bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2024–12–01
eleven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. The Mitochondrial Integrated Stress Response: A novel approach to anti-aging and pro-longevity.
  2. Emerging Role of Extracellular pH in Tumor Microenvironment as a Therapeutic Target for Cancer Immunotherapy.
  3. Why and how citrate may sensitize malignant tumors to immunotherapy.
  4. Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer.
  5. GDNF family receptor alpha-like (GFRAL) expression is restricted to the caudal brainstem.
  6. Glucose limitation protects cancer cells from apoptosis induced by pyrimidine restriction and replication inhibition.
  7. Ferroptosis and the tumor microenvironment.
  8. Metabolic Reprogramming of Immune Cells in the Tumor Microenvironment.
  9. The ribotoxic stress response drives acute inflammation, cell death, and epidermal thickening in UV-irradiated skin in vivo.
  10. ER-tethered stress sensor CREBH regulates mitochondrial unfolded protein response to maintain energy homeostasis.
  11. ACSL4 and polyunsaturated lipids support metastatic extravasation and colonization.
  1. Ageing Res Rev. 2024 Nov 26. pii: S1568-1637(24)00421-5. [Epub ahead of print] 102603
    The Mitochondrial Integrated Stress Response: A novel approach to anti-aging and pro-longevity.
    Xiaoding Wang, Guangyu Zhang.
      The ISR is a cellular signaling pathway that responds to various physiological changes and types of stimulation. The mitochondrial integrated stress response (ISRmt) is a stress response specific to mitochondria which is initiated by eIF2α phosphorylation and is responsive to mitochondrial stressors. The ISRmt triggers diverse metabolic responses reliant on activating transcription factor 4 (ATF4). The preliminary phases of ISRmt can provoke an adaptive stress response that antagonizes age-related diseases and promotes longevity. In this review, we provide an overview of the molecular mechanisms of the ISRmt, with a particular focus on its potential as a therapeutic target for age-related disease and the promotion of longevity.
    Keywords:  FGF21; Mitochondrial integrated stress response; aging; longevity
    DOI:  https://doi.org/10.1016/j.arr.2024.102603
  2. Cells. 2024 Nov 20. pii: 1924. [Epub ahead of print]13(22):
    Emerging Role of Extracellular pH in Tumor Microenvironment as a Therapeutic Target for Cancer Immunotherapy.
    Md Ataur Rahman, Mahesh Kumar Yadab, Meser M Ali.
      Identifying definitive biomarkers that predict clinical response and resistance to immunotherapy remains a critical challenge. One emerging factor is extracellular acidosis in the tumor microenvironment (TME), which significantly impairs immune cell function and contributes to immunotherapy failure. However, acidic conditions in the TME disrupt the interaction between cancer and immune cells, driving tumor-infiltrating T cells and NK cells into an inactivated, anergic state. Simultaneously, acidosis promotes the recruitment and activation of immunosuppressive cells, such as myeloid-derived suppressor cells and regulatory T cells (Tregs). Notably, tumor acidity enhances exosome release from Tregs, further amplifying immunosuppression. Tumor acidity thus acts as a "protective shield," neutralizing anti-tumor immune responses and transforming immune cells into pro-tumor allies. Therefore, targeting lactate metabolism has emerged as a promising strategy to overcome this barrier, with approaches including buffer agents to neutralize acidic pH and inhibitors to block lactate production or transport, thereby restoring immune cell efficacy in the TME. Recent discoveries have identified genes involved in extracellular pH (pHe) regulation, presenting new therapeutic targets. Moreover, ongoing research aims to elucidate the molecular mechanisms driving extracellular acidification and to develop treatments that modulate pH levels to enhance immunotherapy outcomes. Additionally, future clinical studies are crucial to validate the safety and efficacy of pHe-targeted therapies in cancer patients. Thus, this review explores the regulation of pHe in the TME and its potential role in improving cancer immunotherapy.
    Keywords:  T cells; acidic TME; extracellular pH; immunotherapy resistance; lactate metabolism; tumor microenvironment (TME)
    DOI:  https://doi.org/10.3390/cells13221924
  3. Drug Resist Updat. 2024 Nov 26. pii: S1368-7646(24)00135-3. [Epub ahead of print]78 101177
    Why and how citrate may sensitize malignant tumors to immunotherapy.
