bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2024–01–07
sixteen papers selected by
Oltea Sampetrean, Keio University
  1. TAMC-derived creatine sustains glioblastoma growth.
  2. Transgelin 2 guards T cell lipid metabolic programming and anti-tumor function.
  3. Metabolic reprogramming in the tumor microenvironment: unleashing T cell stemness for enhanced cancer immunotherapy.
  4. Nanotechnology Reprogramming Metabolism for Enhanced Tumor Immunotherapy.
  5. Caloric restriction and metformin selectively improved LKB1-mutated NSCLC tumor response to chemo- and chemo-immunotherapy.
  6. Metabolism-Related Prognostic Biomarkers, Purine Metabolism and Anti-Tumor Immunity in Colon Adenocarcinoma.
  7. The multifaceted roles of small extracellular vesicles in metabolic reprogramming in the tumor microenvironments.
  8. Shaping immune landscape of colorectal cancer by cholesterol metabolites.
  9. Fatty Acid Metabolism: A New Perspective in Breast Cancer Precision Therapy.
  10. Dietary approaches for exploiting metabolic vulnerabilities in cancer.
  11. Mitochondrial isocitrate dehydrogenase impedes CAR T cell function by restraining antioxidant metabolism and histone acetylation.
  12. Excessive Lipid Production Shapes Glioma Tumor Microenvironment.
  13. Intercellular crosstalk shapes purinergic metabolism and signaling in cancer cells.
  14. Carnosine regulation of intracellular pH homeostasis promotes lysosome-dependent tumor immunoevasion.
  15. Lymphatic endothelial-like cells promote glioblastoma stem cell growth through cytokine-driven cholesterol metabolism.
  16. PRUNE1 and NME/NDPK family proteins influence energy metabolism and signaling in cancer metastases.
  1. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00463-1. [Epub ahead of print]36(1): 1-3
    TAMC-derived creatine sustains glioblastoma growth.
    Huiwen Yan, Pengcheng Bu.
      Tumor-associated myeloid cells (TAMCs) are the predominant immune population in glioblastoma (GBM), but the definite role of TAMCs in GBM tumorigenicity remains uncertain. In this issue of Cell Metabolism, Rashidi et al. identify a specific population of TAMCs surrounding hypoxic regions of GBM. These TAMCs provide creatine to nearby tumor cells to promote GBM progression.
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.012
  2. Res Sq. 2023 Dec 14. pii: rs.3.rs-3683989. [Epub ahead of print]
    Transgelin 2 guards T cell lipid metabolic programming and anti-tumor function.
    Sung-Min Hwang, Deepika Awasthi, Jieun Jeong, Tito Sandoval, Chang-Suk Chae, Yusibeska Ramos, Chen Tan, Matias Marin Falco, Ian McBain, Bikash Mishra, Lionel B Ivashkiv, Dmitriy Zamarin, Evelyn Cantillo, Eloise Chapman-Davis, Kevin Holcomb, Diana Morales, Paulo Rodriguez, Jose Conejo-Garcia, Martin Kaczocha, Anna Vähärautio, Minkyung Song, Juan Cubillos-Ruiz.
      Mounting effective immunity against pathogens and tumors relies on the successful metabolic programming of T cells by extracellular fatty acids 1-3 . During this process, fatty-acid-binding protein 5 (FABP5) imports lipids that fuel mitochondrial respiration and sustain the bioenergetic requirements of protective CD8 + T cells 4,5 . Importantly, however, the mechanisms governing this crucial immunometabolic axis remain unexplored. Here we report that the cytoskeletal organizer Transgelin 2 (TAGLN2) is necessary for optimal CD8 + T cell fatty acid uptake, mitochondrial respiration, and anti-cancer function. We found that TAGLN2 interacts with FABP5, enabling the surface localization of this lipid importer on activated CD8 + T cells. Analysis of ovarian cancer specimens revealed that endoplasmic reticulum (ER) stress responses elicited by the tumor microenvironment repress TAGLN2 in infiltrating CD8 + T cells, enforcing their dysfunctional state. Restoring TAGLN2 expression in ER-stressed CD8 + T cells bolstered their lipid uptake, mitochondrial respiration, and cytotoxic capacity. Accordingly, chimeric antigen receptor T cells overexpressing TAGLN2 bypassed the detrimental effects of tumor-induced ER stress and demonstrated superior therapeutic efficacy in mice with metastatic ovarian cancer. Our study unveils the role of cytoskeletal TAGLN2 in T cell lipid metabolism and highlights the potential to enhance cellular immunotherapy in solid malignancies by preserving the TAGLN2-FABP5 axis.
