bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2024–09–01
ten papers selected by
Oltea Sampetrean, Keio University
  1. Multifaceted metabolic role of infections in the tumor microenvironment.
  2. The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade.
  3. Reprogramming the immunosuppressive tumor microenvironment through nanomedicine: an immunometabolism perspective.
  4. Lactate helps cancer cells resist chemotherapy.
  5. Metabolism of organic carcinogens by gut bacteria induces bladder tumours.
  6. Reprogramming of breast tumor-associated macrophages with modulation of arginine metabolism.
  7. Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and cytotoxicity.
  8. Activation and antitumor immunity of CD8+ T cells are supported by the glucose transporter GLUT10 and disrupted by lactic acid.
  9. Immunometabolism of ferroptosis in the tumor microenvironment.
  10. A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.
  1. Curr Opin Biotechnol. 2024 Aug 27. pii: S0958-1669(24)00119-8. [Epub ahead of print]89 103183
    Multifaceted metabolic role of infections in the tumor microenvironment.
    Hanna F Willenbockel, Birte Dowerg, Thekla Cordes.
      The impact of bacteria and viruses on tumor growth has long been recognized. In recent decades, interest in the role of microorganisms in the tumor microenvironment (TME) has expanded. Infections induce metabolic reprogramming and influence immune responses within the TME that may either support proliferation and metastasis or limit tumor growth. The natural ability to infect cells and alter the TME is also utilized for cancer detection and treatment. In this review, we discuss recent discoveries about the mechanisms of bacteria and viruses affecting TME, as well as strategies in cancer therapy focusing on metabolic alterations. Infections with engineered bacteria and viruses represent promising therapeutic approaches to develop novel and more effective therapies to constrain tumor growth.
    DOI:  https://doi.org/10.1016/j.copbio.2024.103183
  2. Nat Metab. 2024 Aug;6(8): 1529-1548
    The unique catalytic properties of PSAT1 mediate metabolic adaptation to glutamine blockade.
    Yijian Qiu, Olivia T Stamatatos, Qingting Hu, Jed Ruiter Swain, Suzanne Russo, Ava Sann, Ana S H Costa, Sara Violante, David L Spector, Justin R Cross, Michael J Lukey.
      Cultured cancer cells frequently rely on the consumption of glutamine and its subsequent hydrolysis by glutaminase (GLS). However, this metabolic addiction can be lost in the tumour microenvironment, rendering GLS inhibitors ineffective in the clinic. Here we show that glutamine-addicted breast cancer cells adapt to chronic glutamine starvation, or GLS inhibition, via AMPK-mediated upregulation of the serine synthesis pathway (SSP). In this context, the key product of the SSP is not serine, but α-ketoglutarate (α-KG). Mechanistically, we find that phosphoserine aminotransferase 1 (PSAT1) has a unique capacity for sustained α-KG production when glutamate is depleted. Breast cancer cells with resistance to glutamine starvation or GLS inhibition are highly dependent on SSP-supplied α-KG. Accordingly, inhibition of the SSP prevents adaptation to glutamine blockade, resulting in a potent drug synergism that suppresses breast tumour growth. These findings highlight how metabolic redundancy can be context dependent, with the catalytic properties of different metabolic enzymes that act on the same substrate determining which pathways can support tumour growth in a particular nutrient environment. This, in turn, has practical consequences for therapies targeting cancer metabolism.
    DOI:  https://doi.org/10.1038/s42255-024-01104-w
  3. EBioMedicine. 2024 Aug 22. pii: S2352-3964(24)00337-2. [Epub ahead of print]107 105301
    Reprogramming the immunosuppressive tumor microenvironment through nanomedicine: an immunometabolism perspective.
    Jieyu Liu, Yinan Bai, Yinggang Li, Xiaoling Li, Kui Luo.
      Increasing evidence indicates that immunotherapy is hindered by a hostile tumor microenvironment (TME) featured with deprivation of critical nutrients and pooling of immunosuppressive metabolites. Tumor cells and immunosuppressive cells outcompete immune effector cells for essential nutrients. Meanwhile, a wide range of tumor cell-derived toxic metabolites exerts negative impacts on anti-tumor immune response, diminishing the efficacy of immunotherapy. Nanomedicine with excellent targetability offers a novel approach to improving cancer immunotherapy via metabolically reprogramming the immunosuppressive TME. Herein, we review recent strategies of enhancing immunotherapeutic effects through rewiring tumor metabolism via nanomedicine. Attention is drawn on immunometabolic tactics for immune cells and stromal cells in the TME via nanomedicine. Additionally, we discuss future directions of developing metabolism-regulating nanomedicine for precise and efficacious cancer immunotherapy.
    Keywords:  Anti-tumor immunity; Immunometabolism; Metabolic reprogramming; Nanomedicine; Tumor immune microenvironment
    DOI:  https://doi.org/10.1016/j.ebiom.2024.105301
  4. Nature. 2024 Aug 23.
    Lactate helps cancer cells resist chemotherapy.
