bims-stacyt Biomed News
on Metabolism and the paracrine crosstalk between cancer and the organism
Issue of 2026–03–01
seven papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge
  1. Tumor-Derived LIF Promotes GDF15-Driven Cachexia and Adverse Outcomes in Gastric Cancer.
  2. High Fat Diet and Obesity Each Increase Tumor Cell Proliferation and Muscle Wasting in Experimental Cancer Cachexia.
  3. NF-κB Signaling as a Central Driver of Cancer Cachexia.
  4. Circulating Inflammatory and Mitochondrial Biomarkers Associated with Cachexia in Advanced Non-Small Cell Lung Cancer.
  5. Coordinated stimulation of axon regenerative and neurodegenerative transcriptional programs by ATF4 following optic nerve injury.
  6. Stress-Induced ADGRL4 Orchestrates Tumor Progression and Metastasis by Inhibiting YAP1 Signaling and Activating Angiogenesis.
  7. Upregulation of Parathyroid Hormone Receptor 1 (PTH1R) in Non-Mechanostimulated Osteocytes Under High-Glucose Conditions Promotes a Macrophage Pro-Inflammatory and Osteoclastogenic Phenotype via IL-6 Secretion.
  1. Cells. 2026 Feb 16. pii: 355. [Epub ahead of print]15(4):
    Tumor-Derived LIF Promotes GDF15-Driven Cachexia and Adverse Outcomes in Gastric Cancer.
    Cristina Di Giorgio, Nicola Natalizi, Maria Rosaria Sette, Martina Bordoni, Benedetta Sensini, Ginevra Lachi, Eleonora Giannelli, Francesca Paniconi, Luigi Cari, Silvia Marchianò, Michele Biagioli, Elva Morretta, Maria Chiara Monti, Bruno Charlier, Fabrizio Dal Piaz, Angela Zampella, Eleonora Distrutti, Luigina Graziosi, Annibale Donini, Stefano Fiorucci.
      Cancer cachexia is a multifactorial metabolic syndrome characterized by progressive skeletal muscle and adipose tissue loss, systemic inflammation, and poor clinical outcomes, and represents a major unmet clinical need in gastric cancer. Growth Differentiation Factor 15 (GDF15) is a key mediator of cachexia-associated anorexia and tissue wasting; however, the upstream mechanisms regulating its expression in gastric cancer remain poorly defined. Leukemia Inhibitory Factor (LIF), a pleiotropic cytokine implicated in tumor progression and metabolic dysregulation, has emerged as a potential regulator of cachexia-related pathways. Here, we investigated the association between LIF in regulating GDF15 expression and its relationship with metabolic, inflammatory, and body composition alterations in gastric cancer. Transcriptomic profiling of paired neoplastic and non-neoplastic gastric mucosa from 61 gastric cancer patients revealed a significant upregulation of both LIF and GDF15 in tumor tissue, with a strong positive correlation between their expression levels. High GDF15 expression was associated with reduced overall survival, a finding validated in independent TCGA-STAD and ACRG cohorts. Intratumoral bile acid profiling uncovered a marked enrichment of primary bile acids and a depletion of secondary bile acids, resulting in reduced levels of bile acids with endogenous LIF receptor (LIFR) antagonist activity; elevated primary, LIFR non-antagonist bile acids were associated with worse survival outcomes. Clinically, increased LIF and GDF15 expression correlated with weight loss, heightened inflammatory burden, reduced serum protein and albumin levels, and impaired body composition in a sub-cohort of 19 patients. Notably, LIF expression showed a significant inverse association with both lumbar skeletal muscle index (L3SMI) and subcutaneous adipose tissue index (SATI). Mechanistically, experimental models demonstrated that LIF enhances proliferative activity in gastric cancer spheroids and exerts paracrine effects that impair myogenic differentiation and suppress hepatic metabolic gene expression. Collectively, these findings identify the LIF/GDF15 axis as a central driver of cancer-associated cachexia in gastric cancer and highlight LIF signaling as a potential therapeutic target.
    Keywords:  bile acids; cancer cachexia; gastric cancer; growth differentiation factor 15 (GDF15); leukemia inhibitory factor (LIF); metabolic remodeling; skeletal muscle wasting
    DOI:  https://doi.org/10.3390/cells15040355
  2. Am J Physiol Cell Physiol. 2026 Feb 21.
    High Fat Diet and Obesity Each Increase Tumor Cell Proliferation and Muscle Wasting in Experimental Cancer Cachexia.
    Brittany R Counts, Andrea Bonetto, Ho Lam Chan, Ernie D Au, Yanlin Jiang, Marion E Couch, Denis C Guttridge, Michael C Ostrowski, Leonidas G Koniaris, Teresa A Zimmers.