    DOI:  https://doi.org/10.21203/rs.3.rs-3683989/v1
  3. Front Pharmacol. 2023 ;14 1327717
    Metabolic reprogramming in the tumor microenvironment: unleashing T cell stemness for enhanced cancer immunotherapy.
    Youhan Liu, Tao Wang, Wen Ma, Zixuan Jia, Qinglu Wang, Maoling Zhang, Ying Luo, Hongmei Sun.
      T cells play a pivotal role in the immune system by distinguishing between various harmful pathogens and cancerous cells within the human body and initiating an immune response. Within the tumor microenvironment (TME), immune effector T cells encounter both immunosuppressive cells and factors that hinder their functionality. Additionally, they endure robust and persistent antigenic stimulation, often leading to exhaustion and apoptosis. However, the stemness of T cells, characterized by their ability to survive and self-renew over extended periods, represents a primary target in immune checkpoint therapies such as anti-PD-1 therapy. T cell stemness encompasses specific memory T cell subsets and progenitor-exhausted T cells with stem cell-like properties. Therefore, understanding the impact of the TME on T cell stemness, including factors like K+, lactate, and H+, holds significant importance and can facilitate the mitigation of terminal T-cell depletion, the identification of potential resilient biomarkers or therapeutic targets resistant to immune checkpoint therapies, and ultimately lead to sustained anti-tumor effects. Thus, it offers a novel perspective for advancing tumor immunotherapy.
    Keywords:  H+; K+; cancer; lactate; tumor microenvironment
    DOI:  https://doi.org/10.3389/fphar.2023.1327717
  4. ACS Nano. 2024 Jan 05.
    Nanotechnology Reprogramming Metabolism for Enhanced Tumor Immunotherapy.
    Yangkai Zhou, Jing Yuan, Ke Xu, Shilin Li, Ying Liu.
      Mutation burden, hypoxia, and immunoediting contribute to altered metabolic profiles in tumor cells, resulting in a tumor microenvironment (TME) characterized by accumulation of toxic metabolites and depletion of various nutrients, which significantly hinder the antitumor immunity via multiple mechanisms, hindering the efficacy of tumor immunotherapies. In-depth investigation of the mechanisms underlying these phenomena are vital for developing effective antitumor drugs and therapies, while the therapeutic effects of metabolism-targeting drugs are restricted by off-target toxicity toward effector immune cells and high dosage-mediated side effects. Nanotechnologies, which exhibit versatility and plasticity in targeted delivery and metabolism modulation, have been widely applied to boost tumor immunometabolic therapies via multiple strategies, including targeting of metabolic pathways. In this review, recent advances in understanding the roles of tumor cell metabolism in both immunoevasion and immunosuppression are reviewed, and nanotechnology-based metabolic reprogramming strategies for enhanced tumor immunotherapies are discussed.
    Keywords:  Adaptive immunity; Innate immunity; Metabolism; Metabolites; Nanotechnology; Tumor heterogenicity; Tumor immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1021/acsnano.3c11260
  5. J Exp Clin Cancer Res. 2024 Jan 02. 43(1): 6
    Caloric restriction and metformin selectively improved LKB1-mutated NSCLC tumor response to chemo- and chemo-immunotherapy.
    Gloriana Ndembe, Ilenia Intini, Massimo Moro, Chiara Grasselli, Andrea Panfili, Nicolò Panini, Augusto Bleve, Mario Occhipinti, Cristina Borzi, Marina Chiara Garassino, Mirko Marabese, Simone Canesi, Eugenio Scanziani, Gabriella Sozzi, Massimo Broggini, Monica Ganzinelli.
       BACKGROUND: About 10% of NSCLCs are mutated in KRAS and impaired in STK11/LKB1, a genetic background associated with poor prognosis, caused by an increase in metastatic burden and resistance to standard therapy. LKB1 is a protein involved in a number of biological processes and is particularly important for its role in the regulation of cell metabolism. LKB1 alterations lead to protein loss that causes mitochondria and metabolic dysfunction that makes cells unable to respond to metabolic stress. Different studies have shown how it is possible to interfere with cancer metabolism using metformin and caloric restriction (CR) and both modify the tumor microenvironment (TME), stimulating the switch from "cold" to "hot". Given the poor therapeutic response of KRASmut/LKB1mut patients, and the role of LKB1 in cell metabolism, we examined whether the addition of metformin and CR enhanced the response to chemo or chemo-immunotherapy in LKB1 impaired tumors.
