bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2025–03–09
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. MIF-ACKR3 causes irreversible fat loss by impairing adipogenesis in cancer cachexia.
  2. Interactions between the metabolic reprogramming of liver cancer and tumor microenvironment.
  3. The integrated stress response pathway controls cytokine production in tissue-resident memory CD4+ T cells.
  4. FOXA2 loss results in an increase of endometriosis development and LIF reveals a therapeutic effect for endometriosis.
  5. Endoplasmic Reticulum Stress: Triggers Microenvironmental Regulation and Drives Tumor Evolution.
  6. Asparagine deprivation enhances T cell antitumour response in patients via ROS-mediated metabolic and signal adaptations.
  7. Unfolded protein response-activated NLRP3 inflammasome contributes to pyroptotic and apoptotic podocyte injury in diabetic kidney disease via the CHOP-TXNIP axis.
  8. Secretomes From Non-Small Cell Lung Cancer Cells Induce Endothelial Plasticity Through a Partial Endothelial-to-Mesenchymal Transition.
  1. Cell Metab. 2025 Feb 26. pii: S1550-4131(25)00018-X. [Epub ahead of print]
    MIF-ACKR3 causes irreversible fat loss by impairing adipogenesis in cancer cachexia.
    Qionghua Cui, Shijin Li, Xidan Liu, Jie Liu, Wenxin Chen, Ye Sheng, Peng Xie, Li Jin, Fanxin Zeng, Fengxiang Lv, Xinli Hu, Rui-Ping Xiao.
      Both exercise and cancer can cause adipose tissue shrinkage. However, only cancer-associated weight loss, namely cachexia, is characterized by profound adipose inflammation and fibrosis. Here, we identified tumor-secreted macrophage migration inhibitory factor (MIF) as a major driver that skews the differentiation of adipose stem and progenitor cells (ASPCs) toward a pro-inflammatory and pro-fibrogenic direction, with reduced adipogenic capacity in cancer cachexia. By contrast, circulating MIF is moderately reduced after exercise. Mechanistically, atypical chemokine receptor 3 (ACKR3) in ASPCs serves as the predominant MIF receptor mediating its pathological effects. Inhibition of MIF by gene ablation in tumor cells or pharmacological blockade, as well as ASPC-specific Ackr3 deficiency, markedly alleviates tumor-induced cachexia. These findings unveil MIF-ACKR3 signaling as a critical link between tumors and cachectic manifestations, providing a promising therapeutic target for cancer cachexia.
    Keywords:  ACKR3; MIF; adipose remodeling; adipose stem and progenitor cells; cancer cachexia
    DOI:  https://doi.org/10.1016/j.cmet.2025.01.018
  2. Front Immunol. 2025 ;16 1494788
    Interactions between the metabolic reprogramming of liver cancer and tumor microenvironment.
    Haoqiang Yang, Jinghui Li, Yiting Niu, Tao Zhou, Pengyu Zhang, Yang Liu, Yanjun Li.
      Metabolic reprogramming is one of the major biological features of malignant tumors, playing a crucial role in the initiation and progression of cancer. The tumor microenvironment consists of various non-cancer cells, such as hepatic stellate cells, cancer-associated fibroblasts (CAFs), immune cells, as well as extracellular matrix and soluble substances. In liver cancer, metabolic reprogramming not only affects its own growth and survival but also interacts with other non-cancer cells by influencing the expression and release of metabolites and cytokines (such as lactate, PGE2, arginine). This interaction leads to acidification of the microenvironment and restricts the uptake of nutrients by other non-cancer cells, resulting in metabolic competition and symbiosis. At the same time, metabolic reprogramming in neighboring cells during proliferation and differentiation processes also impacts tumor immunity. This article provides a comprehensive overview of the metabolic crosstalk between liver cancer cells and their tumor microenvironment, deepening our understanding of relevant findings and pathways. This contributes to further understanding the regulation of cancer development and immune evasion mechanisms while providing assistance in advancing personalized therapies targeting metabolic pathways for anti-cancer treatment.
