bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2024–03–17
six papers selected by
Oltea Sampetrean, Keio University
  1. Ex vivo activation of the GCN2 pathway metabolically reprograms T cells, leading to enhanced adoptive cell therapy.
  2. MCT4-driven CAF-mediated metabolic reprogramming in breast cancer microenvironment is a vulnerability targetable by miR-425-5p.
  3. Inversion of the Warburg Effect: Unraveling the Metabolic Nexus between Obesity and Cancer.
  4. Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors.
  5. Metabolic reprogramming and signalling cross-talks in tumour-immune interaction: a system-level exploration.
  6. Reprogramming of Lipid Metabolism Mediates Crosstalk, Remodeling, and Intervention of Microenvironment Components in Breast Cancer.
  1. Cell Rep Med. 2024 Mar 01. pii: S2666-3791(24)00109-5. [Epub ahead of print] 101465
    Ex vivo activation of the GCN2 pathway metabolically reprograms T cells, leading to enhanced adoptive cell therapy.
    Michael St Paul, Samuel D Saibil, Meghan Kates, SeongJun Han, Scott C Lien, Rob C Laister, Kebria Hezaveh, Andreas Kloetgen, Susanne Penny, Tingxi Guo, Carlos Garcia-Batres, Logan K Smith, Douglas C Chung, Alisha R Elford, Azin Sayad, Devanand Pinto, Tak W Mak, Naoto Hirano, Tracy McGaha, Pamela S Ohashi.
      The manipulation of T cell metabolism to enhance anti-tumor activity is an area of active investigation. Here, we report that activating the amino acid starvation response in effector CD8+ T cells ex vivo using the general control non-depressible 2 (GCN2) agonist halofuginone (halo) enhances oxidative metabolism and effector function. Mechanistically, we identified autophagy coupled with the CD98-mTOR axis as key downstream mediators of the phenotype induced by halo treatment. The adoptive transfer of halo-treated CD8+ T cells into tumor-bearing mice led to robust tumor control and curative responses. Halo-treated T cells synergized in vivo with a 4-1BB agonistic antibody to control tumor growth in a mouse model resistant to immunotherapy. Importantly, treatment of human CD8+ T cells with halo resulted in similar metabolic and functional reprogramming. These findings demonstrate that activating the amino acid starvation response with the GCN2 agonist halo can enhance T cell metabolism and anti-tumor activity.
    Keywords:  4-1BB; CD8(+) T cell; GCN2; Halofuginone; adoptive Cell therapy; autophagy; immunometabolism; immunotherapy
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101465
  2. Cell Death Discov. 2024 Mar 14. 10(1): 140
    MCT4-driven CAF-mediated metabolic reprogramming in breast cancer microenvironment is a vulnerability targetable by miR-425-5p.
    Alessandra Affinito, Cristina Quintavalle, Rosario Vincenzo Chianese, Giuseppina Roscigno, Danilo Fiore, Valeria D'Argenio, Guglielmo Thomas, Alessia Savarese, Francesco Ingenito, Lorenza Cocca, Silvia Nuzzo, Maxim V Berezovski, Maria Patrizia Stoppelli, Gerolama Condorelli.
      Multiple oncogenic alterations contribute to breast cancer development. Metabolic reprogramming, deeply contributing to tumor microenvironment (TME) education, is now widely recognized as a hallmark of cancer. The reverse Warburg effect induces cancer-associated fibroblasts (CAFs) to produce and secrete L-lactate, enhancing malignant characteristics such as neoangiogenesis, metastatic dissemination, and treatment resistance. Monocarboxylate transporter (MCT) 4 is involved in lactate efflux from CAFs into stromal and epithelial cells. Here, we first assess the expression of miR-425-5p and its target MCT4 in breast cancer CAFs and normal fibroblasts. We analyzed the metabolic changes induced by miR-425-5p in CAFs and its role in the education of breast cancer epithelial cells. We show that miR-425-5p-induced MCT4 knockdown decreased lactate extrusion from CAFs and its availability in the TME. miR-425-5p overexpression induced profound metabolic transformation in CAFs, ultimately influencing breast cancer metabolism. Furthermore, miR-425-5p impaired the capacity of CAFs to sustain vessel formation and breast cancer cell migration, viability, and proliferation. These findings emphasize the key role of miR-425-5p in breast cancer metabolism and aggressiveness, and its possible importance for breast cancer therapy and monitoring.
    DOI:  https://doi.org/10.1038/s41420-024-01910-x
  3. ACS Pharmacol Transl Sci. 2024 Mar 08. 7(3): 560-569
    Inversion of the Warburg Effect: Unraveling the Metabolic Nexus between Obesity and Cancer.
    Reshmi Akter, Muhammad Awais, Vinothini Boopathi, Jong Chan Ahn, Deok Chun Yang, Se Chan Kang, Dong Uk Yang, Seok-Kyu Jung.
      Obesity is a well-established risk factor for cancer, significantly impacting both cancer incidence and mortality. However, the intricate molecular mechanisms connecting adipose tissue to cancer cell metabolism are not fully understood. This Review explores the historical context of tumor energy metabolism research, tracing its origins to Otto Warburg's pioneering work in 1920. Warburg's discovery of the "Warburg effect", wherein cancer cells prefer anaerobic glycolysis even in the presence of oxygen, laid the foundation for understanding cancer metabolism. Building upon this foundation, the "reverse Warburg effect" emerged in 2009, elucidating the role of aerobic glycolysis in cancer-associated fibroblasts (CAFs) and its contribution to lactate accumulation in the tumor microenvironment, subsequently serving as a metabolic substrate for cancer cells. In contrast, within high-adiposity contexts, cancer cells exhibit a unique metabolic shift termed the "inversion of the Warburg effect". This phenomenon, distinct from the stromal-dependent reverse Warburg effect, relies on increased nutrient abundance in obesity environments, leading to the generation of glucose from lactate as a metabolic substrate. This Review underscores the heightened tumor proliferation and aggressiveness associated with obesity, introducing the "inversion of the Warburg effect" as a novel mechanism rooted in the altered metabolic landscape within an obese milieu. The insights presented here open promising avenues for therapeutic exploration, offering fresh perspectives and opportunities for the development of innovative cancer treatment strategies.
