a promising approach to induce senescence in β-catenin mutant HCC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0673
  5. Trends Endocrinol Metab. 2024 Feb 29. pii: S1043-2760(24)00027-4. [Epub ahead of print]
    Nucleosides are overlooked fuels in central carbon metabolism.
    Abigail Strefeler, Joan Blanco-Fernandez, Alexis A Jourdain.
      From our daily nutrition and synthesis within cells, nucleosides enter the bloodstream and circulate throughout the body and tissues. Nucleosides and nucleotides are classically viewed as precursors of nucleic acids, but recently they have emerged as a novel energy source for central carbon metabolism. Through catabolism by nucleoside phosphorylases, the ribose sugar group is released and can provide substrates for lower steps in glycolysis. In environments with limited glucose, such as at sites of infection or in the tumor microenvironment (TME), cells can use, and may even require, this alternative energy source. Here, we discuss the implications of these new findings in health and disease and speculate on the potential new roles of nucleosides and nucleic acids in energy metabolism.
    Keywords:  Metabolism; UPP1; cancer; immunity; uridine; uridinolysis
    DOI:  https://doi.org/10.1016/j.tem.2024.01.013
  6. Cell Rep. 2024 Feb 26. pii: S2211-1247(24)00163-3. [Epub ahead of print]43(3): 113835
    IL-37 dampens immunosuppressive functions of MDSCs via metabolic reprogramming in the tumor microenvironment.
    Yu Mei, Ying Zhu, Kylie Su Mei Yong, Zuhairah Binte Hanafi, Huanle Gong, Yonghao Liu, Huey Yee Teo, Muslima Hussain, Yuan Song, Qingfeng Chen, Haiyan Liu.
      Interleukin-37 (IL-37) has been shown to inhibit tumor growth in various cancer types. However, the immune regulatory function of IL-37 in the tumor microenvironment is unclear. Here, we established a human leukocyte antigen-I (HLA-I)-matched humanized patient-derived xenograft hepatocellular carcinoma (HCC) model and three murine orthotopic HCC models to study the function of IL-37 in the tumor microenvironment. We found that IL-37 inhibited HCC growth and promoted T cell activation. Further study revealed that IL-37 impaired the immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs). Pretreatment of MDSCs with IL-37 before adoptive transfer attenuated their tumor-promoting function in HCC tumor-bearing mice. Moreover, IL-37 promoted both glycolysis and oxidative phosphorylation in MDSCs, resulting in the upregulation of ATP release, which impaired the immunosuppressive capacity of MDSCs. Collectively, we demonstrated that IL-37 inhibited tumor development through dampening MDSCs' immunosuppressive capacity in the tumor microenvironment via metabolic reprogramming, making it a promising target for future cancer immunotherapy.
    Keywords:  ATP; CP: Cancer; CP: Immunology; Interleukin-37; hepatocellular carcinoma; metabolism; myeloid-derived suppressor cells
    DOI:  https://doi.org/10.1016/j.celrep.2024.113835
  7. Sci Adv. 2024 Mar;10(9): eadj3551
    Nutrient scavenging-fueled growth in pancreatic cancer depends on caveolae-mediated endocytosis under nutrient-deprived conditions.
    Adam R Wolfe, Tiantian Cui, Sooin Baie, Sergio Corrales-Guerrero, Amy Webb, Veronica Castro-Aceituno, Duan-Liang Shyu, Joanna M Karasinska, James T Topham, Daniel J Renouf, David F Schaeffer, Megan Halloran, Rebecca Packard, Ryan Robb, Wei Chen, Nicholas Denko, Michael Lisanti, Timothy C Thompson, Philippe Frank, Terence M Williams.
