bims-tumime Biomed News
on Tumor microenvironment and metabolism
Issue of 2023–12–24
ten papers selected by
Alex Muir, University of Chicago
  1. A Metabolic Axis of Immune Intractability.
  2. Targeting lipid metabolism in cancer metastasis.
  3. Metabolic interplay: tumor macrophages and regulatory T cells.
  4. DON of Hope: Starving Pancreatic Cancer by Glutamine Antagonism.
  5. Nutrient inputs and social metabolic control of T cell fate.
  6. Metabolic Interplay in the Tumor Microenvironment: Implications for Immune Function and Anticancer Response.
  7. The Role of Tumor Metabolic Reprogramming in Tumor Immunity.
  8. SERS analysis of cancer cell-secreted purines reveals a unique paracrine crosstalk in MTAP-deficient tumors.
  9. Understanding the microenvironment and how this controls cell fate.
  10. Myeloid cell-derived creatine in the hypoxic niche promotes glioblastoma growth.
  1. Cancer Immunol Res. 2023 Dec 21. OF1-OF5
    A Metabolic Axis of Immune Intractability.
    Dominique C Hinshaw, Meet Patel, Lalita A Shevde.
      Immune cells in the tumor niche robustly influence disease progression. Remarkably, in cancer, developmental pathways are reenacted. Many parallels between immune regulation of embryonic development and immune regulation of tumor progression can be drawn, with evidence clearly supporting an immune-suppressive microenvironment in both situations. In these ecosystems, metabolic and bioenergetic circuits guide and regulate immune cell differentiation, plasticity, and functional properties of suppressive and inflammatory immune subsets. As such, there is an emerging pattern of intersection across the dynamic process of ontogeny and the ever-evolving tumor neighborhood. In this article, we focus on the convergence of immune programming during ontogeny and in the tumor microenvironment. Exemplifying dysregulation of Hedgehog (Hh) activity, a key player during ontogeny, we highlight a critical convergence of these fields and the metabolic axis of the nutrient sensing hexosamine biosynthetic pathway (HBP) that integrates glucose, glutamine, amino acids, acetyl CoA, and uridine-5'-triphosphate (UTP), culminating in the synthesis of UDP-GlcNAc, a metabolite that functions as a metabolic and bioenergetic sensor. We discuss an emerging pattern of immune regulation, orchestrated by O-GlcNAcylation of key transcriptional regulators, spurring suppressive activity of dysfunctional immune cells in the tumor microenvironment.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-0433
  2. Biochim Biophys Acta Rev Cancer. 2023 Dec 13. pii: S0304-419X(23)00200-7. [Epub ahead of print] 189051
    Targeting lipid metabolism in cancer metastasis.
    Gloria Pascual, Blanca Majem, Salvador Aznar-Benitah.
      This review delves into the most recent research on the metabolic adaptability of cancer cells and examines how their metabolic functions can impact their progression into metastatic forms. We emphasize the growing significance of lipid metabolism and dietary lipids within the tumor microenvironment, underscoring their influence on tumor progression. Additionally, we present an outline of the interplay between metabolic processes and the epigenome of cancer cells, underscoring the importance regarding the metastatic process. Lastly, we examine the potential of targeting metabolism as a therapeutic approach in combating cancer progression, shedding light on innovative drugs/targets currently undergoing preclinical evaluation.
    Keywords:  Epigenetics; Lipid metabolism; Metastasis; Microenvironment; Therapies
    DOI:  https://doi.org/10.1016/j.bbcan.2023.189051
  3. Trends Cancer. 2023 Dec 22. pii: S2405-8033(23)00238-8. [Epub ahead of print]
    Metabolic interplay: tumor macrophages and regulatory T cells.
    Stefania Vilbois, Yingxi Xu, Ping-Chih Ho.