    DOI:  https://doi.org/10.1021/acsptsci.3c00301
  4. Nat Commun. 2024 Mar 11. 15(1): 2203
    Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors.
    Luca Simula, Mattia Fumagalli, Lene Vimeux, Irena Rajnpreht, Philippe Icard, Gary Birsen, Dongjie An, Frédéric Pendino, Adrien Rouault, Nadège Bercovici, Diane Damotte, Audrey Lupo-Mansuet, Marco Alifano, Marie-Clotilde Alves-Guerra, Emmanuel Donnadieu.
      The ability of CD8+ T cells to infiltrate solid tumors and reach cancer cells is associated with improved patient survival and responses to immunotherapy. Thus, identifying the factors controlling T cell migration in tumors is critical, so that strategies to intervene on these targets can be developed. Although interstitial motility is a highly energy-demanding process, the metabolic requirements of CD8+ T cells migrating in a 3D environment remain unclear. Here, we demonstrate that the tricarboxylic acid (TCA) cycle is the main metabolic pathway sustaining human CD8+ T cell motility in 3D collagen gels and tumor slices while glycolysis plays a more minor role. Using pharmacological and genetic approaches, we report that CD8+ T cell migration depends on the mitochondrial oxidation of glucose and glutamine, but not fatty acids, and both ATP and ROS produced by mitochondria are required for T cells to migrate. Pharmacological interventions to increase mitochondrial activity improve CD8+ T cell intratumoral migration and CAR T cell recruitment into tumor islets leading to better control of tumor growth in human xenograft models. Our study highlights the rationale of targeting mitochondrial metabolism to enhance the migration and antitumor efficacy of CAR T cells in treating solid tumors.
    DOI:  https://doi.org/10.1038/s41467-024-46377-7
  5. R Soc Open Sci. 2024 Mar;11(3): 231574
    Metabolic reprogramming and signalling cross-talks in tumour-immune interaction: a system-level exploration.
    Mudita Shukla, Rupa Bhowmick, Piyali Ganguli, Ram Rup Sarkar.
      Tumour-immune microenvironment (TIME) is pivotal in tumour progression and immunoediting. Within TIME, immune cells undergo metabolic adjustments impacting nutrient supply and the anti-tumour immune response. Metabolic reprogramming emerges as a promising approach to revert the immune response towards a pro-inflammatory state and conquer tumour dominance. This study proposes immunomodulatory mechanisms based on metabolic reprogramming and employs the regulatory flux balance analysis modelling approach, which integrates signalling, metabolism and regulatory processes. For the first time, a comprehensive system-level model is constructed to capture signalling and metabolic cross-talks during tumour-immune interaction and regulatory constraints are incorporated by considering the time lag between them. The model analysis identifies novel features to enhance the immune response while suppressing tumour activity. Particularly, altering the exchange of succinate and oxaloacetate between glioma and macrophage enhances the pro-inflammatory response of immune cells. Inhibition of glutamate uptake in T-cells disrupts the antioxidant mechanism of glioma and reprograms metabolism. Metabolic reprogramming through adenosine monophosphate (AMP)-activated protein kinase (AMPK), coupled with glutamate uptake inhibition, was identified as the most impactful combination to restore T-cell function. A comprehensive understanding of metabolism and gene regulation represents a favourable approach to promote immune cell recovery from tumour dominance.
    Keywords:  metabolic reprogramming; signalling-metabolic cross-talks; system modelling; tumour–immune interaction
    DOI:  https://doi.org/10.1098/rsos.231574
  6. Int J Biol Sci. 2024 ;20(5): 1884-1904
    Reprogramming of Lipid Metabolism Mediates Crosstalk, Remodeling, and Intervention of Microenvironment Components in Breast Cancer.
    Jia Wang, Wenfeng Zhang, Cun Liu, LongYun Wang, Jibiao Wu, Changgang Sun, Qibiao Wu.
      Due to the unique characteristics of breast cancer initiation sites and significant alterations in tumor metabolism, breast cancer cells rely on lipid metabolic reprogramming to effectively regulate metabolic programs during the disease progression cascade. This adaptation enables them to meet the energy demands required for proliferation, invasion, metastasis, and responses to signaling molecules in the breast cancer microenvironment. In this review, we comprehensively examined the distinctive features of lipid metabolic reprogramming in breast cancer and elucidated the underlying mechanisms driving aberrant behavior of tumor cells. Additionally, we emphasize the potential role and adaptive changes in lipid metabolism within the breast cancer microenvironment, while summarizing recent preclinical studies. Overall, precise control over lipid metabolism rewiring and understanding of plasticity within the breast cancer microenvironment hold promising implications for developing targeted treatment strategies against this disease. Therefore, interventions targeting the lipid metabolism in breast cancer may facilitate innovative advancements in clinical applications.
    Keywords:  Breast cancer; Lipid metabolism; Targeted intervention; Tumor microenvironment
    DOI:  https://doi.org/10.7150/ijbs.92125
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