bims-tumime Biomed News
on Tumor microenvironment and metabolism
Issue of 2024–06–09
eleven papers selected by
Alex Muir, University of Chicago
  1. Diet and Tumor Genetics Conspire to Promote Prostate Cancer Metabolism and Shape the Tumor Microenvironment.
  2. In vivo CRISPR screening identifies geranylgeranyl diphosphate as a pancreatic cancer tumor growth dependency.
  3. Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance.
  4. De novo and salvage purine synthesis pathways across tissues and tumors.
  5. Tumor-associated macrophages restrict CD8+ T cell function through collagen deposition and metabolic reprogramming of the breast cancer microenvironment.
  6. Obesogenic High-Fat Diet and MYC Cooperate to Promote Lactate Accumulation and Tumor Microenvironment Remodeling in Prostate Cancer.
  7. Hypoxia-mediated repression of pyruvate carboxylase drives immunosuppression.
  8. Enhancing tumor-infiltrating T cells with an exclusive fuel source.
  9. Hungry for fat: Metabolic crosstalk with lipid-rich CAFs fuels pancreatic cancer.
  10. Vitamin B6 deficiency cooperates with oncogenic Ras to induce malignant tumors in Drosophila.
  11. Dietary commensal wrestles iron from tumor microenvironment to activate antitumoral macrophages.
  1. Cancer Res. 2024 Jun 04. 84(11): 1742-1744
    Diet and Tumor Genetics Conspire to Promote Prostate Cancer Metabolism and Shape the Tumor Microenvironment.
    Daniel E Frigo.
      Obesity has been linked to prostate cancer in a stage-dependent manner, having no association with cancer initiation but correlating with disease progression in men with prostate cancer. Given the rising obesity rate and its association to aggressive prostate cancer, there is a growing need to understand the mechanisms underlying this relationship to identify patients at increased risk of lethal disease and inform therapeutic approaches. In this issue of Cancer Research, Boufaied and colleagues describe how diets high in saturated fatty acids promote MYC-driven prostate cancer. Leveraging MYC-expressing genetically engineered and allograft mouse models fed either a control low-fat or high-fat diet (HFD) enriched in saturated fatty acids, the authors found using digital pathology that HFD-fed mice exhibited increased tumor invasion. Metabolomics, transcriptomics, immunoblotting, and positron emission tomography of tumors from these mice demonstrated that a HFD promoted a metabolic shift in the tumors towards glycolysis. These preclinical data were supported by findings from two large clinical cohorts revealing that men diagnosed with prostate cancer and who consumed high levels of saturated fatty acids possessed tumors bearing glycolytic signatures. Deconvolution analyses and immunohistochemistry validation showed that these tumors also displayed increased angiogenesis and infiltration of immunosuppressive macrophages and regulatory T cells, the latter of which was also correlated with high saturated fat intake-associated glycolytic signatures in patient tumors. Together, these findings suggest that diets rich in saturated fatty acids, rather than obesity alone, accelerate MYC-driven prostate cancers through shifting tumor metabolism and shaping the tumor microenvironment. See related article by Boufaied et al., p. 1834.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-0302
  2. Mol Metab. 2024 May 31. pii: S2212-8778(24)00095-4. [Epub ahead of print] 101964
    In vivo CRISPR screening identifies geranylgeranyl diphosphate as a pancreatic cancer tumor growth dependency.
    Casie S Kubota, Stephanie L Myers, Toni T Seppälä, Richard A Burkhart, Peter J Espenshade.
      Cancer cells must maintain lipid supplies for their proliferation and do so by upregulating lipogenic gene programs. The sterol regulatory element-binding proteins (SREBPs) act as modulators of lipid homeostasis by acting as transcriptional activators of genes required for fatty acid and cholesterol synthesis and uptake. SREBPs have been recognized as chemotherapeutic targets in multiple cancers, however it is not well understood which SREBP target genes are essential for tumorigenesis. Using parallel in vitro and in vivo CRISPR knockout screens, we identified terpenoid backbone biosynthesis genes as essential for pancreatic ductal adenocarcinoma (PDAC) tumor development. Specifically, we identified the non-sterol isoprenoid product of the mevalonate pathway, geranylgeranyl diphosphate (GGPP), as an essential lipid for tumor growth. Mechanistically, we observed that restricting mevalonate pathway activity using statins and SREBP inhibitors synergistically induced apoptosis and caused disruptions in small G protein prenylation that have pleiotropic effects on cellular signaling pathways. Finally, we demonstrated that geranylgeranyl diphosphate synthase 1 (GGPS1) knockdown significantly reduces tumor burden in an orthotopic xenograft mouse model. These findings indicate that PDAC tumors selectively require GGPP over other lipids such as cholesterol and fatty acids and that this is a targetable vulnerability of pancreatic cancer cells.