    Philippe Icard, Mathilde Prieto, Antoine Coquerel, Ludovic Fournel, Joseph Gligorov, Johanna Noel, Adrien Mouren, Anthony Dohan, Marco Alifano, Luca Simula.
      Immunotherapy, either alone or in combination with chemotherapy, has demonstrated limited efficacy in a variety of solid cancers. Several factors contribute to explaining primary or secondary resistance. Among them, cancer cells, whose metabolism frequently relies on aerobic glycolysis, promote exhaustion of cytotoxic immune cells by diverting the glucose in the tumor microenvironment (TME) to their own profit, while secreting lactic acid that sustains the oxidative metabolism of immunosuppressive cells. Here, we propose to combine current treatment based on the use of immune checkpoint inhibitors (ICIs) with high doses of sodium citrate (SCT) because citrate inhibits cancer cell metabolism (by targeting both glycolysis and oxidative metabolism) and may active anti-tumor immune response. Indeed, as showed in preclinical studies, SCT reduces cancer cell growth, promoting cell death and chemotherapy effectiveness. Furthermore, since the plasma membrane citrate carrier pmCIC is mainly expressed in cancer cells and low or not expressed in immune and non-transformed cells, we argue that the inhibition of cancer cell metabolism by SCT may increase glucose availability in the TME, thus promoting functionality of anti-tumor immune cells. Concomitantly, the decrease in the amount of lactic acid in the TME may reduce the functionality of immunosuppressive cells. Preclinical studies have shown that SCT can enhance the anti-tumor immune response through an enhancement of T cell infiltration and activation, and a repolarization of macrophages towards a TAM1-like phenotype. Therefore, this simple and cheap strategy may have a major impact to increase the efficacy of current immunotherapies in human solid tumors and we encourage testing it in clinical trials.
    Keywords:  ICI; cancer; citrate; immunotherapy; lactate; metabolism
    DOI:  https://doi.org/10.1016/j.drup.2024.101177
  4. J Exp Med. 2025 Jan 06. pii: e20231106. [Epub ahead of print]222(1):
    Hypoxia is linked to acquired resistance to immune checkpoint inhibitors in lung cancer.
    Camila Robles-Oteíza, Katherine Hastings, Jungmin Choi, Isabelle Sirois, Arvind Ravi, Francisco Expósito, Fernando de Miguel, James R Knight, Francesc López-Giráldez, Hyejin Choi, Nicholas D Socci, Taha Merghoub, Mark Awad, Gad Getz, Justin Gainor, Matthew D Hellmann, Étienne Caron, Susan M Kaech, Katerina Politi.
      Despite the established use of immune checkpoint inhibitors (ICIs) to treat non-small cell lung cancer (NSCLC), only a subset of patients benefit from treatment and ∼50% of patients whose tumors respond eventually develop acquired resistance (AR). To identify novel drivers of AR, we generated murine Msh2 knock-out (KO) lung tumors that initially responded but eventually developed AR to anti-PD-1, alone or in combination with anti-CTLA-4. Resistant tumors harbored decreased infiltrating T cells and reduced cancer cell-intrinsic MHC-I and MHC-II levels, yet remained responsive to IFNγ. Resistant tumors contained extensive regions of hypoxia, and a hypoxia signature derived from single-cell transcriptional profiling of resistant cancer cells was associated with decreased progression-free survival in a cohort of NSCLC patients treated with anti-PD-1/PD-L1 therapy. Targeting hypoxic tumor regions using a hypoxia-activated pro-drug delayed AR to ICIs in murine Msh2 KO tumors. Thus, this work provides a rationale for targeting tumor metabolic features, such as hypoxia, in combination with immune checkpoint inhibition.
    DOI:  https://doi.org/10.1084/jem.20231106
  5. Mol Metab. 2024 Nov 26. pii: S2212-8778(24)00201-1. [Epub ahead of print] 102070
    GDNF family receptor alpha-like (GFRAL) expression is restricted to the caudal brainstem.
