bims-stacyt 2026-01-25 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2026–01–25
thirteen papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

GDF15 in the tumor microenvironment: A central mediator of cancer immunometabolism and therapeutic resistance.
Distinct Metabolomic Alterations Are Associated With Physical Function, Weight Loss, and Muscle Mass in Men With Cancer.
Basal level of ATF4 promotes T cell readiness for activation-induced proliferation.
Glycolytic reprogramming of resident alveolar macrophages contributes to reduced SOCS3 secretion in non-small cell lung cancer.
The Integrated Stress Response in Cancer: Paradox and Therapeutic Promise.
IL-6 drives chemoimmunotherapy resistance in NSCLC by reprogramming myeloid cells and impairing cytotoxic lymphocyte function.
Role of Colorectal Cancer-Derived Exosomes in Modulating Macrophage Phenotypes During Tumor Development.
Regulatory role of mTORC1 signaling in osteoblasts in acute myeloid leukemia progression and steady-state hematopoiesis.
The purinergic signaling interfaces in breast cancer angiogenesis.
Angiogenic Potential of Small Extracellular Vesicles Produced by Stimulated Mesenchymal Stromal Cells Under Hypoxic Conditions.
ACSL5 Mediates Adaptation to the Palmitic Acid-Enriched Pulmonary Microenvironment to Enhance Metastatic Breast Cancer Cell Survival and Lung Metastasis.
Stc2a inhibits IGF-stimulated somatic growth in favor of organismal survival under hypoxic stress.
Mitochondrial Calcium Uniporter Drives Chemoresistance in Pancreatic Cancer via Glutathione-Mediated Stemness Maintenance.

Cytokine Growth Factor Rev. 2026 Jan 13. pii: S1359-6101(26)00004-3. [Epub ahead of print]88 47-57

GDF15 in the tumor microenvironment: A central mediator of cancer immunometabolism and therapeutic resistance.

Lingeng Lu, Caroline H Johnson, Sajid A Khan, Melinda L Irwin.

  Growth differentiation factor 15 (GDF15), a divergent member of the transforming growth factor-β (TGFβ) superfamily, has emerged as a pivotal cytokine linking cancer metabolism, immune suppression, and systemic energy balance. Initially characterized as a stress-induced cytokine with roles in appetite regulation and cachexia, GDF15 was first identified in activated macrophages and is also secreted by tumor cells, stromal cells and stressed epithelial cells across multiple tissues. Functionally, GDF15 exerts pleiotropic effects on both immune and nonimmune cell populations, modulating T cells, dendritic cells, and macrophages in the tumor microenvironment (TME), and metabolic tissues such as liver, adipose and muscle, thereby promoting tumor progression, therapeutic resistance, and cancer-associated metabolic dysregulation. In several human cancers of such as colorectal, pancreatic, breast and brain, elevated GDF15 levels correlate with poor prognosis, immune evasion, and chemoresistance. Mechanistically, GDF15 modulates fatty acid metabolism, promotes epithelial-mesenchymal transition, and suppresses anti-tumor immunity by impairing dendritic cell maturation and excluding CD8+ T cell infiltration. Targeting GDF15 may reprogram immunometabolic suppression and enhance checkpoint blockade efficacy. This review synthesizes current knowledge on GDF15's multifaceted roles in tumor biology, emphasizing its function as a central node of cancer immunometabolism. We highlight advances in spatial multi-omics, integrating transcriptomics and immune imaging, that reveal GDF15 spatially restricted immunosuppression in the tumor microenvironment.

Keywords:  Cancer immunotherapy; Colorectal cancer; GDF15; Immunometabolism; Obesity; Pancreatic cancer; Spatial metabolomics; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.cytogfr.2026.01.004
J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70183

Distinct Metabolomic Alterations Are Associated With Physical Function, Weight Loss, and Muscle Mass in Men With Cancer.

Lindsey J Anderson, Lu Xia, Haiming Kerr, Marin Cabrera, Fabien Chu, Jaqueline Rose, Peter C Wu, Atreya Dash, Sina A Gharib, Jose M Garcia.