    DOI:  https://doi.org/10.1016/j.molmet.2024.101964
  3. Nat Cancer. 2024 Jun 06.
    Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance.
    Tommaso Scolaro, Marta Manco, Mathieu Pecqueux, Ricardo Amorim, Rosa Trotta, Heleen H Van Acker, Matthias Van Haele, Niranjan Shirgaonkar, Stefan Naulaerts, Jan Daniluk, Fran Prenen, Chiara Varamo, Donatella Ponti, Ginevra Doglioni, Ana Margarida Ferreira Campos, Juan Fernandez Garcia, Silvia Radenkovic, Pegah Rouhi, Aleksandar Beatovic, Liwei Wang, Yu Wang, Amalia Tzoumpa, Asier Antoranz, Ara Sargsian, Mario Di Matteo, Emanuele Berardi, Jermaine Goveia, Bart Ghesquière, Tania Roskams, Stefaan Soenen, Thomas Voets, Bella Manshian, Sarah-Maria Fendt, Peter Carmeliet, Abhishek D Garg, Ramanuj DasGupta, Baki Topal, Massimiliano Mazzone.
      Many individuals with cancer are resistant to immunotherapies. Here, we identify the gene encoding the pyrimidine salvage pathway enzyme cytidine deaminase (CDA) among the top upregulated metabolic genes in several immunotherapy-resistant tumors. We show that CDA in cancer cells contributes to the uridine diphosphate (UDP) pool. Extracellular UDP hijacks immunosuppressive tumor-associated macrophages (TAMs) through its receptor P2Y6. Pharmacologic or genetic inhibition of CDA in cancer cells (or P2Y6 in TAMs) disrupts TAM-mediated immunosuppression, promoting cytotoxic T cell entry and susceptibility to anti-programmed cell death protein 1 (anti-PD-1) treatment in resistant pancreatic ductal adenocarcinoma (PDAC) and melanoma models. Conversely, CDA overexpression in CDA-depleted PDACs or anti-PD-1-responsive colorectal tumors or systemic UDP administration (re)establishes resistance. In individuals with PDAC, high CDA levels in cancer cells correlate with increased TAMs, lower cytotoxic T cells and possibly anti-PD-1 resistance. In a pan-cancer single-cell atlas, CDAhigh cancer cells match with T cell cytotoxicity dysfunction and P2RY6high TAMs. Overall, we suggest CDA and P2Y6 as potential targets for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s43018-024-00771-8
  4. Cell. 2024 May 30. pii: S0092-8674(24)00520-8. [Epub ahead of print]
    De novo and salvage purine synthesis pathways across tissues and tumors.
    Diem H Tran, Dohun Kim, Rushendhiran Kesavan, Harrison Brown, Trishna Dey, Mona Hoseini Soflaee, Hieu S Vu, Alpaslan Tasdogan, Jason Guo, Divya Bezwada, Houssam Al Saad, Feng Cai, Ashley Solmonson, Halie Rion, Rawand Chabatya, Salma Merchant, Nathan J Manales, Vanina T Tcheuyap, Megan Mulkey, Thomas P Mathews, James Brugarolas, Sean J Morrison, Hao Zhu, Ralph J DeBerardinis, Gerta Hoxhaj.
      Purine nucleotides are vital for RNA and DNA synthesis, signaling, metabolism, and energy homeostasis. To synthesize purines, cells use two principal routes: the de novo and salvage pathways. Traditionally, it is believed that proliferating cells predominantly rely on de novo synthesis, whereas differentiated tissues favor the salvage pathway. Unexpectedly, we find that adenine and inosine are the most effective circulating precursors for supplying purine nucleotides to tissues and tumors, while hypoxanthine is rapidly catabolized and poorly salvaged in vivo. Quantitative metabolic analysis demonstrates comparative contribution from de novo synthesis and salvage pathways in maintaining purine nucleotide pools in tumors. Notably, feeding mice nucleotides accelerates tumor growth, while inhibiting purine salvage slows down tumor progression, revealing a crucial role of the salvage pathway in tumor metabolism. These findings provide fundamental insights into how normal tissues and tumors maintain purine nucleotides and highlight the significance of purine salvage in cancer.