    Cecilia Hes, Luting Gui, Alexandre Bay, Fernando Alvarez, Pierce Katz, Tanushree Paul, Nadejda Bozadjieva-Kramer, Randy J Seeley, Ciriaco A Piccirillo, Paul Sabatini.
       OBJECTIVES: Growth differentiation factor 15 (GDF15) acts on the receptor dimer of GDNF family receptor alpha-like (GFRAL) and Rearranged during transfection (RET). While Gfral-expressing cells are known to be present in the area postrema and nucleus of the solitary tract (AP/NTS) located in the brainstem, the presence of Gfral- expressing cells in other sites within the central nervous system and peripheral tissues is not been fully addressed. Our objective was to thoroughly investigate whether GFRAL is expressed in peripheral tissues and in brain sites different from the brainstem.
    METHODS: From Gfral::eGFP mice we collected tissue from 12 different tissues, including brain, and used single molecule in-situ hybridizations to identify cells within those tissues expressing Gfral. We then contrasted the results with human Gfral-expression by analyzing publicly available single-cell RNA sequencing data.
    RESULTS: In mice we found readably detectable Gfral mRNA within the AP/NTS but not within other brain sites. Within peripheral tissues, we failed to detect any Gfral-labelled cells in the vast majority of examined tissues and when present, were extremely rare. Single cell sequencing of human tissues confirmed GFRAL-expressing cells are detectable in some sites outside the AP/NTS in an extremely sparse manner. Importantly, across the utilized methodologies, smFISH, genetic Gfral reporter mice and scRNA-Seq, we failed to detect Gfral-labelled cells with all three.
    CONCLUSIONS: Through highly sensitive and selective technologies we show Gfral expression is overwhelmingly restricted to the brainstem and expect that GDF15 and GFRAL-based therapies in development for cancer cachexia will specifically target AP/NTS cells.
    Keywords:  GDF15; GFRAL; area postrema; nucleus of the solitary tract
    DOI:  https://doi.org/10.1016/j.molmet.2024.102070
  6. Nat Metab. 2024 Nov 26.
    Glucose limitation protects cancer cells from apoptosis induced by pyrimidine restriction and replication inhibition.
    Minwoo Nam, Wenxin Xia, Abdul Hannan Mir, Alexandra Jerrett, Jessica B Spinelli, Tony T Huang, Richard Possemato.
      Cancer cells often experience nutrient-limiting conditions because of their robust proliferation and inadequate tumour vasculature, which results in metabolic adaptation to sustain proliferation. Most cancer cells rapidly consume glucose, which is severely reduced in the nutrient-scarce tumour microenvironment. In CRISPR-based genetic screens to identify metabolic pathways influenced by glucose restriction, we find that tumour-relevant glucose concentrations (low glucose) protect cancer cells from inhibition of de novo pyrimidine biosynthesis, a pathway that is frequently targeted by chemotherapy. We identify two mechanisms to explain this result, which is observed broadly across cancer types. First, low glucose limits uridine-5-diphosphate-glucose synthesis, preserving pyrimidine nucleotide availability and thereby prolonging the time to replication fork stalling. Second, low glucose directly modulates apoptosis downstream of replication fork stalling by suppressing BAK activation and subsequent cytochrome c release, key events that activate caspase-9-dependent mitochondrial apoptosis. These results indicate that the low glucose levels frequently observed in tumours may limit the efficacy of specific chemotherapeutic agents, highlighting the importance of considering the effects of the tumour nutrient environment on cancer therapy.
    DOI:  https://doi.org/10.1038/s42255-024-01166-w
  7. J Exp Clin Cancer Res. 2024 Nov 30. 43(1): 315
    Ferroptosis and the tumor microenvironment.
    Kaisa Cui, Kang Wang, Zhaohui Huang.
      Ferroptosis is a type of regulated cell death characterized by its non-apoptotic, iron-dependent and oxidative nature. Since its discovery in 2012, extensive research has demonstrated its pivotal roles in tumorigenesis, metastasis and cancer therapy. The tumor microenvironment (TME) is a complex ecosystem comprising cancer cells, non-cancer cells, extracellular matrix, metabolites and cytokines. Recent studies have underscored a new paradigm in which non-cancer cells in the TME, such as immune and stromal cells, also play significant roles in regulating tumor progression and therapeutic resistance typically through complicated crosstalk with cancer cells. Notably, this crosstalk in the TME were partially mediated through ferrotopsis-related mechanisms. This review provides a comprehensive and systematic summary of the current findings concerning the roles of ferroptosis in the TME and how ferroptosis-mediated TME reprogramming impacts cancer therapeutic resistance and progression. Additionally, this review outlines various ferroptosis-related therapeutic strategies aimed at targeting the TME.