    Keywords:  hepatocellular carcinoma; immune evasion; metabolism reprogram; signaling pathways; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1494788
  3. Nat Immunol. 2025 Mar 06.
    The integrated stress response pathway controls cytokine production in tissue-resident memory CD4+ T cells.
    Nariaki Asada, Pauline Ginsberg, Hans-Joachim Paust, Ning Song, Jan-Hendrik Riedel, Jan-Eric Turner, Anett Peters, Anna Kaffke, Jonas Engesser, Huiying Wang, Yu Zhao, Robin Khatri, Philipp Gild, Roland Dahlem, Björn-Philipp Diercks, Sarada Das, Zoya Ignatova, Tobias B Huber, Immo Prinz, Nicola Gagliani, Hans-Willi Mittrücker, Christian F Krebs, Ulf Panzer.
      Tissue-resident memory T (TRM) cells are a specialized T cell population that reside in tissues and provide a rapid protective response upon activation. Here, we showed that human and mouse CD4+ TRM cells existed in a poised state and stored messenger RNAs encoding proinflammatory cytokines without protein production. At steady state, cytokine mRNA translation in TRM cells was suppressed by the integrated stress response (ISR) pathway. Upon activation, the central ISR regulator, eIF2α, was dephosphorylated and stored cytokine mRNA was translated for immediate cytokine production. Genetic or pharmacological activation of the ISR-eIF2α pathway reduced cytokine production and ameliorated autoimmune kidney disease in mice. Consistent with these results, the ISR pathway in CD4+ TRM cells was downregulated in patients with immune-mediated diseases of the kidney and the intestine compared to healthy controls. Our results indicated that stored cytokine mRNA and translational regulation in CD4+ TRM cells facilitate rapid cytokine production during local immune response.
    DOI:  https://doi.org/10.1038/s41590-025-02105-x
  4. FASEB J. 2025 Mar 15. 39(5): e70436
    FOXA2 loss results in an increase of endometriosis development and LIF reveals a therapeutic effect for endometriosis.
    Md Saidur Rahman, Tae Hoon Kim, Breton F Barrier, Thomas E Spencer, Andrew M Kelleher, Jae-Wook Jeong.
      Endometriosis, characterized by the growth of uterine-like tissue outside the uterus, causes chronic pain and infertility. Current diagnostic and therapeutic strategies have notable limitations, including delayed diagnosis and adverse effects. The transcription factor forkhead box A2 (FOXA2), which is exclusively expressed in the uterine glandular epithelium, regulates key genes involved in endometrial proliferation, differentiation, fertility, and hormone response. While FOXA2 expression is reduced in the endometrial tissue of women with endometriosis, its pathophysiological role in the disease is not well understood. In this study, we report that endometriosis significantly reduced FOXA2 expression in the eutopic endometrium of mice with endometriosis compared to sham controls, accompanied by decreased expression of its downstream gene, CXCL15. To evaluate the effect of FOXA2 loss in endometriosis, we surgically induced endometriosis by transplanting control Rosa26mTmG/+ or Pgrcre/+Foxa2f/fRosa26mTmG/+ (Foxa2d/dRosa26mTmG/+) endometrial tissue into the peritoneal cavity of mice. The number and weight of ectopic lesions were significantly increased in the mice with Foxa2d/dRosa26mTmG/+ ectopic lesions compared to controls. Furthermore, progesterone receptor expression was significantly reduced in the endometrial epithelium from mice with Foxa2d/dRosa26mTmG/+ ectopic lesions compared to mice with control ectopic lesions. Importantly, treatment with leukemia inhibitory factor (LIF), a cytokine regulated by FOXA2, significantly reduced ectopic lesion formation in Foxa2d/dRosa26mTmG/+ endometriosis mice compared to vehicle-treated mice. This study demonstrates that FOXA2 loss results in an increase in endometriosis incidence and that treatment with LIF offers a novel promising therapeutic approach for endometriosis.
    Keywords:  FOXA2; endometriosis; leukemia inhibitory factor; progesterone receptor
    DOI:  https://doi.org/10.1096/fj.202403182R
  5. Cancer Med. 2025 Mar;14(5): e70684
    Endoplasmic Reticulum Stress: Triggers Microenvironmental Regulation and Drives Tumor Evolution.