    METHODS: Mouse cell lines were derived from lung nodules of transgenic mice carrying KRASG12D with either functional LKB1 (KRASG12D/LKB1wt) or mutated LKB1 (KRASG12D/LKB1mut). Once stabilized in vitro, these cell lines were inoculated subcutaneously and intramuscularly into immunocompetent mice. Additionally, a patient-derived xenograft (PDX) model was established by directly implanting tumor fragments from patient into immunocompromised mice. The mice bearing these tumor models were subjected to treatment with chemotherapy or chemo-immunotherapy, both as standalone regimens and in combination with metformin and CR.
    RESULTS: Our preclinical results indicate that in NSCLC KRASmut/LKB1mut tumors, metformin and CR do enhance the response to chemo and chemo-immunotherapy, inducing a metabolic stress condition that these tumors are not able to overcome. Analysis of immune infiltrating cells did not bring to light any strong correlation between the TME immune-modulation and the tumor response to metformin and CR.
    CONCLUSION: Our in vitro and in vivo preliminary studies confirm our hypothesis that the addition of metformin and CR is able to improve the antitumor activity of chemo and chemoimmunotherapy in LKB1 impaired tumors, exploiting their inability to overcome metabolic stress.
    Keywords:  Caloric restriction; Cancer metabolism; KRAS; LKB1; Metformin; NSCLC
    DOI:  https://doi.org/10.1186/s13046-023-02933-5
  6. Front Biosci (Landmark Ed). 2023 Dec 01. 28(12): 328
    Metabolism-Related Prognostic Biomarkers, Purine Metabolism and Anti-Tumor Immunity in Colon Adenocarcinoma.
    Hui Liu, Yuexin Zhang, Quanzheng Zhang, Tongtong Zhang, Tianqi Lu.
       BACKGROUND: Metabolic reprogramming provides a new perspective for understanding cancer. The targeting of dysregulated metabolic pathways may help to reprogram the immune status of the tumor microenvironment (TME), thereby increasing the effectiveness of immune checkpoint therapy. Colorectal cancer (CRC), especially colon adenocarcinoma (COAD), is associated with poor patient survival. The aim of the present study was to identify novel pathways involved in the development and prognosis of COAD, and to explore whether these pathways could be used as targets to improve the efficacy of immunotherapy.
    METHODS: Metabolism-related differentially expressed genes (MRDEGs) between tumor and normal tissues were identified using The Cancer Genome Atlas (TCGA) dataset, together with metabolism-related prognostic genes (MRPGs). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed separately for the MRDEGs and MRPGs. Gene Set Variation Analysis (GSVA) was also performed to explore the role of purine metabolism in COAD tumorigenesis. Consensus clustering of purine metabolism genes with the overall survival (OS) of patients and with anti-tumor immunity was also performed. Pearson correlation analysis was used to identify potential targets that correlated strongly with the expression of immune checkpoints.
    RESULTS: A 6-gene signature that had independent prognostic significance for COAD was identified, together with a predictive model for risk stratification and prognosis. The most significantly enriched pathway amongst MRDEGs and MRPGs was purine metabolism. Differentially expressed purine metabolism genes could divide patients into two clusters with distinct prognosis and anti-tumor immunity. Further analysis suggested that purine metabolism was involved in anti-tumor immunity.
    CONCLUSIONS: This study confirmed the importance of metabolism-related pathways and in particular purine metabolism in the tumorigenesis, prognosis and anti-tumor immunity of COAD. We identified a 6-gene prognostic signature comprised of EPHX2, GPX3, PTGDS, NAT2, ACOX1 and CPT2. In addition, four potential immune-metabolic checkpoints (GUCY1A1, GUCY1B1, PDE1A and PDE5A) were identified, which could be used to improve the efficacy of immunotherapy in COAD.
    Keywords:  colon adenocarcinoma; immune-metabolic checkpoints; metabolic reprogramming; purine metabolism
    DOI:  https://doi.org/10.31083/j.fbl2812328
  7. Proteomics. 2024 Jan 03. e2300021
    The multifaceted roles of small extracellular vesicles in metabolic reprogramming in the tumor microenvironments.