    Keywords:  CD8+ T cell; Cancer-associated fibroblast; Ferroptosis; Immunotherapy; Tumor microenvironment; Tumor-associated macrophage
    DOI:  https://doi.org/10.1186/s13046-024-03235-0
  8. Int J Mol Sci. 2024 Nov 14. pii: 12223. [Epub ahead of print]25(22):
    Metabolic Reprogramming of Immune Cells in the Tumor Microenvironment.
    Jing Wang, Yuanli He, Feiming Hu, Chenchen Hu, Yuanjie Sun, Kun Yang, Shuya Yang.
      Metabolic reprogramming of immune cells within the tumor microenvironment (TME) plays a pivotal role in shaping tumor progression and responses to therapy. The intricate interplay between tumor cells and immune cells within this ecosystem influences their metabolic landscapes, thereby modulating the immune evasion tactics employed by tumors and the efficacy of immunotherapeutic interventions. This review delves into the metabolic reprogramming that occurs in tumor cells and a spectrum of immune cells, including T cells, macrophages, dendritic cells, and myeloid-derived suppressor cells (MDSCs), within the TME. The metabolic shifts in these cell types span alterations in glucose, lipid, and amino acid metabolism. Such metabolic reconfigurations can profoundly influence immune cell function and the mechanisms by which tumors evade immune surveillance. Gaining a comprehensive understanding of the metabolic reprogramming of immune cells in the TME is essential for devising novel cancer therapeutic strategies. By targeting the metabolic states of immune cells, it is possible to augment their anti-tumor activities, presenting new opportunities for immunotherapeutic approaches. These strategies hold promise for enhancing treatment outcomes and circumventing the emergence of drug resistance.
    Keywords:  immune cells; immunotherapy; metabolic reprogramming; the tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms252212223
  9. Mol Cell. 2024 Nov 19. pii: S1097-2765(24)00884-0. [Epub ahead of print]
    The ribotoxic stress response drives acute inflammation, cell death, and epidermal thickening in UV-irradiated skin in vivo.
    Anna Constance Vind, Zhenzhen Wu, Muhammad Jasrie Firdaus, Goda Snieckute, Gee Ann Toh, Malin Jessen, José Francisco Martínez, Peter Haahr, Thomas Levin Andersen, Melanie Blasius, Li Fang Koh, Nina Loeth Maartensson, John E A Common, Mads Gyrd-Hansen, Franklin L Zhong, Simon Bekker-Jensen.
      Solar UVB light causes damage to the outermost layer of skin. This insult induces rapid local responses, such as dermal inflammation, keratinocyte cell death, and epidermal thickening, all of which have traditionally been associated with DNA damage response signaling. Another stress response that is activated by UVB light is the ribotoxic stress response (RSR), which depends on the ribosome-associated mitogen-activated protein 3 kinases (MAP3K) ZAKα and culminates in p38 and JNK activation. Using ZAK knockout mice, we here show that it is the RSR that is responsible for the early manifestation of UVB-induced skin inflammation and keratinocyte death and subsequent proliferation in vivo. We also show that the RSR controls both p38-mediated pyroptotic and JNK-mediated apoptotic programmed cell death of human keratinocytes in vitro. In sum, our work highlights that skin cells rely on a cytoplasmic and ribosomal stress signal rather than a nuclear and DNA-templated signal for rapid inflammatory responses to UV exposure.
    Keywords:  JNK; UV; ZAK-alpha; apoptosis; inflammation; p38; pyroptosis; ribotoxic stress response; skin
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.044
  10. Proc Natl Acad Sci U S A. 2024 Dec 03. 121(49): e2410486121
    ER-tethered stress sensor CREBH regulates mitochondrial unfolded protein response to maintain energy homeostasis.
