bims-stacyt 2025-08-03 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2025–08–03
twelve papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

The Power of Drosophila in Modeling Cancer Cachexia.
Hypoxic link between cancer cells and the immune system: The role of adenosine and lactate.
Translational control by general control nonderepressible 2 kinase regulates methylglyoxal-induced pain in mice.
Context Matters: Divergent Roles of Exercise-Induced and Tumor-Derived Lactate in Cancer.
Mitochondrial glutathione import enables breast cancer metastasis via integrated stress response signaling.
Mechanism of interleukin-6 cytokine family in bone metastasis of lung cancer and prospects for its application.
Macropinocytosis maintains CAF subtype identity under metabolic stress in pancreatic cancer.
Sympathetic nervous system in tumor progression and metabolic regulation: mechanisms and clinical potential.
Obesity-driven inflammation and cancer risk: A comprehensive review.
Dual-Action Tocilizumab-Conjugated Cisplatin Nanoparticles Overcome Chemoresistance and Metastasis in Non-Small-Cell Lung Cancer.
ER stress-driven unfolded protein response fuels aging-related tumor aggressiveness in gliomas.
Sesn-1 is required for lifespan extension during caloric deprivation in C. elegans through inhibition of mTORC1 and activation of autophagy.

Adv Exp Med Biol. 2025 ;1482 83-100

The Power of Drosophila in Modeling Cancer Cachexia.

Chen Cheng, Ying Liu, Yuchen Chen, Jiaying Li, Weiqi Xu, Norbert Perrimon, Wei Song.

  Late-stage cancer patients often exhibit cachexia, a wasting syndrome characterized by the loss of muscle and adipose tissues. However, the extent to which these wasting effects directly contribute to mortality remains unclear. Drosophila, a well-conserved model organism, has been instrumental in demonstrating systemic energy wasting and mortality in the context of tumors, similar to mice and humans. Research in Drosophila has elucidated the underlying mechanisms by which tumor-associated secreted proteins cause muscle atrophy and lipid loss, ultimately leading to energy wasting. Nevertheless, emerging evidence in both Drosophila and mammals challenges the notion that blocking energy loss in muscle or fat is sufficient to improve tumor-associated mortality, suggesting the existence of additional pathogenic factors in cancer cachexia. This raises two critical questions: how do tumors disrupt the physiological functions of other organs besides muscle and fat, and to what extent do these organ dysfunctions contribute to tumor-induced mortality? In this chapter, we summarize current knowledge regarding how fly tumors interact with host organs or tissues through the production of cachectic secreted proteins, and how they influence disease progression. We also discuss the power of Drosophila models in uncovering the mechanisms and principles of tumor-induced wasting and mortality and exploring therapeutic opportunities using various leading technologies.

Keywords:  Blood-brain barrier disruption; Cancer cachexia; Coagulopathy; Excessive hepatic gluconeogenesis; Host interaction; Host wasting; Kidney injury; Lipid loss; Mortality; Muscle atrophy; Pathogenic organs; Signaling pathways; Tumor; Tumor-secreted proteins

DOI:  https://doi.org/10.1007/978-3-031-97035-1_5
Oncol Res. 2025 ;33(8): 1803-1818

Hypoxic link between cancer cells and the immune system: The role of adenosine and lactate.

Eduardo Alvarado-Ortiz, Miguel Angel Sarabia-SáNCHEZ.

  The tumor microenvironment (TME) is characterized by a symbiosis between cancer cells and the immune cells. The scarcity of oxygen generates hostility that forces cancer cells to alter their biological features in solid tumors. In response to low oxygen availability, the Hypoxia Inducible Factors (HIF-1/2/3α) act as metabolic mediators, producing extracellular metabolites in the tumor microenvironment that influence the immune cells. The modulation of lactate and adenosine on immune evasion has been widely described; however, under hypoxic conditions, it has been barely addressed. Evidence has demonstrated an interplay between cancer and the immune cells, and the present review explores the findings that support HIFs bridging the gap between the rise of these metabolites and the immunosurveillance failure in a hypoxic context. Moreover, new insights based on systemic oxygen administration are discussed, which might counterbalance the effect mediated by lactate and adenosine, to recover anti-tumor immunity. Thus, the disruption of anti-tumor immunity has been the focus of recent research and this novel avenue opens therapeutic vulnerabilities that can be useful for cancer patients.

Keywords:  Adenosine; Hypoxia; Hypoxia inducible factors (HIF-1/2/3α); Immune evasion; Lactate; Tumor microenvironment (TME)

DOI:  https://doi.org/10.32604/or.2025.065953
Pain. 2025 Jul 30.