      
    Keywords:  Cancer; Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-02731-9
  5. Nature. 2024 Aug 28.
    Metabolism of organic carcinogens by gut bacteria induces bladder tumours.
      
    Keywords:  Cancer; Microbiome; Therapeutics
    DOI:  https://doi.org/10.1038/d41586-024-02740-8
  6. Life Sci Alliance. 2024 Nov;pii: e202302339. [Epub ahead of print]7(11):
    Reprogramming of breast tumor-associated macrophages with modulation of arginine metabolism.
    Veani Fernando, Xunzhen Zheng, Vandana Sharma, Osama Sweef, Eun-Seok Choi, Saori Furuta.
      HER2+ breast tumors have abundant immune-suppressive cells, including M2-type tumor-associated macrophages (TAMs). Although TAMs consist of the immune-stimulatory M1 type and immune-suppressive M2 type, the M1/M2-TAM ratio is reduced in immune-suppressive tumors, contributing to their immunotherapy refractoriness. M1- versus M2-TAM formation depends on differential arginine metabolism, where M1-TAMs convert arginine to nitric oxide (NO) and M2-TAMs convert arginine to polyamines (PAs). We hypothesize that such distinct arginine metabolism in M1- versus M2-TAMs is attributed to different availability of BH4 (NO synthase cofactor) and that its replenishment would reprogram M2-TAMs to M1-TAMs. Recently, we reported that sepiapterin (SEP), the endogenous BH4 precursor, elevates the expression of M1-TAM markers within HER2+ tumors. Here, we show that SEP restores BH4 levels in M2-like macrophages, which then redirects arginine metabolism to NO synthesis and converts M2 type to M1 type. The reprogrammed macrophages exhibit full-fledged capabilities of antigen presentation and induction of effector T cells to trigger immunogenic cell death of HER2+ cancer cells. This study substantiates the utility of SEP in the metabolic shift of the HER2+ breast tumor microenvironment as a novel immunotherapeutic strategy.
    DOI:  https://doi.org/10.26508/lsa.202302339
  7. Nat Immunol. 2024 Aug 28.
    Sodium chloride in the tumor microenvironment enhances T cell metabolic fitness and cytotoxicity.
    Dominik Soll, Chang-Feng Chu, Shan Sun, Veronika Lutz, Mahima Arunkumar, Mariam Gachechiladze, Sascha Schäuble, Maha Alissa-Alkhalaf, Trang Nguyen, Michelle-Amirah Khalil, Ignacio Garcia-Ribelles, Michael Mueller, Katrin Buder, Bernhard Michalke, Gianni Panagiotou, Kai Ziegler-Martin, Pascal Benz, Philipp Schatzlmaier, Karsten Hiller, Hannes Stockinger, Maik Luu, Kilian Schober, Carolin Moosmann, Wolfgang W Schamel, Magdalena Huber, Christina E Zielinski.
      The efficacy of antitumor immunity is associated with the metabolic state of cytotoxic T cells, which is sensitive to the tumor microenvironment. Whether ionic signals affect adaptive antitumor immune responses is unclear. In the present study, we show that there is an enrichment of sodium in solid tumors from patients with breast cancer. Sodium chloride (NaCl) enhances the activation state and effector functions of human CD8+ T cells, which is associated with enhanced metabolic fitness. These NaCl-induced effects translate into increased tumor cell killing in vitro and in vivo. Mechanistically, NaCl-induced changes in CD8+ T cells are linked to sodium-induced upregulation of Na+/K+-ATPase activity, followed by membrane hyperpolarization, which magnifies the electromotive force for T cell receptor (TCR)-induced calcium influx and downstream TCR signaling. We therefore propose that NaCl is a positive regulator of acute antitumor immunity that might be modulated for ex vivo conditioning of therapeutic T cells, such as CAR T cells.
    DOI:  https://doi.org/10.1038/s41590-024-01918-6
  8. Sci Transl Med. 2024 Aug 28. 16(762): eadk7399
    Activation and antitumor immunity of CD8+ T cells are supported by the glucose transporter GLUT10 and disrupted by lactic acid.
    Ying Liu, Feng Wang, Dongxue Peng, Dan Zhang, Luping Liu, Jun Wei, Jian Yuan, Luyao Zhao, Huimin Jiang, Tingting Zhang, Yunxuan Li, Chenxi Zhao, Shuhua He, Jie Wu, Yechao Yan, Peitao Zhang, Chunyi Guo, Jiaming Zhang, Xia Li, Huan Gao, Ke Li.