      The tumor microenvironment (TME) contains a complex cellular ecosystem where cancer, stromal, vascular, and immune cells interact. Macrophages and regulatory T cells (Tregs) are critical not only for maintaining immunological homeostasis and tumor growth but also for monitoring the functional states of other immune cells. Emerging evidence reveals that metabolic changes in macrophages and Tregs significantly influence their pro-/antitumor functions through the regulation of signaling cascades and epigenetic reprogramming. Hence, they are increasingly recognized as therapeutic targets in cancer immunotherapy. Specific metabolites in the TME may also affect their pro-/antitumor functions by intervening with the metabolic machinery. We discuss how metabolites influence the immunosuppressive phenotypes of tumor-associated macrophages (TAMs) and Tregs. We then describe how TAMs and Tregs, independently or collaboratively, utilize metabolic mechanisms to suppress the activity of CD8+ T cells. Finally, we highlight promising metabolic interventions that can improve the outcome of current cancer therapies.
    Keywords:  cancer immunotherapy; immunometabolism; immunosuppression; macrophage; regulatory T cell; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2023.11.007
  4. Cancer Res. 2023 Dec 20.
    DON of Hope: Starving Pancreatic Cancer by Glutamine Antagonism.
    Ray Pillai, Thales Papagiannakopoulos.
      A promising approach to treat solid tumors involves disrupting their reliance on glutamine, a key component for various metabolic processes. Traditional attempts using glutamine inhibitors like 6-diazo-5-oxo-L-norleucine (DON) and CB-839 were unsuccessful, but new hope arises with DRP-104, a pro-drug of DON. This compound effectively targets tumor metabolism while minimizing side effects. In a recent study published in Nature Cancer, Encarnación-Rosado and colleagues demonstrated in pre-clinical models that pancreatic ductal adenocarcinoma (PDAC) responds well to DRP-104, though tumors adapt through the MEK/ERK signaling pathway, which can be countered by the MEK inhibitor trametinib. In a related study, Recouvreux and colleagues found that DON is effective against pancreatic tumors, revealing that PDAC tumors upregulate asparagine synthesis in response to DON, making them susceptible to asparaginase treatment. Both studies underscore the potential of inhibiting glutamine metabolism and adaptive pathways as a promising strategy against PDAC. These findings pave the way for upcoming clinical trials utilizing DRP-104 and similar glutamine antagonists in the battle against solid tumors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3954
  5. Cell Metab. 2023 Dec 12. pii: S1550-4131(23)00460-6. [Epub ahead of print]
    Nutrient inputs and social metabolic control of T cell fate.
    Zachary A Bacigalupa, Madelyn D Landis, Jeffrey C Rathmell.
      Cells in multicellular organisms experience diverse neighbors, signals, and evolving physical environments that drive functional and metabolic demands. To maintain proper development and homeostasis while avoiding inappropriate cell proliferation or death, individual cells interact with their neighbors via "social" cues to share and partition available nutrients. Metabolic signals also contribute to cell fate by providing biochemical links between cell-extrinsic signals and available resources. In addition to metabolic checkpoints that sense nutrients and directly supply molecular intermediates for biosynthetic pathways, many metabolites directly signal or provide the basis for post-translational modifications of target proteins and chromatin. In this review, we survey the landscape of T cell nutrient sensing and metabolic signaling that supports proper immunity while avoiding immunodeficiency or autoimmunity. The integration of cell-extrinsic microenvironmental cues with cell-intrinsic metabolic signaling provides a social metabolic control model to integrate cell signaling, metabolism, and fate.
    Keywords:  T cells; epigenetics; immunometabolism; metabolic signaling; social control model
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.009
  6. Curr Issues Mol Biol. 2023 Dec 05. 45(12): 9753-9767
    Metabolic Interplay in the Tumor Microenvironment: Implications for Immune Function and Anticancer Response.
    Reem Youssef, Rohan Maniar, Jaffar Khan, Hector Mesa.