Translational control by general control nonderepressible 2 kinase regulates methylglyoxal-induced pain in mice.

Angela R Meyer, Guadalupe García, Alexander R Mikesell, Sydney O'Flanagan, Cheryl L Stucky, Zachary T Campbell.

   ABSTRACT: Neuropathic pain is pervasive among people with diabetes. The integrated stress response (ISR) is a key mechanism of translational regulation implicated in diabetic pain. In this study, we demonstrate that a reactive glycolytic metabolite, methylglyoxal (MGO), which is strongly associated with painful diabetic neuropathy, activates the ISR through the kinase general control nonderepressible 2 (GCN2). Methylglyoxal disrupts elongating ribosomes, triggering the recruitment of ribosome quality control factors and collision sensors. GCN2 activation by MGO requires the ribosomal P-stalk, a critical sensor for elongation factors. Moreover, neuronal sensitization and mechanical allodynia produced by MGO are GCN2-dependent. Overall, this study links ribosomal elongation dysfunction to metabolic pain and identifies GCN2 as a novel analgesic target for diabetic neuropathy.

Keywords:  DPN; GCN2; ISR; MGO; eIF2

DOI:  https://doi.org/10.1097/j.pain.0000000000003761
Biomolecules. 2025 Jul 14. pii: 1010. [Epub ahead of print]15(7):

Context Matters: Divergent Roles of Exercise-Induced and Tumor-Derived Lactate in Cancer.

Amir Hossein Ahmadi Hekmatikar, Ghazal Zolfaghari, Aref Basereh, D Maryama Awang Daud, Kayvan Khoramipour.

  Instead of being waste product of metabolism, lactate, has become a key metabolic and signaling molecule in both exercise physiology and tumor biology. Carcinogenic cells produce huge amounts of lactate through the Warburg effect, which is a hallmark of aggressive tumors, increasing acidity in the environment that can stimulates angiogenesis, immune evasion, and metastasis. Conversely, while exercise acutely elevates blood lactate concentration but it consider helpful for cancer patients. This paradox raises the following question: is exercise-induced lactate a friend or foe in cancer? This study reviews current evidence on the mechanistic, metabolic, immunological, and clinical impacts of exercise-induced lactate in cancer patients, highlighting the context-dependent effects that render lactate either beneficial or detrimental. Tumor-derived lactate seems to be pro-tumorigenic, driving immune suppression and disease progression, whereas short bursts of lactate from exercise can enhance anti-tumor immunity and metabolic reprogramming under the right conditions. Therefore, lactate's impact on cancer is "all about the context".

Keywords:  cancer; exercise; lactate; metabolism

DOI:  https://doi.org/10.3390/biom15071010
Cancer Discov. 2025 Jul 31.

Mitochondrial glutathione import enables breast cancer metastasis via integrated stress response signaling.

Hsi-Wen Yeh, Nicole Lauren DelGaudio, Beste Uygur, Alon Millet, Artem Khan, Gokhan Unlu, Michael Xiao, Rebecca C Timson, Caifan Li, Kerem Ozcan, Karl W Smith, Luiza Martins Nascentes Melo, Gabriele Allies, Olca Basturk, Albert Sickmann, Erol C Bayraktar, Richard Possemato, Alpaslan Tasdogan, Kivanc Birsoy.

Cancer cells require substantial metabolic adaptations to metastasize to distant organs, but the metabolites essential for successful colonization remain poorly defined. Here, we used a mitochondrial metabolomics approach to compare primary and metastatic breast cancer cells. This analysis revealed accumulation of mitochondrial glutathione (GSH) during lung metastasis, driven by elevated expression of SLC25A39, a mitochondrial GSH transporter. Loss of SLC25A39 impairs metastatic colonization in genetic screens, cell line models, and patient-derived xenografts, without affecting primary tumor growth. Mitochondrial GSH import is specifically required during early colonization and functions independently of its canonical antioxidant role. CRISPR activation screens identified ATF4, a stress-induced transcription factor, as a bypass mechanism that restores metastatic potential in SLC25A39-deficient cells. Mechanistically, SLC25A39 is required for optimal ATF4 activation during metastasis and under hypoxia, linking mitochondrial GSH availability to integrated stress response signaling. These findings identify mitochondrial GSH as a necessary and limiting metabolite for metastatic progression.