    Zhixian Chen, Judy Wai Ping Yam, Xiaowen Mao.
      The link between metabolism and tumor progression has been extensively researched for a long time. With the increasing number of studies uncovering the multiple functions of metabolic reprogramming in tumor microenvironments, the regulatory network seems to become even more intricate at the same time. Small extracellular vesicles (sEV), as crucial mediators facilitating intercellular communications, exhibit significant involvement in regulating metabolic reprogramming within the complicated network of tumor microenvironments. sEV derived from tumor cells and those released by other cell populations such as tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) can mutually influence each other, giving rise to diverse complex feedback loops. This review includes multiple studies conducted in recent years to summarize the functions of sEV in altering metabolism in various cell types within tumor microenvironments. Additionally, it aims to highlight potential therapeutic targets based on the commonly observed mechanisms identified in different studies.
    Keywords:  small extracellular vesicles; tumor microenvironment
    DOI:  https://doi.org/10.1002/pmic.202300021
  8. EMBO Mol Med. 2024 Jan 02.
    Shaping immune landscape of colorectal cancer by cholesterol metabolites.
    Yibing Bai, Tongzhou Li, Qinshu Wang, Weiqiang You, Haochen Yang, Xintian Xu, Ziyi Li, Yu Zhang, Chengsong Yan, Lei Yang, Jiaqian Qiu, Yuanhua Liu, Shiyang Chen, Dongfang Wang, Binlu Huang, Kexin Liu, Bao- Liang Song, Zhuozhong Wang, Kang Li, Xin Liu, Guangchuan Wang, Weiwei Yang, Jianfeng Chen, Pei Hao, Zemin Zhang, Zhigang Wang, Zheng-Jiang Zhu, Chenqi Xu.
      Cancer immunotherapies have achieved unprecedented success in clinic, but they remain largely ineffective in some major types of cancer, such as colorectal cancer with microsatellite stability (MSS CRC). It is therefore important to study tumor microenvironment of resistant cancers for developing new intervention strategies. In this study, we identify a metabolic cue that determines the unique immune landscape of MSS CRC. Through secretion of distal cholesterol precursors, which directly activate RORγt, MSS CRC cells can polarize T cells toward Th17 cells that have well-characterized pro-tumor functions in colorectal cancer. Analysis of large human cancer cohorts revealed an asynchronous pattern of the cholesterol biosynthesis in MSS CRC, which is responsible for the abnormal accumulation of distal cholesterol precursors. Inhibiting the cholesterol biosynthesis enzyme Cyp51, by pharmacological or genetic interventions, reduced the levels of intratumoral distal cholesterol precursors and suppressed tumor progression through a Th17-modulation mechanism in preclinical MSS CRC models. Our study therefore reveals a novel mechanism of cancer-immune interaction and an intervention strategy for the difficult-to-treat MSS CRC.
    Keywords:  Asynchronous Cholesterol Biosynthesis; Colorectal Cancer with Microsatellite Stability; Cyp51 Targeted Therapy; Distal Cholesterol Precursors; Th17
    DOI:  https://doi.org/10.1038/s44321-023-00015-9
  9. Front Biosci (Landmark Ed). 2023 Dec 26. 28(12): 348
    Fatty Acid Metabolism: A New Perspective in Breast Cancer Precision Therapy.
    Mengye He, Suzhen Xu, Feifei Yan, Jian Ruan, Xiaochen Zhang.
      Breast cancer has a special tumor microenvironment compared to other solid tumors, which is usually surrounded by a large number of adipocytes that can produce and secrete fatty acids and adipokines. Adipocytes have a remodeling effect on breast cancer lipid metabolism, while fatty acids and lipid droplets can make breast cancer cells more aggressive. Lipid metabolism, especially the synthesis of fatty acids, is an important cellular process for membrane biosynthesis, energy storage, and signal molecule production. Therefore, blocking the lipid supply to cancer cells or changing the lipid composition has an important impact on the signal transmission and cell proliferation of cancer cells. Alterations in lipid availability can also affect cancer cell migration, induction of angiogenesis, metabolic symbiosis, evasion of immune surveillance, and cancer drug resistance. Fatty acid synthesis and metabolism have received extensive attention as potential targets for cancer therapy, and studies on modulating the tumor lipid microenvironment to improve the sensitivity of antitumor drugs have also been discussed; however, strategies to target these processes have not been translated into clinical practice.
