bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2026–04–12
six papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. LIFe of the sugar-free party in cancer metabolism.
  2. Overcoming immunotherapy resistance in breast cancer: a novel strategy by targeting the integrated stress response.
  3. Pseudo-senescence induced by palbociclib does not sensitise pleural mesothelioma cells to combinations with senolytics.
  4. Molecular Mechanism of Caspase-8-Dependent Interleukin-18 Activation in Pancreatic Cancer Cells Induced by 5-Fluorouracil and Nutrient Starvation.
  5. Sphingosine-1-Phosphate Receptor 1 Promotes Ovarian Cancer Tumorsphere Proliferation and Metastasis.
  6. Nuclear hexokinase 2 couples hyperglycemia to MYC-driven glycolytic and stemness programs in bladder cancer.
  1. Trends Endocrinol Metab. 2026 Apr 09. pii: S1043-2760(26)00071-8. [Epub ahead of print]
    LIFe of the sugar-free party in cancer metabolism.
    Khaled Tighanimine, Brendan D Manning.
      Tumor cells can thrive in nutrient-scarce environments. Glucose deprivation can trigger adaptive responses that coordinate cell-cell communication within the tumor microenvironment (TME). Recently, Luciano-Mateo et al. demonstrated that glucose withdrawal promotes cancer cell secretion of the cytokine leukemia inhibitory factor (LIF), which exerts protumorigenic effects on the TME.
    Keywords:  LIF; N-glycosylation; PERK; glucose; lung cancer; metastasis
    DOI:  https://doi.org/10.1016/j.tem.2026.03.010
  2. Front Cell Dev Biol. 2026 ;14 1720480
    Overcoming immunotherapy resistance in breast cancer: a novel strategy by targeting the integrated stress response.
    Jian Yue, Tianyi Pu, Dele He, Yangyong Luo, Simin Ruan, Huahan Li, Jianwei Zhan, Guosen Su, Jianyuan Su, Sheng Chen, Guoxing Huang.
      Immunotherapy resistance remains a major obstacle in treating breast cancer, particularly aggressive subtypes like triple-negative breast cancer (TNBC). This review delineates the pivotal role of the Integrated Stress Response (ISR) as a central metabolic-immune regulator driving this resistance. The ISR is activated in the tumor microenvironment (TME) by diverse stressors-including hypoxia, nutrient scarcity, and ER stress-via four upstream kinases (PERK (PKR-like ER kinase), GCN2, PKR, HRI). These kinases converge to phosphorylate eukaryotic initiation factor 2α (eIF2α), leading to the selective translation and robust activation of the transcription factor ATF4. The ensuing ATF4-driven program fosters an immunosuppressive TME through multifaceted mechanisms: tumor-intrinsic upregulation of PD-L1, secretion of immunosuppressive exosomes, metabolic reprogramming that depletes critical amino acids, and direct impairment of T cell function and antigen presentation. Concurrently, ISR activation in immune cells-such as myeloid-derived suppressor cells (MDSCs) and dendritic cells-further dampens antitumor immunity. Targeting the ISR with small-molecule inhibitors (PERK or GCN2 inhibitors, ISRIB) or repurposed agents (metformin) demonstrates compelling preclinical efficacy in reversing immunosuppression and synergizing with immune checkpoint inhibitors. Biomarker-driven strategies, including ISR gene signatures and p-eIF2α immunohistochemistry, offer promising avenues for patient stratification. Thus, pharmacological targeting of the ISR represents a strategically viable approach to reprogram the immunosuppressive TME and overcome immunotherapy resistance in breast cancer, warranting urgent clinical investigation.
    Keywords:  breast cancer; eIF2α-ATF4 axis; immune checkpoint inhibitors; immunotherapy resistance; integrated stress response (ISR); tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2026.1720480
  3. Cell Death Dis. 2026 Apr 10.
    Pseudo-senescence induced by palbociclib does not sensitise pleural mesothelioma cells to combinations with senolytics.