      High fat diet (HFD) and associated obesity are suggested to predispose to cancer development, complicate cancer treatment, and accelerate mortality. Paradoxically, obese patients with lung cancer are reported to live longer, suggesting that high body mass is protective. Given that cachexia-tumor-induced weight loss with adipose and muscle wasting-is prevalent in lung cancer, we speculated that obese patients might survive longer due to the protective effect of larger tissue reservoirs, slowing time to fatal wasting. Thus, we modeled this condition using lean and high fat diet (HFD)-induced obese mice with Lewis lung carcinoma (LLC) tumors versus non-tumor bearing controls. We also assessed the effects of feeding HFD to lean mice with and without LLC tumors. HFD and obese-HFD without tumors gained weight over the study, with obese HFD mice exhibiting low muscle mass with obesity at endpoint. Low fat diet (LFD)-fed lean mice with LLC tumors (LFD-LLC) showed no change in total body weight, but exhibited reduced skeletal muscle, heart, and fat pad mass along with hepatosplenomegaly at endpoint. HFD and pre-existing obesity both modified the response to Lewis lung carcinoma (LLC) tumors. HFD did not affect tumor-induced weight loss, fat loss, or tumor burden, but worsened loss of gastrocnemius, tibialis anterior, and heart muscle, prevented hepatosplenomegaly, and enhanced tumor cell proliferation and expression of the cachexia-inducing cytokine, Interleukin-6 (IL-6). Obese-HFD mice showed greater tumor burden versus LFD and the worst cachexia phenotypes, including greater weight loss and muscle loss than HFD or LFD. This worsened cachexia was associated with increased blood-born inflammatory cytokines, increased phosphorylated STAT3 in muscle, and increased IL-6 expression in muscle, spleen, and tumor. Obese-HFD was associated with the highest rate of tumor cell proliferation in vivo and serum from obese HFD mice increased LLC cell proliferation in vitro. Thus, HFD and pre-existing obesity each separately enhance inflammation, cachexia, and tumor growth. These distinct contributions of HFD and chronic adiposity are potential therapeutic targets to slow cachexia and tumor growth in cancer.
    Keywords:  Interleukin-6; cancer cachexia; high fat diet; obesity; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpcell.00545.2025
  3. Cancers (Basel). 2026 Feb 09. pii: 557. [Epub ahead of print]18(4):
    NF-κB Signaling as a Central Driver of Cancer Cachexia.
    Yan Li, Hao Jiang, Rui Chen, Haitao Huang, Shengguang Ding.
      Cancer cachexia is a multifactorial metabolic syndrome characterized by progressive skeletal muscle wasting, chronic systemic inflammation, and profound metabolic imbalance. Sustained activation of the nuclear factor κB (NF-κB) signaling pathway lies at the core of its pathogenesis, driving muscle proteolysis, impairing regenerative capacity, disrupting adipose tissue homeostasis, and promoting insulin resistance and anorexia. By transcriptionally regulating catabolic and pro-inflammatory gene programs across skeletal muscle, adipose tissue, the liver, and the central nervous system, NF-κB establishes a self-amplifying inflammatory-metabolic loop that perpetuates tissue wasting and systemic dysfunction. Accumulating preclinical and clinical evidence identifies NF-κB as a viable therapeutic target in cancer cachexia. Pharmacologic inhibitors (e.g., SR12343, DHMEQ), anti-inflammatory strategies (e.g., nonsteroidal anti-inflammatory drugs and IL-6 receptor-targeting antibodies), and nutritional interventions (e.g., omega-3 fatty acids) have shown efficacy in attenuating cachexia-associated inflammation, metabolic dysregulation, and tissue loss. Notably, emerging multimodal approaches integrating NF-κB modulation with metabolic support, chemotherapy, and behavioral interventions demonstrate synergistic benefits. This review integrates current mechanistic insights and therapeutic advances, highlighting NF-κB as a central pathogenic axis and a compelling target for translational intervention in cancer cachexia.
    Keywords:  NF-κB signaling; adipose tissue remodeling; cancer cachexia; muscle wasting; systemic inflammation; therapeutic targeting
    DOI:  https://doi.org/10.3390/cancers18040557
  4. Cancers (Basel). 2026 Feb 17. pii: 655. [Epub ahead of print]18(4):
    Circulating Inflammatory and Mitochondrial Biomarkers Associated with Cachexia in Advanced Non-Small Cell Lung Cancer.
    Kamya Sankar, Elham Kazemian, Nicole Lorona, Carlos D Cruz-Hernández, Alex K Bryant, Mitra Mastali, Akil A Merchant, Jennifer Van Eyk, Karen L Reckamp, Puneeth Iyengar, Neil A Bhowmick, Jane C Figueiredo.