    Chaosheng Peng, Juan Wang, Shu Wang, Yan Zhao, Haoyuan Wang, Yuhao Wang, Yuxuan Ma, Jianjun Yang.
       BACKGROUND: The endoplasmic reticulum (ER) serves as a crucial hub for protein synthesis and processing, playing an essential role in maintaining protein homeostasis. Perturbations, such as hypoxia, oxidative stress, inadequate amino acid supply, Ca2+ imbalance, and acidosis, can disrupt cellular equilibrium and result in the accumulation of misfolded/unfolded proteins within the ER lumen. This triggers ER stress. In response to this stress, an unfolded protein response (UPR) is activated as a mechanism to cope with the stress and restore internal balance. The UPR is regulated by three sensors located in the ER: inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). However, the UPR can promote tumor growth in vivo by affecting tumor angiogenesis, cell migration, cell metabolism, and treatment resistance, and has a huge impact on the tumor microenvironment.
    MATERIALS AND METHODS: We conducted a literature review of scientific papers on the topic of ER stress in the tumor microenvironment.
    RESULTS AND DISCUSSION: This review focuses on the inducing factors of ER stress, the mechanism of the UPR signaling pathway induced by ER stress, and the effect of ER stress on the tumor microenvironment and immune-infiltrating cells. Tumors can regulate their evolution by affecting themselves and the tumor microenvironment through endoplasmic reticulum stress. This study reveals the important role of endoplasmic reticulum stress in the occurrence and development of tumors, and provides new ideas and potential therapeutic targets for the precision treatment of tumors. Future studies can further explore the molecular mechanism of ER stress regulating tumor microenvironment and explore its application potential in clinical diagnosis and treatment.
    Keywords:  endoplasmic reticulum stress; tumor microenvironment; unfolded protein response
    DOI:  https://doi.org/10.1002/cam4.70684
  6. Nat Metab. 2025 Mar 05.
    Asparagine deprivation enhances T cell antitumour response in patients via ROS-mediated metabolic and signal adaptations.
    Hsuan-Chia Chang, Chung-Ying Tsai, Cheng-Lung Hsu, Tzong-Shyuan Tai, Mei-Ling Cheng, Yu-Ming Chuang, Hsiang-Yu Tang, Kun-Ju Lin, Jia-Jin Chen, Szu-Han Chang, Yi-Ching Ko, Yu-Wen Chi, Hsuan Liu, Bertrand Chin-Ming Tan, Chia-Rui Shen, Chih-Wei Yang, Ping-Chih Ho, Huang-Yu Yang.
      Preclinical studies have shown that asparagine deprivation enhances T cell antitumour responses. Here we apply compassionate use of L-asparaginase, usually employed to treat blood malignancies, on patients with recurrent metastatic nasopharyngeal carcinoma. The use of L-asparaginase notably enhances immune-checkpoint blockade therapy in patients by strengthening CD8+T cell fitness. Our study shows that this combination is a promising avenue for clinical application and provides further mechanistic insight into how asparagine restriction rewires T cell metabolism.
    DOI:  https://doi.org/10.1038/s42255-025-01245-6
  7. Cell Signal. 2025 Feb 26. pii: S0898-6568(25)00115-9. [Epub ahead of print]130 111702
    Unfolded protein response-activated NLRP3 inflammasome contributes to pyroptotic and apoptotic podocyte injury in diabetic kidney disease via the CHOP-TXNIP axis.
    Yun Cao, Langtao Hu, Ruike Chen, Yao Chen, Huafeng Liu, Jiali Wei.
       BACKGROUND: Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease and end-stage renal disease worldwide. Podocyte injury and death is a key event in DKD progression. Emerging evidence has indicated that crosstalk between unfolded protein response (UPR) and NLR family pyrin domain containing 3 (NLRP3) inflammasome plays an essential role in DKD progression. However, the involvement of these pathways in podocyte injury and death during DKD remains unclear.