    Keywords:  cancer metabolism; de novo purine synthesis; in vivo isotope tracing; nucleotide diet; nucleotide metabolism; purine bases; purine degradation; purine salvage; tissue; tumor growth
    DOI:  https://doi.org/10.1016/j.cell.2024.05.011
  5. Nat Cancer. 2024 Jun 03.
    Tumor-associated macrophages restrict CD8+ T cell function through collagen deposition and metabolic reprogramming of the breast cancer microenvironment.
    Kevin M Tharp, Kelly Kersten, Ori Maller, Greg A Timblin, Connor Stashko, Fernando P Canale, Rosa E Menjivar, Mary-Kate Hayward, Ilona Berestjuk, Johanna Ten Hoeve, Bushra Samad, Alastrair J Ironside, Marina Pasca di Magliano, Alexander Muir, Roger Geiger, Alexis J Combes, Valerie M Weaver.
      Tumor progression is accompanied by fibrosis, a condition of excessive extracellular matrix accumulation, which is associated with diminished antitumor immune infiltration. Here we demonstrate that tumor-associated macrophages (TAMs) respond to the stiffened fibrotic tumor microenvironment (TME) by initiating a collagen biosynthesis program directed by transforming growth factor-β. A collateral effect of this programming is an untenable metabolic milieu for productive CD8+ T cell antitumor responses, as collagen-synthesizing macrophages consume environmental arginine, synthesize proline and secrete ornithine that compromises CD8+ T cell function in female breast cancer. Thus, a stiff and fibrotic TME may impede antitumor immunity not only by direct physical exclusion of CD8+ T cells but also through secondary effects of a mechano-metabolic programming of TAMs, which creates an inhospitable metabolic milieu for CD8+ T cells to respond to anticancer immunotherapies.
    DOI:  https://doi.org/10.1038/s43018-024-00775-4
  6. Cancer Res. 2024 Jun 04. 84(11): 1834-1855
    Obesogenic High-Fat Diet and MYC Cooperate to Promote Lactate Accumulation and Tumor Microenvironment Remodeling in Prostate Cancer.
    Nadia Boufaied, Paolo Chetta, Tarek Hallal, Stefano Cacciatore, Daniela Lalli, Carole Luthold, Kevin Homsy, Eddie L Imada, Sudeepa Syamala, Cornelia Photopoulos, Anna Di Matteo, Anna de Polo, Alessandra Maria Storaci, Ying Huang, Francesca Giunchi, Patricia A Sheridan, Gregory Michelotti, Quang-De Nguyen, Xin Zhao, Yang Liu, Elai Davicioni, Daniel E Spratt, Simone Sabbioneda, Giovanni Maga, Lorelei A Mucci, Claudia Ghigna, Luigi Marchionni, Lisa M Butler, Leigh Ellis, François Bordeleau, Massimo Loda, Valentina Vaira, David P Labbé, Giorgia Zadra.
      Cancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation of metabolites that reprogram the tumor microenvironment (TME) and drive cancer could facilitate development of precision nutrition approaches. Using the Hi-MYC prostate cancer mouse model, we demonstrated that an obesogenic high-fat diet (HFD) rich in saturated fats accelerates the development of c-MYC-driven invasive prostate cancer through metabolic rewiring. Although c-MYC modulated key metabolic pathways, interaction with an obesogenic HFD was necessary to induce glycolysis and lactate accumulation in tumors. These metabolic changes were associated with augmented infiltration of CD206+ and PD-L1+ tumor-associated macrophages (TAM) and FOXP3+ regulatory T cells, as well as with the activation of transcriptional programs linked to disease progression and therapy resistance. Lactate itself also stimulated neoangiogenesis and prostate cancer cell migration, which were significantly reduced following treatment with the lactate dehydrogenase inhibitor FX11. In patients with prostate cancer, high saturated fat intake and increased body mass index were associated with tumor glycolytic features that promote the infiltration of M2-like TAMs. Finally, upregulation of lactate dehydrogenase, indicative of a lactagenic phenotype, was associated with a shorter time to biochemical recurrence in independent clinical cohorts. This work identifies cooperation between genetic drivers and systemic metabolism to hijack the TME and promote prostate cancer progression through oncometabolite accumulation. This sets the stage for the assessment of lactate as a prognostic biomarker and supports strategies of dietary intervention and direct lactagenesis blockade in treating advanced prostate cancer.
