bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2025–01–05
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. mTOR Signaling Regulates Multiple Metabolic Pathways in Human Lung Fibroblasts After TGF-β and in Pulmonary Fibrosis.
  2. Metabolism of cancer cells and immune cells in the initiation, progression, and metastasis of cancer.
  3. AMPK-regulated glycerol excretion maintains metabolic crosstalk between reductive and energetic stress.
  4. Sensory quiescence induces a cell-non-autonomous integrated stress response curbed by condensate formation of the ATF4 and XRP1 effectors.
  5. Inhibition of Endoplasmic Reticulum Stress Cooperates with SLC7A11 to Promote Disulfidptosis and Suppress Tumor Growth upon Glucose Limitation.
  6. Targeting glutamine metabolism crosstalk with tumor immune response.
  7. Angiogenesis and EMT regulators in the tumor microenvironment in lung cancer and immunotherapy.
  8. Kupffer Cell-derived IL6 Promotes Hepatocellular Carcinoma Metastasis Via the JAK1-ACAP4 Pathway.
  1. Am J Physiol Lung Cell Mol Physiol. 2025 Jan 02.
    mTOR Signaling Regulates Multiple Metabolic Pathways in Human Lung Fibroblasts After TGF-β and in Pulmonary Fibrosis.
    Kun Woo D Shin, M Volkan Atalay, Rengul Cetin-Atalay, Erin M O'Leary, Mariel E Glass, Jennifer C Houpy Szafran, Parker S Woods, Angelo Y Meliton, Obada R Shamaa, Yufeng Tian, Gökhan M Mutlu, Robert B Hamanaka.
      Idiopathic pulmonary fibrosis is a fatal disease characterized by the TGF-β-dependent activation of lung fibroblasts, leading to excessive deposition of collagen proteins and progressive replacement of healthy lung with scar tissue. We and others have shown that TGF-β-mediated activation of the Mechanistic Target of Rapamycin Complex 1 (mTORC1) and downstream upregulation of Activating Transcription Factor 4 (ATF4) promote metabolic reprogramming in lung fibroblasts characterized by upregulation of the de novo synthesis of glycine, the most abundant amino acid found in collagen protein. Whether mTOR and ATF4 regulate other metabolic pathways in lung fibroblasts has not been explored. Here, we used RNA sequencing to determine how both ATF4 and mTOR regulate gene expression in human lung fibroblasts following TGF-β. We found that ATF4 primarily regulates enzymes and transporters involved in amino acid homeostasis as well as aminoacyl-tRNA synthetases. mTOR inhibition resulted not only in the loss of ATF4 target gene expression, but also in the reduced expression of glycolytic enzymes and mitochondrial electron transport chain subunits. Analysis of TGF-β-induced changes in cellular metabolite levels confirmed that ATF4 regulates amino acid homeostasis in lung fibroblasts while mTOR also regulates glycolytic and TCA cycle metabolites. We further analyzed publicly available single-cell RNA-seq data sets and found increased expression of ATF4 and mTOR-regulated genes in pathologic fibroblast populations from the lungs of IPF patients. Our results provide insight into the mechanisms of metabolic reprogramming in lung fibroblasts and highlight novel ATF4 and mTOR-dependent pathways that may be targeted to inhibit fibrotic processes.
    Keywords:  ATF4; Fibrosis; Metabolism; mTOR
    DOI:  https://doi.org/10.1152/ajplung.00189.2024
  2. Theranostics. 2025 ;15(1): 155-188
    Metabolism of cancer cells and immune cells in the initiation, progression, and metastasis of cancer.
    Mingxia Jiang, Huapan Fang, Huayu Tian.