      CD8+ T cell activation leads to the rapid proliferation and differentiation of effector T cells (Teffs), which mediate antitumor immunity. Although aerobic glycolysis is preferentially activated in CD8+ Teffs, the mechanisms that regulate CD8+ T cell glucose uptake in the low-glucose and acidic tumor microenvironment (TME) remain poorly understood. Here, we report that the abundance of the glucose transporter GLUT10 is increased during CD8+ T cell activation and antitumor immunity. Specifically, GLUT10 deficiency inhibited glucose uptake, glycolysis, and antitumor efficiency of tumor-infiltrating CD8+ T cells. Supplementation with glucose alone was insufficient to rescue the antitumor function and glucose uptake of CD8+ T cells in the TME. By analyzing tumor environmental metabolites, we found that high concentrations of lactic acid reduced the glucose uptake, activation, and antitumor effects of CD8+ T cells by directly binding to GLUT10's intracellular motif. Disrupting the interaction of lactic acid and GLUT10 by the mimic peptide PG10.3 facilitated CD8+ T cell glucose utilization, proliferation, and antitumor functions. The combination of PG10.3 and GLUT1 inhibition or anti-programmed cell death 1 antibody treatment showed synergistic antitumor effects. Together, our data indicate that GLUT10 is selectively required for glucose uptake of CD8+ T cells and identify that TME accumulated lactic acid inhibits CD8+ T cell effector function by directly binding to GLUT10 and reducing its glucose transport capacity. Last, our study suggests disrupting lactate-GLUT10 binding as a promising therapeutic strategy to enhance CD8+ T cell-mediated antitumor effects.
    DOI:  https://doi.org/10.1126/scitranslmed.adk7399
  9. Front Oncol. 2024 ;14 1441338
    Immunometabolism of ferroptosis in the tumor microenvironment.
    Gian Luca Lupica-Tondo, Emily N Arner, Denis A Mogilenko, Kelsey Voss.
      Ferroptosis is an iron-dependent form of cell death that results from excess lipid peroxidation in cellular membranes. Within the last decade, physiological and pathological roles for ferroptosis have been uncovered in autoimmune diseases, inflammatory conditions, infection, and cancer biology. Excitingly, cancer cell metabolism may be targeted to induce death by ferroptosis in cancers that are resistant to other forms of cell death. Ferroptosis sensitivity is regulated by oxidative stress, lipid metabolism, and iron metabolism, which are all influenced by the tumor microenvironment (TME). Whereas some cancer cell types have been shown to adapt to these stressors, it is not clear how immune cells regulate their sensitivities to ferroptosis. In this review, we discuss the mechanisms of ferroptosis sensitivity in different immune cell subsets, how ferroptosis influences which immune cells infiltrate the TME, and how these interactions can determine epithelial-to-mesenchymal transition (EMT) and metastasis. While much focus has been placed on inducing ferroptosis in cancer cells, these are important considerations for how ferroptosis-modulating strategies impact anti-tumor immunity. From this perspective, we also discuss some promising immunotherapies in the field of ferroptosis and the challenges associated with targeting ferroptosis in specific immune cell populations.
    Keywords:  TME; ferroptosis; immunometabolism; iron; metastasis
    DOI:  https://doi.org/10.3389/fonc.2024.1441338
  10. EMBO J. 2024 Aug 27.
    A cell state-specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.
    Matei A Banu, Athanassios Dovas, Michael G Argenziano, Wenting Zhao, Colin P Sperring, Henar Cuervo Grajal, Zhouzerui Liu, Dominique Mo Higgins, Misha Amini, Brianna Pereira, Ling F Ye, Aayushi Mahajan, Nelson Humala, Julia L Furnari, Pavan S Upadhyayula, Fereshteh Zandkarimi, Trang Tt Nguyen, Damian Teasley, Peter B Wu, Li Hai, Charles Karan, Tyrone Dowdy, Aida Razavilar, Markus D Siegelin, Jan Kitajewski, Mioara Larion, Jeffrey N Bruce, Brent R Stockwell, Peter A Sims, Peter Canoll.
      Glioma cells hijack developmental programs to control cell state. Here, we uncover a glioma cell state-specific metabolic liability that can be therapeutically targeted. To model cell conditions at brain tumor inception, we generated genetically engineered murine gliomas, with deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling astrocyte differentiation during brain development. N1IC tumors harbored quiescent astrocyte-like transformed cell populations while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. Further, N1IC transformed cells exhibited increased mitochondrial lipid peroxidation, high ROS production and depletion of reduced glutathione. This altered mitochondrial phenotype rendered the astrocyte-like, quiescent populations more sensitive to pharmacologic or genetic inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Treatment of patient-derived early-passage cell lines and glioma slice cultures generated from surgical samples with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles. Collectively, these findings reveal a specific therapeutic vulnerability to ferroptosis linked to mitochondrial redox imbalance in a subpopulation of quiescent astrocyte-like glioma cells resistant to standard forms of treatment.
    Keywords:  Astrocytic; Ferroptosis; Glioma; Mitochondrial-metabolism; Quiescent
    DOI:  https://doi.org/10.1038/s44318-024-00176-4
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