    RESULTS: Here, we found that inositol-requiring enzyme 1 (IRE1) and protein kinase RNA-like ER kinase (PERK) branches of the UPR, NLRP3 inflammasome, and apoptosis were activated in podocytes under DKD and high glucose (HG) conditions. In vitro, inducing ER stress by thapsigargin, and IRE1 or PERK overexpression upon HG treatment stimulated NLRP3 inflammasome-mediated pyroptosis and apoptosis, whereas inhibiting IRE1 or PERK suppressed them. Importantly, we discovered that the newly identified NLRP3-binding partner, thioredoxin-interacting protein (TXNIP), upon activation by the transcription factor (TF) PERK/CCAAT-enhancer-binding protein homologous protein (CHOP), served as a link between IRE1 or PERK branches with NLRP3 inflammasome-mediated pyroptosis and apoptosis. TXNIP expression was promoted in podocytes from DKD patients and db/db mice, as well as in HG-exposed conditionally immortalized human podocyte (HPC). In HG-exposed HPC, IRE1 or PERK overexpression upregulated TXNIP expression, while IRE1 or PERK inhibition downregulated it. TXNIP or CHOP silencing both inhibited HG-upregulated TXNIP, further blocking NLRP3 inflammasome-mediated pyroptosis and apoptosis. Furthermore, NLRP3 overexpression aggravated HG-induced pyroptosis and apoptosis, whereas additional TXNIP silencing reversed them without affecting IRE1 or PERK branches.
    CONCLUSION: In conclusion, our results suggested that UPR/NLRP3 inflammasome-mediated pyroptosis/apoptosis pathway was involved in diabetic podocyte injury, and that targeting the CHOP-TXNIP axis may serve as a promising therapeutic target for DKD.
    Keywords:  Apoptosis; Diabetic kidney disease; Endoplasmic reticulum stress; NLRP3 inflammasome; Podocyte; Pyroptosis
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111702
  8. Cancer Med. 2025 Mar;14(5): e70707
    Secretomes From Non-Small Cell Lung Cancer Cells Induce Endothelial Plasticity Through a Partial Endothelial-to-Mesenchymal Transition.
    Clara Bourreau, Emilie Navarro, Marine Cotinat, Morgane Krejbich, François Guillonneau, Catherine Guette, Alice Boissard, Cécile Henry, Isabelle Corre, Lucas Treps, Nicolas Clere.
       AIM: The tumor microenvironment (TME) of non-small cell lung cancer (NSCLC) is highly heterogeneous and is involved in tumorigenesis and resistance to therapy. Among the cells of the TME, endothelial cells are associated with the latter processes through endothelial-to-mesenchymal transition (EndMT). During EndMT, endothelial cells (ECs) progressively lose their endothelial phenotype in favor of a mesenchymal phenotype, which favors the production of cancer-associated fibroblasts (CAFs). Our study aimed to investigate the consequences of exposure to different lung tumor secretomes on EC phenotype and plasticity.
    MATERIALS AND METHODS: Conditioned media (CM) were prepared from the tumor cell lines A549, H1755, H23, H1437, and H1975. Proliferation and migration of ECs treated with these CMs were assessed by Cyquant and Incucyte technologies, respectively. The angiogenic capacity of ECs was assessed by following tubulogenesis on Matrigel. Phenotypic changes in treated ECs were detected by flow cytometry. Morphological analysis of actin fibers was performed by immunohistochemistry, while proteomic analysis by mass spectrometry was used to identify the protein content of secretomes.
    RESULTS: A change of the endothelial phenotype was found when human umbilical vein endothelial cells (HUVECs) were treated with different CMs. This phenotypic change was associated with a morphological change, an increase in both stress fiber expression and spontaneous migration. Furthermore, an increase in mesenchymal markers (α-SMA and CD44) confirmed the phenotypic changes. However, the secretomes did not modify the rate of double-labeled cells (vWF+/α-SMA+ or CD31+/CD44+). Proteomic analysis identified potential targets involved in the EndMT with therapeutic relevance.
    CONCLUSION: Taken together, these data suggest that CMs can induce partial EndMT.
    Keywords:  EndMT; endothelial cell plasticity; endothelial‐to‐mesenchymal transition; non‐small cell lung cancer; secretome
    DOI:  https://doi.org/10.1002/cam4.70707
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