      The metabolism of cancer and immune cells plays a crucial role in the initiation, progression, and metastasis of cancer. Cancer cells often undergo metabolic reprogramming to sustain their rapid growth and proliferation, along with meeting their energy demands and biosynthetic needs. Nevertheless, immune cells execute their immune response functions through the specific metabolic pathways, either to recognize, attack, and eliminate cancer cells or to promote the growth or metastasis of cancer cells. The alteration of cancer niches will impact the metabolism of both cancer and immune cells, modulating the survival and proliferation of cancer cells, and the activation and efficacy of immune cells. This review systematically describes the key characteristics of cancer cell metabolism and elucidates how such metabolic traits influence the metabolic behavior of immune cells. Moreover, this article also highlights the crucial role of immune cell metabolism in anti-tumor immune responses, particularly in priming T cell activation and function. By comprehensively exploring the metabolic crosstalk between cancer and immune cells in cancer niche, the aim is to discover novel strategies of cancer immunotherapy and provide effective guidance for clinical research in cancer treatment. In addition, the review also discusses current challenges such as the inadequacy of relevant diagnostic technologies and the issue of multidrug resistance, and proposes potential solutions including bolstering foundational cancer research, fostering technological innovation, and implementing precision medicine approaches. In-depth research into the metabolic effects of cancer niches can improve cancer treatment outcomes, prolong patients' survival period and enhance their quality of life.
    Keywords:  Anti-tumor immune responses; Cancer immunotherapy; Cancer niches; Metabolic reprogramming; Metabolism of cancer and immune cells
    DOI:  https://doi.org/10.7150/thno.103376
  3. Nat Cell Biol. 2025 Jan 02.
    AMPK-regulated glycerol excretion maintains metabolic crosstalk between reductive and energetic stress.
    Xuewei Zhai, Ronghui Yang, Qiaoyun Chu, Zihao Guo, Pengjiao Hou, Xuexue Li, Changsen Bai, Ziwen Lu, Luxin Qiao, Yanxia Fu, Jing Niu, Binghui Li.
      Glucose metabolism has been studied extensively, but the role of glucose-derived excretory glycerol remains unclear. Here we show that hypoxia induces NADH accumulation to promote glycerol excretion and this pathway consumes NADH continuously, thus attenuating its accumulation and reductive stress. Aldolase B accounts for glycerol biosynthesis by forming a complex with glycerol 3-phosphate dehydrogenases GPD1 and GPD1L. Blocking GPD1, GPD1L or glycerol 3-phosphate phosphatase exacerbates reductive stress and suppresses cell proliferation under hypoxia and tumour growth in vivo. Overexpression of these enzymes increases glycerol excretion but still reduces cell viability under hypoxia and tumour proliferation due to energy stress. AMPK inactivates aldolase B to mitigate glycerol synthesis that dissipates ATP, alleviating NADH accumulation-induced energy crisis. Therefore, glycerol biosynthesis/excretion regulates the trade-off between reductive stress and energy stress. Moreover, this mode of regulation seems to be prevalent in reductive stress-driven transformations, enhancing our understanding of the metabolic complexity and guiding tumour treatment.
    DOI:  https://doi.org/10.1038/s41556-024-01549-x
  4. Nat Commun. 2025 Jan 02. 16(1): 252
    Sensory quiescence induces a cell-non-autonomous integrated stress response curbed by condensate formation of the ATF4 and XRP1 effectors.
    Shashank Shekhar, Charles Tracy, Peter V Lidsky, Raul Andino, Katherine J Wert, Helmut Krämer.
      Sensory disabilities have been identified as significant risk factors for dementia but underlying molecular mechanisms are unknown. In different Drosophila models with loss of sensory input, we observe non-autonomous induction of the integrated stress response (ISR) deep in the brain, as indicated by eIF2αS50 phosphorylation-dependent elevated levels of the ISR effectors ATF4 and XRP1. Unlike during canonical ISR, however, the ATF4 and XRP1 transcription factors are enriched in cytosolic granules that are positive for RNA and the stress granule markers Caprin, FMR1, and p62, and are reversible upon restoration of vision for blind flies. Cytosolic restraint of the ATF4 and XRP1 transcription factors dampens expression of their downstream targets including genes of cell death pathways activated during chronic cellular stress and thus constitutes a chronic stress protective response (CSPR). Cytosolic granules containing both p62 and ATF4 are also evident in the thalamus and hippocampus of mouse models of congenital or degenerative blindness. These data indicate a conserved link between loss of sensory input and curbed stress responses critical for protein quality control in the brain.