DOI: https://doi.org/10.1158/2159-8290.CD-24-1556
Biochim Biophys Acta Rev Cancer. 2025 Jul 24. pii: S0304-419X(25)00140-4. [Epub ahead of print]1880(5): 189398

Mechanism of interleukin-6 cytokine family in bone metastasis of lung cancer and prospects for its application.

Jinbai Huang, Qingting Zhang, Yuanshan Yang, Wei Wang, Jun Cai.

  Bone metastasis is a significant clinical problem for lung cancer patients. Current studies have reported a strong relationship between the progression of bone metastases from lung cancer and inflammatory cytokines, which can modulate the tumor microenvironment (TME) and promote the migration of tumor cells. Interleukin-6 (IL-6) family cytokines are critical components of the immune microenvironment secreted by several cell types in vivo. They can regulate immune homeostasis, inflammatory response, etc., and activate multiple signal pathways involved in tumor progression. Some of these factors (e.g., IL-6 and IL-11) increase the serum expression levels of patients with bone metastases from lung cancer; the level of expression correlates with a poor prognosis in patients with lung cancer. However, the role of this family of novel cytokines in lung cancer bone metastasis remains unclear. Besides, limited studies exist on the related regulatory mechanisms, and there is a lack of direct evidence for their relationship with bone metastasis. Thus, this review discusses the current roles and potential mechanisms of all IL-6 family members in lung cancer bone metastasis, as well as the potential of blocking the IL-6 family, its receptors, and signaling pathways for treating lung cancer bone metastasis. This is geared towards providing prospective treatment targets for bone metastases from lung cancer and possible future research directions.

Keywords:  Bone metastasis; IL-6 family cytokines; Immunotherapy; Lung cancer

DOI:  https://doi.org/10.1016/j.bbcan.2025.189398
Cancer Cell. 2025 Jul 15. pii: S1535-6108(25)00271-5. [Epub ahead of print]

Macropinocytosis maintains CAF subtype identity under metabolic stress in pancreatic cancer.

Yijuan Zhang, Li Ling, Rabi Murad, Swetha Maganti, Ambroise Manceau, Hannah A Hetrick, Madelaine Neff, Cheska Marie Galapate, Shea F Grenier, Florent Carrette, Karen Duong-Polk, Anindya Bagchi, David A Scott, Yoav Altman, Jennifer L Hope, Andrew M Lowy, Linda M Bradley, Cosimo Commisso.

  Pancreatic ductal adenocarcinoma (PDAC) tumors are glutamine deficient, and both tumor cells and cancer-associated fibroblasts (CAFs) rely on this amino acid to maintain fitness and induce macropinocytosis as an adaptive response. CAFs play a critical role in sculpting the tumor microenvironment, yet how adaptations to metabolic stress impact the stromal architecture remains elusive. In this study, we find that macropinocytosis sustains the myCAF phenotype under glutamine limitation by preventing inflammatory reprogramming. Our data demonstrate that metabolic stress induces an intrinsic inflammatory CAF (iCAF) program through MEK-ERK signaling. We find that blocking macropinocytosis in vivo promotes myCAF-to-iCAF transitions, remodeling the tumor stroma. Importantly, stromal remodeling driven by macropinocytosis inhibition-including iCAF enrichment, collagen reduction, immune cell infiltration, and vascular expansion-sensitizes PDAC tumors to immunotherapy and chemotherapy. Our findings reveal that inhibiting macropinocytosis promotes an inflammatory, less fibrotic tumor microenvironment that can be leveraged to improve therapeutic responses in PDAC.

Keywords:  CAF heterogeneity; chemotherapy; drug delivery; immunotherapy; macropinocytosis; metabolic stress; pancreatic cancer; plasticity; stromal architecture; tumor microenvironment

DOI:  https://doi.org/10.1016/j.ccell.2025.06.021
J Transl Med. 2025 Jul 25. 23(1): 836

Sympathetic nervous system in tumor progression and metabolic regulation: mechanisms and clinical potential.

Chen Sun, Yuqing Shen, Fuhua Wang, Tian Lu, Jianqiong Zhang.