      Malignant tumors exhibit rapid growth and high metabolic rates, similar to embryonic stem cells, and depend on aerobic glycolysis, known as the "Warburg effect". This understanding has enabled the use of radiolabeled glucose analogs in tumor staging and therapeutic response assessment via PET scans. Traditional treatments like chemotherapy and radiotherapy target rapidly dividing cells, causing significant toxicity. Despite immunotherapy's impact on solid tumor treatment, gaps remain, leading to research on cancer cell evasion of immune response and immune tolerance induction via interactions with the tumor microenvironment (TME). The TME, consisting of immune cells, fibroblasts, vessels, and the extracellular matrix, regulates tumor progression and therapy responses. TME-targeted therapies aim to transform this environment from supporting tumor growth to impeding it and fostering an effective immune response. This review examines the metabolic disparities between immune cells and cancer cells, their impact on immune function and therapeutic targeting, the TME components, and the complex interplay between cancer cells and nontumoral cells. The success of TME-targeted therapies highlights their potential to achieve better cancer control or even a cure.
    Keywords:  immunotherapy; oncometabolites; tumor microenvironment
    DOI:  https://doi.org/10.3390/cimb45120609
  7. Int J Mol Sci. 2023 Dec 13. pii: 17422. [Epub ahead of print]24(24):
    The Role of Tumor Metabolic Reprogramming in Tumor Immunity.
    Xianhong Zhang, Weiguo Song, Yue Gao, Yu Zhang, Yuqi Zhao, Shuailin Hao, Ting Ni.
      The occurrence and development of tumors require the metabolic reprogramming of cancer cells, namely the alteration of flux in an autonomous manner via various metabolic pathways to meet increased bioenergetic and biosynthetic demands. Tumor cells consume large quantities of nutrients and produce related metabolites via their metabolism; this leads to the remodeling of the tumor microenvironment (TME) to better support tumor growth. During TME remodeling, the immune cell metabolism and antitumor immune activity are affected. This further leads to the escape of tumor cells from immune surveillance and therefore to abnormal proliferation. This review summarizes the regulatory functions associated with the abnormal biosynthesis and activity of metabolic signaling molecules during the process of tumor metabolic reprogramming. In addition, we provide a comprehensive description of the competition between immune cells and tumor cells for nutrients in the TME, as well as the metabolites required for tumor metabolism, the metabolic signaling pathways involved, and the functionality of the immune cells. Finally, we summarize current research targeted at the development of tumor immunotherapy. We aim to provide new concepts for future investigations of the mechanisms underlying the metabolic reprogramming of tumors and explore the association of these mechanisms with tumor immunity.
    Keywords:  immune cells; tumor immunity; tumor metabolism; tumor microenvironment; tumor therapy
    DOI:  https://doi.org/10.3390/ijms242417422
  8. Proc Natl Acad Sci U S A. 2023 Dec 26. 120(52): e2311674120
    SERS analysis of cancer cell-secreted purines reveals a unique paracrine crosstalk in MTAP-deficient tumors.
    Pablo S Valera, Javier Plou, Isabel García, Ianire Astobiza, Cristina Viera, Ana M Aransay, José E Martin, Ivan R Sasselli, Arkaitz Carracedo, Luis M Liz-Marzán.