    SIGNIFICANCE: Lactate accumulation driven by high-fat diet and MYC reprograms the tumor microenvironment and promotes prostate cancer progression, supporting the potential of lactate as a biomarker and therapeutic target in prostate cancer. See related commentary by Frigo, p. 1742.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0519
  7. Breast Cancer Res. 2024 Jun 07. 26(1): 96
    Hypoxia-mediated repression of pyruvate carboxylase drives immunosuppression.
    Michael F Coleman, Eylem Kulkoyluoglu Cotul, Alexander J Pfeil, Emily N Devericks, Muhammad H Safdar, Marvis Monteiro, Hao Chen, Alyssa N Ho, Numair Attaar, Hannah M Malian, Violet A Kiesel, Alexis Ramos, Matthew Smith, Heena Panchal, Adam Mailloux, Dorothy Teegarden, Stephen D Hursting, Michael K Wendt.
       BACKGROUND: Metabolic plasticity mediates breast cancer survival, growth, and immune evasion during metastasis. However, how tumor cell metabolism is influenced by and feeds back to regulate breast cancer progression are not fully understood. We identify hypoxia-mediated suppression of pyruvate carboxylase (PC), and subsequent induction of lactate production, as a metabolic regulator of immunosuppression.
    METHODS: We used qPCR, immunoblot, and reporter assays to characterize repression of PC in hypoxic primary tumors. Steady state metabolomics were used to identify changes in metabolite pools upon PC depletion. In vivo tumor growth and metastasis assays were used to evaluate the impact of PC manipulation and pharmacologic inhibition of lactate transporters. Immunohistochemistry, flow cytometry, and global gene expression analyzes of tumor tissue were employed to characterize the impact of PC depletion on tumor immunity.
    RESULTS: PC is essential for metastatic colonization of the lungs. In contrast, depletion of PC in tumor cells promotes primary tumor growth. This effect was only observed in immune competent animals, supporting the hypothesis that repression of PC can suppress anti-tumor immunity. Exploring key differences between the pulmonary and mammary environments, we demonstrate that hypoxia potently downregulated PC. In the absence of PC, tumor cells produce more lactate and undergo less oxidative phosphorylation. Inhibition of lactate metabolism was sufficient to restore T cell populations to PC-depleted mammary tumors.
    CONCLUSIONS: We present a dimorphic role for PC in primary mammary tumors vs. pulmonary metastases. These findings highlight a key contextual role for PC-directed lactate production as a metabolic nexus connecting hypoxia and antitumor immunity.
    DOI:  https://doi.org/10.1186/s13058-024-01854-1
  8. bioRxiv. 2024 May 21. pii: 2024.05.20.595053. [Epub ahead of print]
    Enhancing tumor-infiltrating T cells with an exclusive fuel source.
    Matthew L Miller, Rina Nagarajan, Timothy J Thauland, Manish J Butte.
      Solid tumors harbor immunosuppressive microenvironments that inhibit tumor infiltrating lymphocytes (TILs) through the voracious consumption of glucose. We sought to restore TIL function by providing them with an exclusive fuel source. The glucose disaccharide cellobiose, which is a building block of cellulose, contains a β-1,4-glycosidic bond that cannot be hydrolyzed by animals (or their tumors), but fungal and bacterial organisms have evolved enzymes to catabolize cellobiose and use the resulting glucose. By equipping T cells with two proteins that enable import and hydrolysis of cellobiose, we demonstrate that supplementation of cellobiose during glucose withdrawal restores T cell cytokine production and cellular proliferation. Murine tumor growth is suppressed and survival is prolonged. Offering exclusive access to a natural disaccharide is a new tool that augments cancer immunotherapies. Beyond cancer, this approach could be used to answer questions about the regulation of glucose metabolism across many cell types, biological processes, and diseases.
    DOI:  https://doi.org/10.1101/2024.05.20.595053
  9. Cell Metab. 2024 Jun 04. pii: S1550-4131(24)00183-9. [Epub ahead of print]36(6): 1172-1174
    Hungry for fat: Metabolic crosstalk with lipid-rich CAFs fuels pancreatic cancer.
    Kostas A Papavassiliou, Athanasios G Papavassiliou.