   BACKGROUND: Treatments for cancer cachexia, defined as involuntary weight and muscle mass loss leading to significant functional impairment, remain unavailable partly due to insufficient improvement of clinically meaningful outcomes in current trials. By reflecting downstream effects of cellular function, metabolomics may identify mechanisms contributing to poor functional performance. Previous metabolomic studies in cancer cachexia have identified alterations in amino acid metabolism with weight loss or low muscularity; none have examined perturbations with poor physical function. We hypothesized that distinct metabolic signals in plasma and muscle are associated with weight loss, low muscle mass, and impaired function in cancer cachexia.
METHODS: We enrolled patients planning elective laparotomy for gastrointestinal or genitourinary cancer. Handgrip strength (HGS), stair climb power (SCP), and fasting plasma were collected within 2 weeks prior to surgery; rectus abdominis samples were obtained during surgery. Metabolomic perturbations associated with physical function (HGS, SCP), muscularity (lumbar cross-sectional area 'CSA' from opportunistic CT), or weight loss (> 5% over previous 6 months) were examined in plasma and muscle. The Mann-Whitney U-test compared metabolite abundance between weight-losing and weight-stable patients, while Spearman's correlation tested associations of abundance with CSA, HGS, or SCP. The 'Globaltest' method assessed pathway alterations with weight loss, CSA, HGS, or SCP; the Benjamini-Hochberg adjustment was used to control for false discovery.
RESULTS: Patients (N = 72) were male, median age 65 [interquartile range: 59-70], with 57% genitourinary cancer. Plasma and skeletal muscle metabolomic data were collected (N = 64 and N = 68, respectively). Weight loss was associated with significantly altered microbial, amino acid/derivative, fatty acid/lipid, and caffeine-related metabolism pathways in plasma (adjusted p < 0.1). Lower CSA was associated with significantly altered fatty acid/lipid, galactose, glycerophospholipid, and histidine metabolism and bile secretion pathways in skeletal muscle (adjusted p < 0.1). Worse HGS was nominally associated with altered plasma branched chain amino acid biosynthesis and altered skeletal muscle glutathione metabolism (unadjusted p ≤ 0.05), while worse SCP was nominally associated with altered skeletal muscle amino sugar/nucleotide sugar metabolism and phenylalanine, tyrosine, and tryptophan biosynthesis (unadjusted p ≤ 0.05).
CONCLUSIONS: Significant metabolomic alterations in plasma and skeletal muscle characterized cancer-related weight loss and reduced CSA, respectively. Nominal, function-specific alterations were detected with worse HGS and SCP, which were distinct from those associated with weight loss or low CSA. Future larger studies may further characterize metabolomic profiles related to various functional outcomes and guide development of therapeutic targets to improve functional performance.

Keywords:  cancer cachexia; functional impairment; handgrip; metabolomics; skeletal muscle; stair climb

DOI:  https://doi.org/10.1002/jcsm.70183
iScience. 2026 Jan 16. 29(1): 114277

Basal level of ATF4 promotes T cell readiness for activation-induced proliferation.

Yushan Yi, Ce Luo, Jingyi Wang, Yujia Wang, Lixue Jin, Xiuyuan Sun, Jie Hao, Guoping Deng, Rong Jin, Qing Ge.

  Stress-response elements are required during late-phase T cell activation and differentiation. To investigate whether they are indispensable during the first 12-24 h post-stimulation when mitochondrial activation and metabolic reprogramming are critical, we activated Atf4-sufficient and Atf4-deficient T cells and tracked their earliest activation dynamics. We demonstrate that T cell activation-induced mTOR and GCN2 phosphorylation leads to the upregulation of ATF4 protein as early as 12 h after stimulation. This early induction of ATF4 has transcriptional activities that regulate stress response, signaling, and metabolism. Loss of Atf4 in T cells alters transcriptome dynamics, impairs amino acid transport and biosynthesis, and disrupts adaptive responses to ER stress and oxidative stress, resulting in defective effector cell differentiation in vitro or in vivo. Our findings suggest that a basal level of ATF4 during the early phase of T cell activation enhances the preparedness of cells to cope with integrated stresses during the activation course.