    Keywords:  drug discovery; drug resistance; fatty acid; lipid metabolism
    DOI:  https://doi.org/10.31083/j.fbl2812348
  10. Biochim Biophys Acta Rev Cancer. 2023 Dec 27. pii: S0304-419X(23)00211-1. [Epub ahead of print] 189062
    Dietary approaches for exploiting metabolic vulnerabilities in cancer.
    Otília Menyhárt, Balázs Győrffy.
      Renewed interest in tumor metabolism sparked an enthusiasm for dietary interventions to prevent and treat cancer. Changes in diet impact circulating nutrient levels in the plasma and the tumor microenvironment, and preclinical studies suggest that dietary approaches, including caloric and nutrient restrictions, can modulate tumor initiation, progression, and metastasis. Cancers are heterogeneous in their metabolic dependencies and preferred energy sources and can be addicted to glucose, fructose, amino acids, or lipids for survival and growth. This dependence is influenced by tumor type, anatomical location, tissue of origin, aberrant signaling, and the microenvironment. This review summarizes nutrient dependencies and the related signaling pathway activations that provide targets for nutritional interventions. We examine popular dietary approaches used as adjuvants to anticancer therapies, encompassing caloric restrictions, including time-restricted feeding, intermittent fasting, fasting-mimicking diets (FMDs), and nutrient restrictions, notably the ketogenic diet. Despite promising results, much of the knowledge on dietary restrictions comes from in vitro and animal studies, which may not accurately reflect real-life situations. Further research is needed to determine the optimal duration, timing, safety, and efficacy of dietary restrictions for different cancers and treatments. In addition, well-designed human trials are necessary to establish the link between specific metabolic vulnerabilities and targeted dietary interventions. However, low patient compliance in clinical trials remains a significant challenge.
    Keywords:  Caloric restriction; Dietary intervention; Fasting-mimicking diet; Ketogenic diet; cancer metabolism
    DOI:  https://doi.org/10.1016/j.bbcan.2023.189062
  11. Cell Metab. 2024 Jan 02. pii: S1550-4131(23)00461-8. [Epub ahead of print]36(1): 176-192.e10
    Mitochondrial isocitrate dehydrogenase impedes CAR T cell function by restraining antioxidant metabolism and histone acetylation.
    Xiaohui Si, Mi Shao, Xinyi Teng, Yue Huang, Ye Meng, Longyuan Wu, Jieping Wei, Lianxuan Liu, Tianning Gu, Junzhe Song, Ruirui Jing, Xingyuan Zhai, Xin Guo, Delin Kong, Xiujian Wang, Bohan Cai, Ying Shen, Zhaoru Zhang, Dongrui Wang, Yongxian Hu, Pengxu Qian, Gang Xiao, He Huang.
      The efficacy of chimeric antigen receptor (CAR) T cell therapy is hampered by relapse in hematologic malignancies and by hyporesponsiveness in solid tumors. Long-lived memory CAR T cells are critical for improving tumor clearance and long-term protection. However, during rapid ex vivo expansion or in vivo tumor eradication, metabolic shifts and inhibitory signals lead to terminal differentiation and exhaustion of CAR T cells. Through a mitochondria-related compound screening, we find that the FDA-approved isocitrate dehydrogenase 2 (IDH2) inhibitor enasidenib enhances memory CAR T cell formation and sustains anti-leukemic cytotoxicity in vivo. Mechanistically, IDH2 impedes metabolic fitness of CAR T cells by restraining glucose utilization via the pentose phosphate pathway, which alleviates oxidative stress, particularly in nutrient-restricted conditions. In addition, IDH2 limits cytosolic acetyl-CoA levels to prevent histone acetylation that promotes memory cell formation. In combination with pharmacological IDH2 inhibition, CAR T cell therapy is demonstrated to have superior efficacy in a pre-clinical model.
    Keywords:  chimeric antigen receptor T cell; enasidenib; exhaustion; histone acetylation; isocitrate dehydrogenase 2; memory T cell formation; nutrient-restricted conditions; pentose phosphate pathway
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.010
  12. Res Sq. 2023 Dec 12. pii: rs.3.rs-3694185. [Epub ahead of print]
    Excessive Lipid Production Shapes Glioma Tumor Microenvironment.