      Pancreatic ductal adenocarcinoma (PDAC) is characterized by its nutrient-scavenging ability, crucial for tumor progression. Here, we investigated the roles of caveolae-mediated endocytosis (CME) in PDAC progression. Analysis of patient data across diverse datasets revealed a strong association of high caveolin-1 (Cav-1) expression with higher histologic grade, the most aggressive PDAC molecular subtypes, and worse clinical outcomes. Cav-1 loss markedly promoted longer overall and tumor-free survival in a genetically engineered mouse model. Cav-1-deficient tumor cell lines exhibited significantly reduced proliferation, particularly under low nutrient conditions. Supplementing cells with albumin rescued the growth of Cav-1-proficient PDAC cells, but not in Cav-1-deficient PDAC cells under low glutamine conditions. In addition, Cav-1 depletion led to significant metabolic defects, including decreased glycolytic and mitochondrial metabolism, and downstream protein translation signaling pathways. These findings highlight the crucial role of Cav-1 and CME in fueling pancreatic tumorigenesis, sustaining tumor growth, and promoting survival through nutrient scavenging.
    DOI:  https://doi.org/10.1126/sciadv.adj3551
  8. Nat Cell Biol. 2024 Mar 01.
    Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis.
    Divya Murthy, Kuldeep S Attri, Surendra K Shukla, Ravi Thakur, Nina V Chaika, Chunbo He, Dezhen Wang, Kanupriya Jha, Aneesha Dasgupta, Ryan J King, Scott E Mulder, Joshua Souchek, Teklab Gebregiworgis, Vikant Rai, Rohit Patel, Tuo Hu, Sandeep Rana, Sai Sundeep Kollala, Camila Pacheco, Paul M Grandgenett, Fang Yu, Vikas Kumar, Audrey J Lazenby, Adrian R Black, Susanna Ulhannan, Ajay Jain, Barish H Edil, David L Klinkebiel, Robert Powers, Amarnath Natarajan, Michael A Hollingsworth, Kamiya Mehla, Quan Ly, Sarika Chaudhary, Rosa F Hwang, Kathryn E Wellen, Pankaj K Singh.
      The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic cancer-associated fibroblasts (CAFs) regulate tumour cell metabolism through the secretion of acetate, which can be blocked by silencing ATP citrate lyase (ACLY) in CAFs. We further show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in an acidic microenvironment. Comparative H3K27ac ChIP-seq and RNA-seq analyses revealed alterations in polyamine homeostasis through regulation of SAT1 gene expression and enrichment of the SP1-responsive signature. We identified acetate/ACSS2-mediated acetylation of SP1 at the lysine 19 residue that increased SP1 protein stability and transcriptional activity. Genetic or pharmacologic inhibition of the ACSS2-SP1-SAT1 axis diminished the tumour burden in mouse models. These results reveal that the metabolic flexibility imparted by the stroma-derived acetate enabled cancer cell survival under acidosis via the ACSS2-SP1-SAT1 axis.
    DOI:  https://doi.org/10.1038/s41556-024-01372-4
  9. Neuro Oncol. 2024 Feb 28. pii: noae020. [Epub ahead of print]
    Lymphatic endothelial-like cells in the glioblastoma tumor niche drive metabolic alterations that promote stem cell proliferation and survival.
    Reilly L Kidwell, Manish K Aghi.
      
    DOI:  https://doi.org/10.1093/neuonc/noae020
  10. Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2320291
    The colibactin-producing Escherichia coli alters the tumor microenvironment to immunosuppressive lipid overload facilitating colorectal cancer progression and chemoresistance.
    Nilmara de Oliveira Alves, Guillaume Dalmasso, Darja Nikitina, Amaury Vaysse, Richard Ruez, Lea Ledoux, Thierry Pedron, Emma Bergsten, Olivier Boulard, Lora Autier, Sofian Allam, Laurence Motreff, Pierre Sauvanet, Diane Letourneur, Pragya Kashyap, Johan Gagnière, Denis Pezet, Catherine Godfraind, Michel Salzet, Emmanuel Lemichez, Mathilde Bonnet, Imène Najjar, Christophe Malabat, Marc Monot, Denis Mestivier, Nicolas Barnich, Pankaj Yadav, Isabelle Fournier, Sean Kennedy, Amel Mettouchi, Richard Bonnet, Iradj Sobhani, Mathias Chamaillard.