Keywords:  Cell biology; Immunology

DOI:  https://doi.org/10.1016/j.isci.2025.114277
Front Immunol. 2025 ;16 1708467

Glycolytic reprogramming of resident alveolar macrophages contributes to reduced SOCS3 secretion in non-small cell lung cancer.

Jennifer M Speth, Mikel D Haggadone, Marc Peters-Golden.

  Alveolar macrophages (AMs), the resident immune cells of the lung, play a critical role in maintaining pulmonary homeostasis, in part through the secretion of suppressor of cytokine signaling 3 (SOCS3)-a recognized tumor suppressor-within extracellular vesicles (EVs). While we have previously observed that SOCS3 secretion by AMs is diminished in tumor-bearing lungs, the mechanisms underlying this impairment remain unclear. Here, we investigated whether increased glycolytic metabolism in AMs contributes to this defect within the tumor microenvironment. The analysis of published single-cell RNA-sequencing datasets from an orthotopic Lewis lung cancer (LLC) model of adenocarcinoma and non-small cell lung cancer (NSCLC) patients revealed distinct AM clusters in tumor-bearing lungs enriched for glycolysis-associated genes. In a Kras G12D mutant mouse model of lung cancer, we found that AMs isolated from tumor-bearing lungs exhibited increased glucose uptake, which inversely correlated with SOCS3 secretion. Importantly, the pharmacologic inhibition of glycolysis with 2-deoxy-d-glucose restored SOCS3 secretion in these AMs. Together, our findings demonstrate that lung tumor-associated AMs undergo a time-dependent metabolic shift toward glycolysis, resulting in impaired SOCS3 secretion-a phenotype that can be reversed by targeting glycolytic flux. These results highlight a potential therapeutic approach for modulating immune suppression in the tumor microenvironment.

Keywords:  SOCS3; alveolar macrophage; extracellular vesicles; glycolysis; lung cancer

DOI:  https://doi.org/10.3389/fimmu.2025.1708467
Compr Physiol. 2026 Feb;16(1): e70105

The Integrated Stress Response in Cancer: Paradox and Therapeutic Promise.

Chenliang Zhang, Ting Zhang, Qiulin Tang, Yu Zeng, Dan Cao.

  The integrated stress response (ISR) is an evolutionarily conserved signaling pathway that converges diverse cellular stresses onto the eIF2α-ATF4 axis, thereby orchestrating a fundamental decision between adaptive survival and cell death. In cancer, malignant cells exploit the ISR to cope with microenvironmental pressure, yet strong or persistent ISR activation can also trigger apoptosis, highlighting its therapeutic potential. However, this duality complicates the targeting of the ISR for cancer therapy. In this review, we systematically outline the upstream regulators and downstream effector networks of the ISR, analyze its context-dependent functions, encompassing both tumor-promoting and tumor-suppressing activities, in tumorigenesis, immune modulation, and therapy resistance, and evaluate the rationale for targeting the ISR under defined conditions. We also comprehensively summarize and discuss recent advances in ISR-targeting agents, including both inhibitors and activators, under preclinical and clinical development, assessing their potential and current constraints. Although numerous challenges remain in therapeutically harnessing the ISR, we conclude that a deeper mechanistic understanding of how the ISR governs cell fate will further establish the ISR as a promising and actionable target for future cancer therapeutics.

Keywords:  ATF4; apoptosis; drug resistance; eIF2α; integrated stress response; tumor immunotherapy; tumor therapy

DOI:  https://doi.org/10.1002/cph4.70105
Cancer Lett. 2026 Jan 17. pii: S0304-3835(26)00022-4. [Epub ahead of print] 218259

IL-6 drives chemoimmunotherapy resistance in NSCLC by reprogramming myeloid cells and impairing cytotoxic lymphocyte function.