  Tumor progression is characterized by profound metabolic alterations and dynamic interactions within the tumor microenvironment (TME), which enable rapid proliferation, immunoinvasion, and metastasis. The sympathetic nervous system (SNS), which has been best known for its role in stress regulation, has emerged as a critical regulator of tumor metabolism. The SNS influences glucose, lipid and glutamine metabolism in tumor cells and stromal components by releasing neurotransmitters such as norepinephrine (NE), creating a pro-tumor metabolic and immunosuppressive microenvironment. SNS signaling enhances glycolysis via upregulation of glucose transporter 1 (GLUT1) and glycolytic enzymes, and supports lipid metabolism through fatty acid synthesis and oxidation. In immune cells, SNS-driven metabolic shifts promote immunosuppressive phenotypes, particularly in T cells and macrophages. Concurrently, SNS signaling enhances glycolysis in endothelial cells, thereby facilitating angiogenesis within the TME. Together, these processes collectively sustain tumor growth, invasion, and resistance to therapy. Therapeutic strategies targeting SNS signaling, such as adrenergic receptors (ARs) blockers, show promise in disrupting these tumor-supportive networks. However, challenges such as the non-specific nature of SNS blockade and the complexity of TME interactions necessitate further research into ARs subtypes, tumor-specific metabolic vulnerabilities, and predictive biomarkers. This review highlights the therapeutic potential of targeting SNS signaling to reshape tumor metabolism and the microenvironment. By elucidating the metabolic impacts of its systemic and local arms, it provides a framework for integrating SNS-directed strategies with existing treatments to improve clinical outcomes.

Keywords:  Cancer therapy; Metabolic reprogramming; Sympathetic nervous system; Tumor microenvironment; Tumor progression

DOI:  https://doi.org/10.1186/s12967-025-06657-2
Semin Cancer Biol. 2025 Jul 25. pii: S1044-579X(25)00100-2. [Epub ahead of print]114 256-266

Obesity-driven inflammation and cancer risk: A comprehensive review.

D A Lamabadusuriya, H Jayasena, A K Bopitiya, A D De Silva, P Jayasekera.

  Obesity is a growing global health challenge, significantly increasing the risk of metabolic diseases and cancer. This review explores the link between obesity-driven inflammation and cancer risk, emphasizing the key biological mechanisms. Chronic low-grade inflammation in obesity, mediated by dysfunctional adipose tissue, promotes a pro-tumorigenic microenvironment through increased secretion of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. These factors contribute to insulin resistance, oxidative stress, and immune cell infiltration, fostering tumorigenesis. Adipokine imbalances, particularly elevated leptin and reduced adiponectin levels, further drive cancer progression by enhancing cell proliferation, angiogenesis, and immune evasion. Additionally, obesity-induced hypoxia, endoplasmic reticulum stress, and gut microbiome dysbiosis amplify systemic inflammation and metabolic dysfunction, further increasing cancer susceptibility. Epidemiological evidence highlights strong associations between obesity and cancers such as breast, colorectal, liver, and pancreatic cancer. Given the rising global prevalence of obesity, addressing inflammation-mediated oncogenesis is crucial. Lifestyle modifications, including weight loss through dietary and physical activity interventions, have demonstrated significant cancer risk reduction. Emerging pharmacological approaches targeting inflammatory pathways and adipokine regulation offer promising therapeutic potential. Understanding the mechanisms linking obesity, inflammation, and cancer provides valuable insights for developing targeted prevention and treatment strategies.

Keywords:  Cancer; Inflammation; Obesity

DOI:  https://doi.org/10.1016/j.semcancer.2025.07.007
Pharmaceutics. 2025 Jul 21. pii: 945. [Epub ahead of print]17(7):

Dual-Action Tocilizumab-Conjugated Cisplatin Nanoparticles Overcome Chemoresistance and Metastasis in Non-Small-Cell Lung Cancer.

Yin Wang, Fanyu Wu, Tan Yang, Bin Li, Han Wang, Peng Ye, Weijie Li.

  Background/Objectives: Cisplatin remains a cornerstone chemotherapeutic agent for non-small-cell lung cancer (NSCLC) treatment, yet its clinical utility is substantially limited by acquired resistance and the inadequate suppression of tumor metastasis. Emerging evidence implicates interleukin 6 (IL-6) as a critical mediator of chemoresistance through cancer stem cell (CSC) enrichment and metastasis promotion via epithelial-mesenchymal transition (EMT) induction, ultimately contributing to cisplatin therapy failure. This study sought to address these challenges by designing a nanoplatform with two innovative aims: (1) to achieve active tumor targeting through binding to the IL-6 receptor (IL-6R), and (2) to concurrently inhibit IL-6-mediated chemoresistance signaling pathways. Methods: A lipid-polymer hybrid nanoparticle (LPC) encapsulating cisplatin was synthesized and subsequently surface-functionalized with tocilizumab (TCZ), a monoclonal antibody that targets IL-6R. The therapeutic efficacy of this TCZ-modified nanoparticle (LPC-TCZ) was assessed through a series of in vitro and in vivo experiments, focusing on the inhibition of EMT, expression of CSC markers, tumor growth, and metastasis. Results: Systematic in vitro and in vivo evaluations revealed that LPC-TCZ synergistically attenuated both EMT progression and CSC marker expression through the targeted blockade of IL-6/STAT3 signaling. This multimodal therapeutic strategy demonstrated superior tumor growth inhibition and metastatic suppression compared to conventional cisplatin monotherapy. Conclusions: Our findings establish a nanotechnology-enabled approach to potentiate cisplatin efficacy by simultaneously countering chemoresistance mechanisms and metastatic pathways in NSCLC management.