    DOI:  https://doi.org/10.1038/s41467-024-55576-1
  5. Adv Sci (Weinh). 2024 Dec 30. e2408789
    Inhibition of Endoplasmic Reticulum Stress Cooperates with SLC7A11 to Promote Disulfidptosis and Suppress Tumor Growth upon Glucose Limitation.
    Jin Wang, Jing Chen, Kexin Fan, Minglin Wang, Min Gao, Yakun Ren, Shaobo Wu, Qian He, Kangsheng Tu, Qiuran Xu, Yilei Zhang.
      Disulfidptosis is a newly discovered type of regulated cell death triggered by disulfide bond accumulation and NADPH (nicotinamide adenine dinucleotide phosphate) depletion due to glucose deprivation. However, the regulatory mechanisms involving additional cellular circuits remain unclear. Excessive disulfide bond accumulation can impair endoplasmic reticulum (ER) homeostasis and activate the ER stress response. In this study, we found that SLC7A11-mediated disulfidptosis upon glucose deprivation is accompanied by ER stress induction. Pharmacological inhibition of SLC7A11-mediated cystine uptake or cystine withdrawal not only blocks disulfidptosis under glucose starvation but also suppresses the ER stress response, indicating a close link between these processes. Moreover, inhibitors targeting the ER stress response promote disulfidptosis, while ER stress inducers suppress glucose starvation-induced disulfidptosis in SLC7A11-high-expressing cells, suggesting a protective role for ER stress during disulfidptosis. Similar effects are observed in cells treated with glucose transporter inhibitors (GLUTi). Finally, combined treatment with ER stress inhibitors and GLUTi significantly suppresses tumor growth both in vitro and in vivo by inducing disulfide stress and subsequent disulfidptosis. In summary, these findings reveal a novel role for ER stress in regulating disulfidptosis and provide theoretical insights into the potential application of GLUTi and ER stress inhibitors in cancer therapy.
    Keywords:  SLC7A11; disulfidptosis; endoplasmic reticulum stress; glucose deprivation; tumor
    DOI:  https://doi.org/10.1002/advs.202408789
  6. Biochim Biophys Acta Rev Cancer. 2024 Dec 31. pii: S0304-419X(24)00188-4. [Epub ahead of print] 189257
    Targeting glutamine metabolism crosstalk with tumor immune response.
    Chenshuang Dong, Yan Zhao, Yecheng Han, Ming Li, Guiling Wang.
      Glutamine, akin to glucose, is a fundamental nutrient for human physiology. Tumor progression is often accompanied by elevated glutamine consumption, resulting in a disrupted nutritional balance and metabolic reprogramming within the tumor microenvironment. Furthermore, immune cells, which depend on glutamine for metabolic support, may experience functional impairments and dysregulation. Although the role of glutamine in tumors has been extensively studied, the specific impact of glutamine competition on immune responses, as well as the precise cellular alterations within immune cells, remains incompletely understood. In this review, we summarize the consequences of glutamine deprivation induced by tumor-driven glutamine uptake on immune cells, assessing the underlying mechanisms from the perspective of various components of the immune microenvironment. Additionally, we discuss the potential synergistic effects of glutamine supplementation and immunotherapy, offering insights into future research directions. This review provides compelling evidence for the integration of glutamine metabolism and immunotherapy as a promising strategy in cancer therapy.
    Keywords:  Glutamine deprivation; Glutamine therapy; Immune cells; Immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2024.189257
  7. Front Immunol. 2024 ;15 1509195
    Angiogenesis and EMT regulators in the tumor microenvironment in lung cancer and immunotherapy.