Yaning Yang, Chengming Liu, Lu Yang, Sufei Zheng, Haiyan Xu, Shuyang Zhang, Linyan Tian, Nan Sun, Jie He, Yan Wang.

  Primary resistance to first-line chemoimmunotherapy remains a significant challenge in treating advanced non-small cell lung cancer (NSCLC). Although cytokines such as interleukin-6 (IL-6) have been implicated in resistance to immune checkpoint inhibitor (ICI) monotherapy, their predictive value for chemoimmunotherapy outcomes and the underlying mechanisms are less defined. This study investigated the prognostic significance of the baseline plasma IL-6 levels and the role of this cytokine in shaping the tumour immune microenvironment (TIME) of NSCLC. Here, We retrospectively analysed data on 123 advanced NSCLC patients treated with anti-PD-1 inhibitors plus chemotherapy. Baseline plasma IL-6 levels were measured via ELISA. Progression-free survival (PFS) and overall survival (OS) were assessed via Kaplan-Meier and Cox regression analyses. We established murine lung adenocarcinoma (LLC) and squamous cell carcinoma (KLN205) models with IL-6 overexpression (IL6a) or inhibition (IL6i) and treated them with anti-PD-1 therapy ± chemotherapy. Tumour growth was monitored, and single-cell RNA sequencing (scRNA-seq) was performed on tumour-infiltrating immune cells. The results showed that patients with high baseline plasma IL-6 levels (>7.002 pg/mL) exhibited significantly worse PFS (median: 7.20 vs. 16.63 months, P=0.001) and OS (median: 15.63 vs. 32.80 months, P=0.001) than those with low baseline levels. A high IL-6 level was an independent predictor of worse PFS (HR=2.42, P<0.001) and OS (HR=2.96, P<0.001) and was correlated with progressive disease (PD, P=0.018). In murine models, IL-6 overexpression diminished the antitumour efficacy of anti-PD-1 therapy combined with chemotherapy. Moreover, scRNA-seq analysis revealed that IL-6 overexpression skewed macrophage polarisation toward immunosuppressive phenotypes (characterised by Hilpda and Nr4a1 expression) and reduced the proportion of cytotoxic CD8+ T-cells while increasing the proportion of regulatory T-cells (Tregs). Conversely, IL-6 inhibition promoted an immunostimulatory macrophage phenotype (characterised by increased Ccl8 expression) and enhanced CD8+ T-cell infiltration and function. A high IL-6 level was also correlated with impairment of NK cell degranulation pathways. These findings uncovered that an elevated baseline plasma IL-6 level is a robust independent predictor of primary resistance and poor survival in advanced NSCLC patients receiving first-line chemoimmunotherapy. Mechanistically, IL-6 drives formation of an immunosuppressive TIME by promoting protumour macrophage polarisation. This, in turn, suppress cytotoxic T cell infiltration, promoting Treg expansion, and impairing NK cell function, indicating that the targeting of IL-6 represents a promising strategy to overcome resistance to chemoimmunotherapy.

Keywords:  IL-6; chemoimmunotherapy; immunosuppressive tumor microenvironment; non-small cell lung cancer; resistance

DOI:  https://doi.org/10.1016/j.canlet.2026.218259
Carcinogenesis. 2026 Jan 20. pii: bgag003. [Epub ahead of print]

Role of Colorectal Cancer-Derived Exosomes in Modulating Macrophage Phenotypes During Tumor Development.

Khandu Wadhonkar, Dhruv Das, Rajani Kant Chittela, Alexander G Obukhov, Mirza S Baig.