    Iswarya Sreeram, Sílvia Plans-Marin, Mabel Cruz-Rodríguez, Elisabet Aliagas, Didac Palau-Gallinat, Cristina Muñoz-Pinedo, Ernest Nadal.
      Pleural Mesothelioma (PM) is an aggressive neoplasm of the lung pleura with poor survival rates, highlighting the urgent need for novel therapeutic options. The CDK4/6 inhibitors abemaciclib and palbociclib have demonstrated promising results in patient-derived xenograft models of PM. In this study, we observed that palbociclib reduced proliferation, leading to increased cell size, enhanced SA-β-galactosidase activity, and elevated secretion of IL-6 and IL-8 (SASP), all of which are hallmarks of senescence. However, upon drug removal, the cells regrew. To enhance therapeutic efficacy, we attempted to induce cell death in palbociclib-pretreated PM cells with conventional senolytics, such as BH3 mimetics. While some cells showed sensitivity to Bcl-xL inhibitors, neither navitoclax nor the specific Bcl-xL inhibitor A-1331852, nor other BH3 mimetics targeting Bcl-2 (venetoclax) or Mcl-1 (S63845) increased cell death when combined with palbociclib. We explored the activity of signalling pathways after treatment with palbociclib and identified higher Src and STAT3 phosphorylation, as well as activation of the mTORC1 axis. Therefore, we employed inhibitors of these pathways, such as dasatinib, momelotinib or Torin-1, which did not synergise with palbociclib to kill the cells. In contrast, we found that the chemotherapeutic drug cisplatin induces permanent cell cycle arrest and complete senescence in PM cells. While both drugs increased the phosphorylation of γH2AX, the effects of cisplatin were stronger and more consistent across cell lines. The differential effects of palbociclib and cisplatin on permanent growth arrest were verified by sorting PM cells based on size and β-galactosidase activity. Our findings underscore the importance of understanding the nature of therapy-induced senescence when assessing the effectiveness of senolytics in different tumour models.
    DOI:  https://doi.org/10.1038/s41419-026-08696-z
  4. Genes Cells. 2026 May;31(3): e70111
    Molecular Mechanism of Caspase-8-Dependent Interleukin-18 Activation in Pancreatic Cancer Cells Induced by 5-Fluorouracil and Nutrient Starvation.
    Hiroki Kamino, Yuko Nariai, Takeshi Urano.
      Interleukin-18 (IL-18) is a pro-inflammatory cytokine, and higher IL-18 expression in pancreatic tumors is associated with poor prognosis. Although 5-fluorouracil (5-FU) has been reported to induce the release of bioactive (mature/cleaved) IL-18 from the pancreatic cancer cell line Capan-2, the underlying mechanism remains unclear. Here, we investigated IL-18 activation in pancreatic cancer cells after 5-FU treatment under low-nutrient conditions that mimic key features of the tumor microenvironment, using a monoclonal antibody we generated that specifically recognizes cleaved, active IL-18. We detected the release of active IL-18 from both Capan-2 and MIA PaCa-2 cells after 5-FU treatment. Analysis of separated attached and detached cell fractions showed that IL-18 cleavage occurred predominantly in detached cells. We also clarified that caspase-8-but not caspase-1/4-was activated in detached cells and was required for IL-18 and GSDMD cleavage that is a hallmark of pyroptosis. Surprisingly, detached cells from only nutrient starvation showed the same phenomenon, and 5-FU contributed to increased pyroptotic cells. On the other hand, the release of active IL-18 was not observed with gemcitabine. These findings suggest that a low-nutrient tumor microenvironment and 5-FU therapy can promote caspase-8-dependent pyroptotic cell death with IL-18 activation, potentially contributing to chronic inflammation in pancreatic tumors.
    Keywords:  5‐fluorouracil; IL‐18; caspase‐8; nutrient starvation; pancreatic cancer; pyroptosis
    DOI:  https://doi.org/10.1111/gtc.70111
  5. Int J Cancer. 2026 Apr 09.
    Sphingosine-1-Phosphate Receptor 1 Promotes Ovarian Cancer Tumorsphere Proliferation and Metastasis.