Keywords:  cancer stem cells; cisplatin; epithelial–mesenchymal transition; interleukin 6; tocilizumab

DOI:  https://doi.org/10.3390/pharmaceutics17070945
Front Mol Biosci. 2025 ;12 1640038

ER stress-driven unfolded protein response fuels aging-related tumor aggressiveness in gliomas.

Xiaodong Shao, Shaolei Guo, Jia Yang, Junjie Dai, Kaihua Cao, Xia Cai, Tianshi Song, Shun Yao, Umar Raza, Kun Chen.

   Background: Gliomas are the most prevalent and aggressive primary brain tumors. Aging significantly influences glioma incidence and progression, yet the molecular mechanisms linking aging-related pathways to tumor aggressiveness remain poorly understood. Here, we aimed to decipher aging-related molecular mechanisms regulating tumor aggressiveness in gliomas.
Methods: We performed comprehensive aging-targeted transcriptomic analyses using TCGA-glioma patient dataset. Differential gene and protein expression, functional annotation and pathway enrichment, gene set enrichment, network construction, CRSISPR-based functional dependency, transcription factor prediction, correlation, clinical association and survival analyses were conducted to identify, develop and validate endoplasmic reticulum (ER) stress-driven unfolded protein response (UPR) as key aging-related molecular mechanism driving tumor aggressiveness in gliomas. Notably, we validated our findings in multiple independent GEO datasets.
Results: We identified ER stress and UPR as key aging-related mechanism behind tumor aggressiveness in gliomas, and developed a six gene "ER Stress and UPR-driven Aging-related Tumor Aggressiveness in Glioma" (ESURATAG) gene signature, comprising DERL2, RPN2, SEC13, SEC61A1, SEC61B, and STT3A. Notably, glioma cell proliferation critically depends on ESURATAG-GS, which is preferentially regulated by MYC and is associated with disease and cell cycle progression, inflammation, and poor clinical outcomes in glioma patients, simultaneously aligning with aging and tumor aggressiveness signatures. Validated in multiple GEO datasets, high ESURATAG expression is linked to disease onset, advanced disease state, and reduced overall and progression-free survival in glioma patients as well as in patients with major subtypes of gliomas, including oligodendrogliomas, astrocytomas and gliobalstomas.
Discussion: ESURATAG-GS serves as a critical MYC-regulated adaptive mechanism that fuels aging-related tumor aggressiveness via ER stress-driven UPR in gliomas, presenting novel prognostic markers and therapeutic targets for elderly glioma patients.

Keywords:  ER stress; UPR; aging; glioma; tumor aggressiveness

DOI:  https://doi.org/10.3389/fmolb.2025.1640038
Aging (Albany NY). 2025 Jul 28. 17

Sesn-1 is required for lifespan extension during caloric deprivation in C. elegans through inhibition of mTORC1 and activation of autophagy.

Andrei O Zheltukhin, Peter M Chumakov, Andrei V Budanov.

  Sestrins, evolutionarily conserved stress-responsive proteins, are increasingly recognized for their potential role in lifespan regulation. This study aimed to elucidate the influence of the sesn-1 gene on lifespan modulation during caloric deprivation (CD) in the model organism C. elegans. Our findings reveal that sesn-1 mediates lifespan extension under CD, primarily through the repression of mTORC1 kinase and activation of autophagy. Moreover, we identified an essential role for sesn-1 in enhancing stress resilience in nematodes, particularly in the context of nutrient sensing. Further investigations demonstrated sesn-1's interaction with the GATOR2 protein complex, its role in maintaining muscle integrity and a potential synergy between sesn-1 and the FOXO pathway. Overall, our research underscores the profound implications of Sestrins in aging and stress resistance, shedding light on possible therapeutic avenues for prevention and treatment of age-associated disorders.

Keywords:  aging; autophagy; mTOR; sesn-1

DOI:  https://doi.org/10.18632/aging.206290