  Colorectal cancer (CRC) is one of the deadliest cancer types and is characterized by a complex tumor microenvironment (TME), which includes cancer and immune cells engaging in intricate signaling crosstalk. TME is dependent on the CRC stage and contributes to cancer aggressiveness and therapy resistance. It has been established that tumor-associated immune cells can support cancer progression. However, the underlying mechanisms are not fully elucidated. Here, we provide evidence that communication between CRC and immune cells, particularly tumor-associated macrophages (TAMs), occurs through the release of soluble factors and extracellular vesicles (EVs), such as exosomes. Our study reveals that TAMs initially recognize exosomes as foreign entities, triggering a pro-inflammatory response. Over time, however, the contents of these phagocytosed exosomes reprogram the TAMs into an anti-inflammatory, tumor-supportive phenotype. Our data indicate that such a phenotypic transition in CRC TAMs is primarily triggered by the activation of the NF-kB transcription factor, and that inhibiting NF-kB signaling may significantly decrease the tumor-supportive functions of TAMs in CRC. Thus, pharmacologically slowing the transition of CRC TAMs from pro-inflammatory to tumor-supportive states may be a promising strategy to reduce cancer aggressiveness.

Keywords:  Colorectal cancer; Exosomes; Macrophages polarization; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1093/carcin/bgag003
iScience. 2026 Jan 16. 29(1): 114533

Regulatory role of mTORC1 signaling in osteoblasts in acute myeloid leukemia progression and steady-state hematopoiesis.

Kazuya Fukasawa, Kazuya Tokumura, Makoto Yoshimoto, Koki Sadamori, Ioanna Mosialou, Yoshiaki Harakawa, Kazuto Isawa, Shohei Tsuji, Haruhiko Inufusa, Atsushi Hirao, Stavroula Kousteni, Eiichi Hinoi.

  Acute myeloid leukemia (AML) is widely recognized for its intrinsic leukemic-cell-driven regulation as well as its extrinsic niche-driven regulation. Despite mounting evidence that bone-forming osteoblasts provide an endosteal niche for AML cells, the precise mechanism remains to be elucidated. The cell-autonomous mammalian target of rapamycin complex 1 (mTORC1) is involved in the onset and progression of AML. Here, we found that mTORC1 signaling was activated in the osteoblasts of an AML murine model and clinical AML specimens. Osteoblast-specific mTORC1 activation in mice promotes AML growth, whereas mTORC1 inactivation suppresses it. Interleukin-6 (IL-6) was identified through screening as a downstream factor in mTORC1-regulated AML progression. Genetic ablation of the IL-6 receptor in AML cells significantly attenuated AML growth in osteoblast-specific mTORC1-activated mice. Collectively, our results suggest that the mTORC1/IL-6 axis in osteoblastic niche non-autonomously contributes to the AML progression, suggesting a viable therapeutic target for AML.

Keywords:  cancer; cell biology

DOI:  https://doi.org/10.1016/j.isci.2025.114533
Purinergic Signal. 2026 Jan 23. 22(1): 13

The purinergic signaling interfaces in breast cancer angiogenesis.

Fernanda Cardoso da Silva, Jeferson Stabile, Cristina Ribas Fürstenau, Thaise Gonçalves Araújo.

  Cancer is a group of diseases characterized by disordered cell proliferation and loss of tissue architecture. Breast cancer (BC) is the most common and lethal cancer among women, standing out for its molecular, histological and pathological heterogeneity. The BC tumor microenvironment (TME) is a complex ecosystem comprising transformed cells and a multitude of non-tumor cells, embedded in an altered extracellular matrix. Endothelial cells are present, driving angiogenesis, a relevant hallmark that ensures nutrition and oxygenation through the formation of new blood vessels. During this process, a complex network of molecules is released by tumor and endothelial cells, such as Vascular Endothelial Growth Factor (VEGF), that, in turn, induce cancer progression, diffusion, and metastasis. Purinergic signaling also regulates the functioning of endothelial cells involving the action of purines (ATP, ADP, UTP, UDP and adenosine) as signaling in purinergic receptors, with their concentration modulated by enzymes known as ectonucleotidases. This review aims to explore the contribution of purinergic signaling to BC angiogenesis, highlighting potential therapeutic targets currently under scientific focus. In general, the TME presents overexpression of ATP and adenosine, which stimulate endothelial cells through purinergic receptors. This stimulus promotes the formation of new vessels, mainly via the release of VEGF. Thus, purinergic signaling emerges as a central mechanism in BC angiogenesis, with potential to be explored in the development of antitumor therapies.