    Taotao Yan, Jiahai Shi.
      Lung cancer remains the primary cause of cancer-related mortality, with factors such as postoperative tumor recurrence, metastasis, and therapeutic drug resistance exacerbating patient outcomes. Immunotherapy has emerged as a transformative approach, challenging conventional treatment paradigms for lung cancer. Consequently, advancing research in lung cancer immunotherapy is imperative. Recent studies indicate that numerous regulators within the tumor microenvironment (TME) drive tumor angiogenesis and epithelial-mesenchymal transition (EMT); these processes are interdependent, reciprocal, and collectively contribute to tumor progression. Tumor angiogenesis not only supplies adequate oxygen and nutrients for cellular proliferation but also establishes pathways facilitating tumor metastasis and creating hypoxic regions that foster drug resistance. Concurrently, EMT enhances metastatic potential and reinforces drug-resistance genes within tumor cells, creating a reciprocal relationship with angiogenesis. This interplay ultimately results in tumor invasion, metastasis, and therapeutic resistance. This paper reviews key regulators of angiogenesis and EMT, examining their impact on lung cancer immunotherapy and progression, and investigates whether newly identified regulators could influence lung cancer treatment, thus offering valuable insights for developing future therapeutic strategies.
    Keywords:  EMT; TME; angiogenesis; immunotherapy; lung cancer
    DOI:  https://doi.org/10.3389/fimmu.2024.1509195
  8. Int J Biol Sci. 2025 ;21(1): 285-305
    Kupffer Cell-derived IL6 Promotes Hepatocellular Carcinoma Metastasis Via the JAK1-ACAP4 Pathway.
    Tao Li, Xiaoyu Song, Jiena Chen, Yuan Li, Jie Lin, Ping Li, Simiao Yu, Olanrewaju Ayodeji Durojaye, Fengrui Yang, Xing Liu, Jian Li, Shiyuan Cheng, Xuebiao Yao, Xia Ding.
      Tumor-associated macrophages (TAMs), which differentiate from tissue-resident macrophages, are recognized for their ability to influence cancer progression and metastasis. However, the specific role of Kupffer cells (KCs), the intrinsic macrophages of the liver, in the progression of hepatocellular carcinoma (HCC) remains unclear. In this study, we describe a novel mechanism by which exosomes derived from HCC cells induce KCs to transition into TAMs, thereby facilitating the metastasis of HCC in an IL6-JAK1-ACAP4 axis-dependent manner. Mechanistically, the exosome-mediated domestication of KCs by hepatoma cells constitutes one of the primary sources of IL6 production in the HCC microenvironment. IL6 then activates JAK1 to phosphorylate its downstream effector ACAP4 at Tyr843, a novel phosphorylation site identified in this context, which in turn promotes ARF6-GTPase activity and hepatoma cell migration. Furthermore, we found that the levels of IL6, as well as the phosphorylation of JAK1 and ACAP4 at Tyr843, were significantly greater in tumor tissues from HCC patients than in adjacent tissues. These findings suggest that the IL6-JAK1-ACAP4 axis may be a promising therapeutic target for HCC. Importantly, we screened bufalin, an active ingredient derived from Venenum Bufonis, and discovered that it inhibits JAK1 and disrupts the IL6-induced phosphorylation of ACAP4. This inhibition not only impairs hepatoma cell migration but also prevents the metastasis of HCC. These findings demonstrate the interplay between hepatoma cells and KCs through the IL6-JAK1-ACAP4 axis, thereby promoting HCC metastasis, and reveal the therapeutic potential of bufalin for the treatment of HCC through JAK1 inhibition.
    Keywords:  ACAP4; Bufalin; Hepatocellular carcinoma; Janus kinase-1; Kupffer cells; Tumor-associated macrophages
    DOI:  https://doi.org/10.7150/ijbs.97109
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