    Haitham Maraqah, John Paul Aboubechara, Mones Abu-Asab, Han Sung Lee, Orwa Aboud.
      Disrupted lipid metabolism is a characteristic of gliomas. This study utilizes an ultrastructural approach to characterize the prevalence and distribution of lipids within gliomas. This study made use of tissue from IDH1 wild type (IDH1-wt) glioblastoma (n = 18) and IDH1 mutant (IDH1-mt) astrocytoma (n = 12) tumors. We uncover a prevalent and intriguing surplus of lipids. The bulk of the lipids manifested as sizable cytoplasmic inclusions and extracellular deposits in the tumor microenvironment (TME); in some tumors the lipids were stored in the classical membraneless spheroidal lipid droplets (LDs). Frequently, lipids accumulated inside mitochondria, suggesting possible dysfunction of the beta-oxidation pathway. Additionally, the tumor vasculature have lipid deposits in their lumen and vessel walls; this lipid could have shifted in from the tumor microenvironment or have been produced by the vessel-invading tumor cells. Lipid excess in gliomas stems from disrupted beta-oxidation and dysfunctional oxidative phosphorylation pathways. The implications of this lipid-driven environment include structural support for the tumor cells and protection against immune responses, non-lipophilic drugs, and free radicals.
    DOI:  https://doi.org/10.21203/rs.3.rs-3694185/v1
  13. Cell Rep. 2024 Jan 03. pii: S2211-1247(23)01654-6. [Epub ahead of print]43(1): 113643
    Intercellular crosstalk shapes purinergic metabolism and signaling in cancer cells.
    Julia Hesse, Bodo Steckel, Peter Dieterich, Siyar Aydin, Andreas Deussen, Jürgen Schrader.
      CD73-derived adenosine suppresses anti-cancer immunity, and CD73 inhibitors are currently evaluated in several clinical trials. Here, we have assessed enzyme kinetics of all key purinergic ectoenzymes in five cancer cell lines (Hodgkin lymphoma, multiple myeloma, pancreas adenocarcinoma, urinary bladder carcinoma, and glioblastoma) under normoxia and hypoxia. We found that adenosine metabolism varied considerably between individual cancer types. All cell lines investigated exhibited high ecto-adenosine deaminase (ADA) activity, which critically influenced the kinetics of adenosine accumulation. Combining kinetics data with single-cell RNA sequencing data on myeloma and glioblastoma cancerous tissue revealed that purine metabolism is not homogeneously organized, but it differs in a cancer type-specific fashion between malignant cells, stromal cells, and immune cells. Since purine metabolism in cancerous tissue is most likely spatially heterogeneous and differs between the various cell types, diffusion distances in the microenvironment as well as ADA activity may be important variables that influence the level of bioactive adenosine.
    Keywords:  CP: Cancer; NAD; adenosine; adenosine deaminase; glioblastoma; hypoxia; multiple myeloma
    DOI:  https://doi.org/10.1016/j.celrep.2023.113643
  14. Nat Immunol. 2024 Jan 04.
    Carnosine regulation of intracellular pH homeostasis promotes lysosome-dependent tumor immunoevasion.
    Ronghui Yan, Pinggen Zhang, Shengqi Shen, Yu Zeng, Ting Wang, Zhaolin Chen, Wenhao Ma, Junru Feng, Caixia Suo, Tong Zhang, Haoran Wei, Zetan Jiang, Rui Chen, Shi-Ting Li, Xiuying Zhong, Weidong Jia, Linchong Sun, Chunlei Cang, Huafeng Zhang, Ping Gao.
      Tumor cells and surrounding immune cells undergo metabolic reprogramming, leading to an acidic tumor microenvironment. However, it is unclear how tumor cells adapt to this acidic stress during tumor progression. Here we show that carnosine, a mobile buffering metabolite that accumulates under hypoxia in tumor cells, regulates intracellular pH homeostasis and drives lysosome-dependent tumor immune evasion. A previously unrecognized isoform of carnosine synthase, CARNS2, promotes carnosine synthesis under hypoxia. Carnosine maintains intracellular pH (pHi) homeostasis by functioning as a mobile proton carrier to accelerate cytosolic H+ mobility and release, which in turn controls lysosomal subcellular distribution, acidification and activity. Furthermore, by maintaining lysosomal activity, carnosine facilitates nuclear transcription factor X-box binding 1 (NFX1) degradation, triggering galectin-9 and T-cell-mediated immune escape and tumorigenesis. These findings indicate an unconventional mechanism for pHi regulation in cancer cells and demonstrate how lysosome contributes to immune evasion, thus providing a basis for development of combined therapeutic strategies against hepatocellular carcinoma that exploit disrupted pHi homeostasis with immune checkpoint blockade.