Keywords:  ATP; Adenosine; Anti-angiogenic; Breast cancer; Tumor angiogenesis

DOI:  https://doi.org/10.1007/s11302-025-10119-1
J Extracell Biol. 2026 Jan;5(1): e70105

Angiogenic Potential of Small Extracellular Vesicles Produced by Stimulated Mesenchymal Stromal Cells Under Hypoxic Conditions.

Nada Serhal, Bertrand Brassart, Lise Nannan, Sandra Audonnet, Christine Terryn, Gaël Poitevin, Pascale Cornillet-Lefebvre, Florine Dubuisson, Hélène Peyret, Philippe Nguyen, Claire Tournois.

  Regenerative vascular medicine research has positioned mesenchymal stromal cells (MSCs) as a leading candidate to treat ischemic diseases. Recent studies have highlighted the emerging role of small extracellular vesicles (sEVs) produced by MSCs in their own potential. This study explores a strategy to improve the angiogenic potential of MSCs through the acquisition of endothelial features. Umbilical cord Wharton's jelly MSCs were cultured in fetal bovine serum-free endothelial growth medium under hypoxic conditions (SH-MSCs). sEVs were characterised by a multimodal approach: visualisation, count and particle size distribution, sEVs surface antigen, proangiogenic potential and ability to internalise into recipient cells. Compared with MSCs, SH-MSCs exhibited significant morphological and phenotypical change characterised by the up-regulation of CD31 and CD144 mRNA as well as a marked increase in sEVs secretion. MSC- and SH-MSC-derived sEVs had the capacity to internalise into endothelial cells, myoblasts and macrophages; exhibited a strong proangiogenic effect in vitro, particularly in promoting endothelial cell proliferation and pseudotube formation, likely due to an enriched cargo of angiogenic factors. These results highlight the dual benefit of hypoxia conditioning and endothelial differentiation of MSCs to optimise the angiogenic potential of their secreted sEVs, thus paving the way for innovative regenerative therapies in ischemic diseases.

Keywords:  angiogenesis; cardiovascular diseases; hypoxia; mesenchymal stromal cells; small extracellular vesicles

DOI:  https://doi.org/10.1002/jex2.70105
Cancer Res. 2026 Jan 22.

ACSL5 Mediates Adaptation to the Palmitic Acid-Enriched Pulmonary Microenvironment to Enhance Metastatic Breast Cancer Cell Survival and Lung Metastasis.

Shanchun Chen, Chao Chang, Xiaoqi Liu, Rui Wang, Yongcan Liu, Die Meng, Boxuan Wang, Yuhang Hai, Chaoqun Deng, Yanran Tong, Xiaojiang Cui, Siyang Wen, Guobing Yin, Manran Liu.

Solid tumors frequently preferentially metastasize to specific organs. Metabolites within metastatic niches have emerged as critical regulators of organotropic metastasis. Here, we found that palmitic acid (PA) accumulated in both pre- and macro-metastatic lung niches. Lung-preferential metastatic breast cancer (LM-BC) cells secreted exosomal USP47 that was taken up by lung-resident alveolar type II epithelial cells (AT2) and enhanced fatty acid synthesis via YAP activation, resulting in PA enrichment and subsequent lung metastasis. ACSL5 in LM-BC cells facilitated PA adaptation by inducing COX2-mediated PGE2 accumulation and subsequent activation of the PI3K/AKT and ERK signaling pathways through EP4, which promoted cell survival and lung metastasis. Moreover, ACSL5 boosted levels of palmitoyltransferases, further enhancing COX2 expression, which could be inhibited by the palmitoylation inhibitor 2-bromopalmitate (2-BP). Notably, the enrichment of PA, accumulation of PGE2, and activation of the ACSL5/COX2/EP4 axis in lung metastases of BC patients correlated with poorer clinical outcomes. Limiting PA intake or targeting the ACSL5/COX2/EP4 axis enhanced paclitaxel efficacy in a breast cancer mouse model. Collectively, these findings highlight the critical role of PA and ACSL5/COX2/EP4 signaling in lung metastasis, which can act as promising targets for enhancing the efficacy of chemotherapy in BC patients with lung metastasis.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0866
Front Endocrinol (Lausanne). 2025 ;16 1729649

Stc2a inhibits IGF-stimulated somatic growth in favor of organismal survival under hypoxic stress.