      Some cancers prefer to metabolize lipids for their growth and metastasis. In a recent Cancer Cell study, Niu et al. revealed that SET domain containing 2, histone lysine methyltransferase (SETD2)-deficient pancreatic cancer cells induce the differentiation of lipid-laden cancer-associated fibroblasts (CAFs), which, in turn, transport lipids to promote tumor growth.
    DOI:  https://doi.org/10.1016/j.cmet.2024.05.007
  10. Cell Death Dis. 2024 Jun 03. 15(6): 388
    Vitamin B6 deficiency cooperates with oncogenic Ras to induce malignant tumors in Drosophila.
    Eleonora Pilesi, Giulia Tesoriere, Angelo Ferriero, Elisa Mascolo, Francesco Liguori, Luca Argirò, Chiara Angioli, Angela Tramonti, Roberto Contestabile, Cinzia Volontè, Fiammetta Vernì.
      Vitamin B6 is a water-soluble vitamin which possesses antioxidant properties. Its catalytically active form, pyridoxal 5'-phosphate (PLP), is a crucial cofactor for DNA and amino acid metabolism. The inverse correlation between vitamin B6 and cancer risk has been observed in several studies, although dietary vitamin B6 intake sometimes failed to confirm this association. However, the molecular link between vitamin B6 and cancer remains elusive. Previous work has shown that vitamin B6 deficiency causes chromosome aberrations (CABs) in Drosophila and human cells, suggesting that genome instability may correlate the lack of this vitamin to cancer. Here we provide evidence in support of this hypothesis. Firstly, we show that PLP deficiency, induced by the PLP antagonists 4-deoxypyridoxine (4DP) or ginkgotoxin (GT), promoted tumorigenesis in eye larval discs transforming benign RasV12 tumors into aggressive forms. In contrast, PLP supplementation reduced the development of tumors. We also show that low PLP levels, induced by 4DP or by silencing the sgllPNPO gene involved in PLP biosynthesis, worsened the tumor phenotype in another Drosophila cancer model generated by concomitantly activating RasV12 and downregulating Discs-large (Dlg) gene. Moreover, we found that RasV12 eye discs from larvae reared on 4DP displayed CABs, reactive oxygen species (ROS) and low catalytic activity of serine hydroxymethyltransferase (SHMT), a PLP-dependent enzyme involved in thymidylate (dTMP) biosynthesis, in turn required for DNA replication and repair. Feeding RasV12 4DP-fed larvae with PLP or ascorbic acid (AA) plus dTMP, rescued both CABs and tumors. The same effect was produced by overexpressing catalase in RasV12 DlgRNAi 4DP-fed larvae, thus allowing to establish a relationship between PLP deficiency, CABs, and cancer. Overall, our data provide the first in vivo demonstration that PLP deficiency can impact on cancer by increasing genome instability, which is in turn mediated by ROS and reduced dTMP levels.
    DOI:  https://doi.org/10.1038/s41419-024-06787-3
  11. Cancer Res. 2024 Jun 04.
    Dietary commensal wrestles iron from tumor microenvironment to activate antitumoral macrophages.
    Amanda H Lee, Simran K Randhawa, Marlies Meisel.
      The microbiome dictates the response to cancer immunotherapy efficacy. However, the mechanisms of how the microbiota impacts on therapy efficacy remains still poorly understood. In a recent issue of Nature Immunology, Sharma and colleagues elucidate a multifaceted, macrophage-driven mechanism exerted by a specific strain of fermented food commensal Lactiplantibacillus plantarum, LpIMB19. LpIMB19 activates tumor macrophages, resulting in the enhancement of cytotoxic CD8 T cells. LpIMB19 administration led to an expansion of tumor-infiltrating CD8 T cells and improved the efficacy of anti-PD-L1 therapy. Rhamnose-rich heteropolysaccharide (RHP), a strain-specific cell wall component, was identified as the primary effector molecule of LplMB19. TLR2 signaling and the ability of macrophages to sequester iron were both critical for RHP-mediated macrophage activation upstream of the CD8 T cell effector response and contributed to tumor cell apoptosis through iron deprivation of tumor cells. These findings reveal a well-defined mechanism connecting diet and health outcomes, suggesting that diet-derived commensals may warrant further investigation. Additionally, this work emphasizes the importance of strain-specific differences in studying microbiome-cancer interactions and the concept of "nutritional immunity" to enhance microbe-triggered antitumor immunity.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-1833
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