    DOI:  https://doi.org/10.1038/s41590-023-01719-3
  15. Nat Cancer. 2024 Jan 03.
    Lymphatic endothelial-like cells promote glioblastoma stem cell growth through cytokine-driven cholesterol metabolism.
    Linjie Zhao, Zhixin Qiu, Zhengnan Yang, Lian Xu, Thomas M Pearce, Qiulian Wu, Kailin Yang, FuLong Li, Olivier Saulnier, Fan Fei, Huaxu Yu, Ryan C Gimple, Venkateshwari Varadharajan, Juxiu Liu, Liam D Hendrikse, Vernon Fong, Wei Wang, Jiao Zhang, Deguan Lv, Derrick Lee, Brandon M Lehrich, Chunyu Jin, Liang Ouyang, Deobrat Dixit, Haoxing Wu, Xiang Wang, Andrew E Sloan, Xiuxing Wang, Tao Huan, J Mark Brown, Steven A Goldman, Michael D Taylor, Shengtao Zhou, Jeremy N Rich.
      Glioblastoma is the most lethal primary brain tumor with glioblastoma stem cells (GSCs) atop a cellular hierarchy. GSCs often reside in a perivascular niche, where they receive maintenance cues from endothelial cells, but the role of heterogeneous endothelial cell populations remains unresolved. Here, we show that lymphatic endothelial-like cells (LECs), while previously unrecognized in brain parenchyma, are present in glioblastomas and promote growth of CCR7-positive GSCs through CCL21 secretion. Disruption of CCL21-CCR7 paracrine communication between LECs and GSCs inhibited GSC proliferation and growth. LEC-derived CCL21 induced KAT5-mediated acetylation of HMGCS1 on K273 in GSCs to enhance HMGCS1 protein stability. HMGCS1 promoted cholesterol synthesis in GSCs, favorable for tumor growth. Expression of the CCL21-CCR7 axis correlated with KAT5 expression and HMGCS1K273 acetylation in glioblastoma specimens, informing patient outcome. Collectively, glioblastomas contain previously unrecognized LECs that promote the molecular crosstalk between endothelial and tumor cells, offering potentially alternative therapeutic strategies.
    DOI:  https://doi.org/10.1038/s43018-023-00658-0
  16. Cancer Metastasis Rev. 2024 Jan 05.
    PRUNE1 and NME/NDPK family proteins influence energy metabolism and signaling in cancer metastases.
    Veronica Ferrucci, Santosh Lomada, Thomas Wieland, Massimo Zollo.
      We describe here the molecular basis of the complex formation of PRUNE1 with the tumor metastasis suppressors NME1 and NME2, two isoforms appertaining to the nucleoside diphosphate kinase (NDPK) enzyme family, and how this complex regulates signaling the immune system and energy metabolism, thereby shaping the tumor microenvironment (TME). Disrupting the interaction between NME1/2 and PRUNE1, as suggested, holds the potential to be an excellent therapeutic target for the treatment of cancer and the inhibition of metastasis dissemination. Furthermore, we postulate an interaction and regulation of the other Class I NME proteins, NME3 and NME4 proteins, with PRUNE1 and discuss potential functions. Class I NME1-4 proteins are NTP/NDP transphosphorylases required for balancing the intracellular pools of nucleotide diphosphates and triphosphates. They regulate different cellular functions by interacting with a large variety of other proteins, and in cancer and metastasis processes, they can exert pro- and anti-oncogenic properties depending on the cellular context. In this review, we therefore additionally discuss general aspects of class1 NME and PRUNE1 molecular structures as well as their posttranslational modifications and subcellular localization. The current knowledge on the contributions of PRUNE1 as well as NME proteins to signaling cascades is summarized with a special regard to cancer and metastasis.
    Keywords:  Energy metabolism; Exopolyphosphatase; Immune system; NME family; NMR structures; Nucleoside diphosphate kinase NDPK; PRUNE1; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s10555-023-10165-4
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