    Núria Gendrau-Sanclemente, Agnès Figueras, Ferran Medina-Jover, Juan A Marín-Jiménez, Michelle De Leeuw, Tianyu Dai, Marina Moreno-Mosquera, Andrea Morales, Marc Guiu, Josefina Casas, José Carlos Perales, Roger R Gomis, Francesc Viñals.
      Despite extensive clinical endeavors to enhance high-grade serous ovarian cancer (HGSOC) detection and treatment, an alarming half of diagnosed women succumb annually to this disease. Significantly, nearly all HGSOC cases manifest ascites at diagnosis, a poor prognostic indicator. Malignant ascites production arises as ovarian cancer cells shed from the primary tumor, creating a new environment that challenges their survival. Consequently, cancer cells aggregate into tumorspheres, the principal metastatic units in HGSOC. The molecular mechanisms that tumorspheres use to overcome the ascites bottleneck and metastasize are still poorly understood. Studying tumorspheres isolated from ascites samples from treatment naïve HGSOC patients, as well as three-dimensional spheroid in vitro and in vivo ovarian cancer cell models, we report that the sphingosine-1-phosphate (S1P) ligand and its receptor S1PR1 axis is especially relevant in ovarian tumorspheres, where it promotes an autocrine positive loop, serving as their primary proliferative mechanism via MEK1/2-ERK activation. Our findings demonstrate that the S1P-S1PR1-MEK1/2 pathway confers ovarian tumorspheres a selective advantage within the ascites environment and, consequently, increases their metastatic potential.
    Keywords:  ERK; HGSOC; S1PR1; metastasis; tumorspheres
    DOI:  https://doi.org/10.1002/ijc.70467
  6. Cell Death Dis. 2026 Apr 08.
    Nuclear hexokinase 2 couples hyperglycemia to MYC-driven glycolytic and stemness programs in bladder cancer.
    Shuangjie Liu, Xi Liu, Guangxu Liu, Zheyu Wang, Chengyi Li, Meng Yu, Jihang Yao, Haotian Xing, Yuyan Zhu.
      Hyperglycemia is common in patients with bladder cancer and has been implicated in disease progression, yet the molecular link between a high-glucose milieu and tumor aggressiveness remains poorly defined. Here we identify a noncanonical, nuclear role of hexokinase 2 (HK2) that couples systemic hyperglycemia to MYC-driven glycolysis and stemness in bladder cancer. High glucose promotes nuclear translocation of HK2, where HK2 directly binds the central region of MYC to form a functional transcriptional complex. This HK2-MYC complex occupies the promoters of key glycolytic genes, including HK2 and lactate dehydrogenase A (LDHA), and synergistically activates their transcription, thereby enhancing glycolytic flux and upregulating stemness-associated markers such as CD44. Genetic or pharmacologic inhibition of HK2 attenuates high glucose-induced proliferation, colony formation, and glycolytic reprogramming in vitro. In mouse models, hyperglycemia accelerates tumor growth, whereas treatment with the HK2 inhibitor lonidamine mitigates tumor progression in the hyperglycemic setting. Analysis of human bladder cancer specimens reveals that HK2 expression positively correlates with MYC and LDHA levels and associates with worse patient survival, particularly in patients with hyperglycemia. Collectively, our findings uncover a metabolic-transcriptional coupling pathway in which nuclear HK2 functions as a MYC cofactor to drive glycolysis and stemness under high-glucose conditions, and they suggest that targeting HK2 may represent a rational therapeutic strategy for patients with bladder cancer and coexisting hyperglycemia or diabetes.Hyperglycemia upregulates HK2 and promotes its nuclear localization in bladder cancer cells, where nuclear HK2 forms a complex with MYC to co-activate HK2 and LDHA transcription, thereby enhancing glycolysis, stemness, and tumor growth in hyperglycemic conditions.
    DOI:  https://doi.org/10.1038/s41419-026-08714-0
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