      Intratumoral bacteria flexibly contribute to cellular and molecular tumor heterogeneity for supporting cancer recurrence through poorly understood mechanisms. Using spatial metabolomic profiling technologies and 16SrRNA sequencing, we herein report that right-sided colorectal tumors are predominantly populated with Colibactin-producing Escherichia coli (CoPEC) that are locally establishing a high-glycerophospholipid microenvironment with lowered immunogenicity. It coincided with a reduced infiltration of CD8+ T lymphocytes that produce the cytotoxic cytokines IFN-γ where invading bacteria have been geolocated. Mechanistically, the accumulation of lipid droplets in infected cancer cells relied on the production of colibactin as a measure to limit genotoxic stress to some extent. Such heightened phosphatidylcholine remodeling by the enzyme of the Land's cycle supplied CoPEC-infected cancer cells with sufficient energy for sustaining cell survival in response to chemotherapies. This accords with the lowered overall survival of colorectal patients at stage III-IV who were colonized by CoPEC when compared to patients at stage I-II. Accordingly, the sensitivity of CoPEC-infected cancer cells to chemotherapies was restored upon treatment with an acyl-CoA synthetase inhibitor. By contrast, such metabolic dysregulation leading to chemoresistance was not observed in human colon cancer cells that were infected with the mutant strain that did not produce colibactin (11G5∆ClbQ). This work revealed that CoPEC locally supports an energy trade-off lipid overload within tumors for lowering tumor immunogenicity. This may pave the way for improving chemoresistance and subsequently outcome of CRC patients who are colonized by CoPEC.
    Keywords:  Colibactin-producing Escherichia coli; land’s cycle; lipid droplet; right-sided colorectal cancer
    DOI:  https://doi.org/10.1080/19490976.2024.2320291
  11. Cancer Immunol Immunother. 2024 Mar 02. 73(4): 63
    Riboflavin-LSD1 axis participates in the in vivo tumor-associated macrophage morphology in human colorectal liver metastases.
    Cristiana Soldani, Giulia De Simone, Michela Anna Polidoro, Aurelia Morabito, Barbara Franceschini, Federico Simone Colombo, Achille Anselmo, Flavio Milana, Ana Lleo, Guido Torzilli, Roberta Pastorelli, Matteo Donadon, Laura Brunelli.
      Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment (TME). In colorectal liver metastasis (CLM), TAM morphology correlates with prognosis, with smaller TAMs (S-TAMs) conferring a more favorable prognosis than larger TAMs (L-TAMs). However, the metabolic profile of in vivo human TAM populations remains unknown. Multiparametric flow cytometry was used to freshly isolate S- and L-TAMs from surgically resected CLM patients (n = 14S-, 14L-TAMs). Mass spectrometry-based metabolomics analyses were implemented for the metabolic characterization of TAM populations. Gene expression analysis and protein activity were used to support the biochemical effects of the enzyme-substrate link between riboflavin and (lysine-specific demethylase 1A, LSD1) with TAM morphologies. L-TAMs were characterized by a positive correlation and a strong association between riboflavin and TAM morphologies. Riboflavin in both L-TAMs and in-vitro M2 polarized macrophages modulates LSD1 protein expression and activity. The inflammatory stimuli promoted by TNFα induced the increased expression of riboflavin transporter SLC52A3 and LSD1 in M2 macrophages. The modulation of the riboflavin-LSD1 axis represents a potential target for reprogramming TAM subtypes, paving the way for promising anti-tumor therapeutic strategies.
    Keywords:  Colorectal liver metastasis; Histone lysine-specific demethylase 1; Riboflavin; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1007/s00262-024-03645-1
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