    Hyunbae Kim, Qi Chen, Donghong Ju, Neeraja Purandare, Xuequn Chen, Lobelia Samavati, Li Li, Ren Zhang, Lawrence I Grossman, Kezhong Zhang.
      The Mitochondrial Unfolded Protein Response (UPRmt), a mitochondria-originated stress response to altered mitochondrial proteostasis, plays important roles in various pathophysiological processes. In this study, we revealed that the endoplasmic reticulum (ER)-tethered stress sensor CREBH regulates UPRmt to maintain mitochondrial homeostasis and function in the liver. CREBH is enriched in and required for hepatic Mitochondria-Associated Membrane (MAM) expansion induced by energy demands. Under a fasting challenge or during the circadian cycle, CREBH is activated to promote expression of the genes encoding the key enzymes, chaperones, and regulators of UPRmt in the liver. Activated CREBH, cooperating with peroxisome proliferator-activated receptor α (PPARα), activates expression of Activating Transcription Factor (ATF) 5 and ATF4, two major UPRmt transcriptional regulators, independent of the ER-originated UPR (UPRER) pathways. Hepatic CREBH deficiency leads to accumulation of mitochondrial unfolded proteins, decreased mitochondrial membrane potential, and elevated cellular redox state. Dysregulation of mitochondrial function caused by CREBH deficiency coincides with increased hepatic mitochondrial oxidative phosphorylation (OXPHOS) but decreased glycolysis. CREBH knockout mice display defects in fatty acid oxidation and increased reliance on carbohydrate oxidation for energy production. In summary, our studies uncover that hepatic UPRmt is activated through CREBH under physiological challenges, highlighting a molecular link between ER and mitochondria in maintaining mitochondrial proteostasis and energy homeostasis under stress conditions.
    Keywords:  ER-mitochondria contact; cell metabolism; michondrial UPR; transcriptional regulation; unfolded protein response
    DOI:  https://doi.org/10.1073/pnas.2410486121
  11. Cell. 2024 Nov 19. pii: S0092-8674(24)01270-4. [Epub ahead of print]
    ACSL4 and polyunsaturated lipids support metastatic extravasation and colonization.
    Yuqi Wang, Mangze Hu, Jian Cao, Fengxiang Wang, Jingrong Regina Han, Tianshu William Wu, Luxiao Li, Jinshi Yu, Yujing Fan, Guanglei Xie, Heyuan Lian, Yueying Cao, Nathchar Naowarojna, Xi Wang, Yilong Zou.
      Metastatic dissemination to distant organs demands that cancer cells possess high morphological and metabolic adaptability. However, contributions of the cellular lipidome to metastasis remain elusive. Here, we uncover a correlation between metastasis potential and ferroptosis susceptibility in multiple cancers. Metastases-derived cancer cells exhibited higher ferroptosis sensitivity and polyunsaturated fatty acyl (PUFA)-lipid contents than primary-tumor-derived cells from ovarian cancer patients. Metabolism-focused CRISPR screens in a mouse model for ovarian cancer distant metastasis established via two rounds of in vivo selection revealed the PUFA-lipid biosynthesis enzyme acyl-coenzyme A (CoA) synthetase long-chain family member 4 (ACSL4) as a pro-hematogenous metastasis factor. ACSL4 promotes metastatic extravasation by enhancing membrane fluidity and cellular invasiveness. While promoting metastasis, the high PUFA-lipid state creates dependencies on abhydrolase-domain-containing 6, acylglycerol lipase (ABHD6), enoyl-CoA delta isomerase 1 (ECI1), and enoyl-CoA hydratase 1 (ECH1)-rate-limiting enzymes preparing unsaturated fatty acids (UFAs) for β-oxidation. ACSL4/ECH1 co-inhibition achieved potent suppression of metastasis. Our work establishes the dual functions of PUFA-lipids in tumor progression and metastasis that may be exploitable for therapeutic development.
    Keywords:  ACSL4; ECH1; cancer metastasis; extravasation; ferroptosis susceptibility; in vivo CRISPR screens; lipid metabolism; metastatic colonization; ovarian cancer; polyunsaturated lipids
    DOI:  https://doi.org/10.1016/j.cell.2024.10.047
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