      The tumor microenvironment (TME) is a dynamic pseudoorgan that shapes the development and progression of cancers. It is a complex ecosystem shaped by interactions between tumor and stromal cells. Although the traditional focus has been on the paracrine communication mediated by protein messengers, recent attention has turned to the metabolic secretome in tumors. Metabolic enzymes, together with exchanged substrates and products, have emerged as potential biomarkers and therapeutic targets. However, traditional techniques for profiling secreted metabolites in complex cellular contexts are limited. Surface-enhanced Raman scattering (SERS) has emerged as a promising alternative due to its nontargeted nature and simplicity of operation. Although SERS has demonstrated its potential for detecting metabolites in biological settings, its application in deciphering metabolic interactions within multicellular systems like the TME remains underexplored. In this study, we introduce a SERS-based strategy to investigate the secreted purine metabolites of tumor cells lacking methylthioadenosine phosphorylase (MTAP), a common genetic event associated with poor prognosis in various cancers. Our SERS analysis reveals that MTAP-deficient cancer cells selectively produce methylthioadenosine (MTA), which is taken up and metabolized by fibroblasts. Fibroblasts exposed to MTA exhibit: i) molecular reprogramming compatible with cancer aggressiveness, ii) a significant production of purine derivatives that could be readily recycled by cancer cells, and iii) the capacity to secrete purine derivatives that induce macrophage polarization. Our study supports the potential of SERS for cancer metabolism research and reveals an unprecedented paracrine crosstalk that explains TME reprogramming in MTAP-deleted cancers.
    Keywords:  Raman spectroscopy; biosensors; metabolic signaling; secretome; tumor metabolism
    DOI:  https://doi.org/10.1073/pnas.2311674120
  9. Dev Cell. 2023 Dec 18. pii: S1534-5807(23)00646-9. [Epub ahead of print]58(24): 2819-2821
    Understanding the microenvironment and how this controls cell fate.
    Elaine Fuchs, Erik Sahai, Ashani T Weeraratna, Benjamin Deneen, Carmen Chak-Lui Wong, András Simon.
      The microenvironment influences cell fate. In this collection of voices, researchers from the fields of cancer and regeneration highlight approaches to establish the importance of the microenvironment and discuss future directions to understand the complex interaction between cells and their surrounding environment and how this impacts on disease and regeneration.
    DOI:  https://doi.org/10.1016/j.devcel.2023.11.025
  10. Cell Metab. 2023 Dec 14. pii: S1550-4131(23)00445-X. [Epub ahead of print]
    Myeloid cell-derived creatine in the hypoxic niche promotes glioblastoma growth.
    Aida Rashidi, Leah K Billingham, Andrew Zolp, Tzu-Yi Chia, Caylee Silvers, Joshua L Katz, Cheol H Park, Suzi Delay, Lauren Boland, Yuheng Geng, Steven M Markwell, Crismita Dmello, Victor A Arrieta, Kaylee Zilinger, Irene M Jacob, Aurora Lopez-Rosas, David Hou, Brandyn Castro, Alicia M Steffens, Kathleen McCortney, Jordain P Walshon, Mariah S Flowers, Hanchen Lin, Hanxiang Wang, Junfei Zhao, Adam Sonabend, Peng Zhang, Atique U Ahmed, Daniel J Brat, Dieter H Heiland, Catalina Lee-Chang, Maciej S Lesniak, Navdeep S Chandel, Jason Miska.
      Glioblastoma (GBM) is a malignancy dominated by the infiltration of tumor-associated myeloid cells (TAMCs). Examination of TAMC metabolic phenotypes in mouse models and patients with GBM identified the de novo creatine metabolic pathway as a hallmark of TAMCs. Multi-omics analyses revealed that TAMCs surround the hypoxic peri-necrotic regions of GBM and express the creatine metabolic enzyme glycine amidinotransferase (GATM). Conversely, GBM cells located within these same regions are uniquely specific in expressing the creatine transporter (SLC6A8). We hypothesized that TAMCs provide creatine to tumors, promoting GBM progression. Isotopic tracing demonstrated that TAMC-secreted creatine is taken up by tumor cells. Creatine supplementation protected tumors from hypoxia-induced stress, which was abrogated with genetic ablation or pharmacologic inhibition of SLC6A8. Lastly, inhibition of creatine transport using the clinically relevant compound, RGX-202-01, blunted tumor growth and enhanced radiation therapy in vivo. This work highlights that myeloid-to-tumor transfer of creatine promotes tumor growth in the hypoxic niche.
    Keywords:  creatine metabolism; glioblastoma; myeloid cells; pseudopalisading necrosis
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.013
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