Zhengyi Wang, Jinay Shah, Shuang Li, Shriya Jaggi, Hui Xu, Cunming Duan.

  In response to hypoxia, animals reduce somatic growth to shift energy resources toward the maintenance of vital functions and organismal survival. Although this phenomenon is widespread, the systemic factors and mechanisms involved remain poorly understood. Here we report that hypoxia causes major changes in zebrafish transcriptomic landscapes with hormonal activity or hormonal signaling identified as most prominently up-regulated GO term and KEGG pathway. Among the top in this group is Stanniocalcin 2a (Stc2a), a secreted glycoprotein that inhibits insulin-like growth factor (IGF) signaling by binding to pappalysin metalloproteinases and inhibiting their activities. The hypoxic induction of stc2a expression is attenuated in Hif2-deficient fish. Genetic deletion of Stc2a increased the developmental speed and growth rate, resulting in enlarged adult organ and body size. Under hypoxia, stc2a -/- fish grew faster than wild-type fish but showed reduced survival rate. These phenotypes were reversed by inhibiting pappalysin metalloproteinase activity and by blocking IGF signaling. These findings suggest that Stc2a limits IGF-mediated somatic growth in favor of survival and that the induction of Stc2a is part of a conserved mechanism regulating the trade-off between somatic growth and organismal survival under hypoxic stress.

Keywords:  IGF1 receptor; PAPP-A; hypoxia-inducible factor; insulin-like growth factor; stanniocalcin 2; zebrafish

DOI:  https://doi.org/10.3389/fendo.2025.1729649
Adv Sci (Weinh). 2026 Jan 21. e07346

Mitochondrial Calcium Uniporter Drives Chemoresistance in Pancreatic Cancer via Glutathione-Mediated Stemness Maintenance.

Zekun Li, Chenyang Meng, Guangcong Shen, Yueying Shan, Junjin Wang, Diliyaer Abudukeremu, Rui Zhao, Bo Ni, Chao Xu, Xiaofan Guo, Jun Yu, Kaiyuan Wang, Shengyu Yang, YunZhan Li, Yongjie Xie, Tianxing Zhou, Jihui Hao, Xiuchao Wang.

  Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with poor prognosis due to chemoresistance. Using integrative single-cell RNA sequencing, we identified that the upregulation of mitochondrial calcium uniporter (MCU) may contribute to chemoresistance and stemness maintenance in PDAC. MCU was highly expressed in chemotherapy-resistant PDAC tumors and correlated with enhanced cancer stem cell properties. Mechanistically, MCU-mediated mitochondrial Ca2+ influx triggered endoplasmic reticulum (ER) stress and the downstream PERK-eIF2α pathway. This cascade activated ATF4 and NRF2, which enhanced the transcriptional regulation of PSAT1 and SLC7A11. These changes promoted de novo glutathione (GSH) synthesis to scavenge reactive oxygen species (ROS) and sustain stemness. Genetic knockdown or pharmacological inhibition of MCU disrupted GSH synthesis, suppressed stemness, and restored sensitivity to nab-paclitaxel plus gemcitabine (AG). High-throughput screening identified MCU inhibitor NB-598, which synergized with AG to inhibit tumor growth in preclinical models. These findings offer a potential novel therapeutic strategy to address chemoresistance in PDAC.

Keywords:  chemoresistance; glutathione synthesis; mitochondrial calcium uniporter; pancreatic ductal adenocarcinoma; stemness maintenance

DOI:  https://doi.org/10.1002/advs.202507346