      Background: Cancer-associated cachexia is a multifactorial metabolic syndrome characterized by progressive skeletal muscle and/or adipose tissue loss and affects approximately 40% of patients with non-small cell lung cancer (NSCLC). However, reliable circulating biomarkers for early detection and risk stratification remain undefined. Based on prior observations linking elevated circulating mitochondrial DNA (mtDNA) to cachexia, we hypothesized that mtDNA and inflammatory protein levels in plasma could predict cachexia onset and trajectories. Methods: We evaluated 27 patients with stage IV NSCLC enrolled in the SeroNet-CORALE cohort with plasma samples collected between 2020 and 2023. Forty biomarkers were quantified at two timepoints (T1 and T2) using a multiplexed MesoScale Discovery platform. Associations between log2-transformed biomarker levels and cachexia status were assessed using Firth's penalized logistic regression. Results: Among 27 patients (65% female; mean age 65 ± 10 years; 89% adenocarcinoma histology), cachectic patients exhibited lower body mass index at both time points (T1: 21.0 ± 2.0 vs. 27.0 ± 7.0; T2: 21.8 ± 4.9 vs. 25.2 ± 4.9). At T1, cachexia was strongly associated with elevated GDF15 (OR 4.29; 95% CI 1.04-29.74; p = 0.044) and IL-15 (OR 43.83; 95% CI 2.39->999; p = 0.007), whereas IL-4 had a protective association (OR 0.09; 95% CI 0.00-0.66; p = 0.013). At T2, cachexia was associated with higher mtDNA levels (OR 2.13; 95% CI 1.07-7.69; p = 0.022) and lower levels of IL-15, IL12/IL23p40, and MDC. Conclusions: Distinct inflammatory and mitochondrial biomarkers tracked cachexia evolution in advanced NSCLC, with early GDF-15/IL-15 elevations and later increases in circulating mtDNA. Larger longitudinal studies are warranted to validate these findings and define their clinical relevance.
    Keywords:  biomarkers; cachexia; mitochondrial DNA; non-small cell lung cancer
    DOI:  https://doi.org/10.3390/cancers18040655
  5. Elife. 2026 Feb 26. pii: RP87528. [Epub ahead of print]12
    Coordinated stimulation of axon regenerative and neurodegenerative transcriptional programs by ATF4 following optic nerve injury.
    Preethi Somasundaram, Madeline M Farley, Melissa A Rudy, Katya Sigal, Andoni I Asencor, David G Stefanoff, Malay Shah, Puneetha Goli, Jenny Heo, Shufang Wang, Nicholas M Tran, Trent A Watkins.
      Stress signaling is important for determining the fates of neurons following axonal insults. Previously, we showed that the stress-responsive kinase PERK contributes to injury-induced neurodegeneration (Larhammar et al., 2017). Here, we show that PERK acts primarily through activating transcription factor-4 (ATF4) to stimulate not only pro-apoptotic but also pro-regenerative responses following optic nerve damage. Using conditional knockout mice, we find an extensive PERK/ATF4-dependent transcriptional response that includes canonical ATF4 target genes and modest contributions by C/EBP Homologous Protein (CHOP). Overlap with c-Jun-dependent transcription suggests interplay with a parallel stress pathway that orchestrates regenerative and apoptotic responses. Accordingly, neuronal knockout of ATF4 recapitulates the neuroprotection afforded by PERK deficiency, and PERK or ATF4 knockout impairs optic axon regeneration enabled by disrupting the tumor suppressor PTEN. These findings reveal an integral role for PERK/ATF4 in coordinating neurodegenerative and regenerative responses to CNS axon injury.
    Keywords:  axon regeneration; integrated stress response; mouse; neurodegeneration; neuroscience; retinal ganglion cell
    DOI:  https://doi.org/10.7554/eLife.87528
  6. Cancer Res. 2026 Feb 24.
    Stress-Induced ADGRL4 Orchestrates Tumor Progression and Metastasis by Inhibiting YAP1 Signaling and Activating Angiogenesis.
    Yalan Wu, Mengdi Cao, Huixia Liu, Junfeng Zhang, Yanxue Mei, Guo Li, Fujun Dai, Xiaolong Tang.
      G-protein-coupled receptors (GPCRs) are cell surface signal transducers that regulate diverse physiological and pathological processes. Here, we identified the adhesion GPCR family member ADGRL4 as a key orchestrator of tumor adaptation to stress. Cellular stress induced ADGRL4 expression via the canonical JNK-ATF2/c-Jun pathway. Elevated ADGRL4 limited tumor expansion and enforced a tumor suppressive state, whereas its loss accelerated tumor growth and metastasis. Mechanistically, stress-induced shedding of the N-terminal fragment activated the C-terminal fragment of ADGRL4, which coupled with Gαs to stimulate cAMP-PKA signaling and consequently suppress YAP1 activity. In the absence of ADGRL4, hyperactivated YAP1 formed a transcriptional complex with β-catenin, reprogramming extracellular matrix (ECM) signaling to bypass tumor suppression and drive growth. Notably, while restraining tumor growth by compromising proliferative activity, stress-induced ADGRL4 simultaneously diminished chemosensitivity and promoted angiogenesis, thereby heightening relapse risk. Thus, ADGRL4 emerges as a stress sensor that integrates YAP1 signaling with tumor angiogenesis to govern the balance between tumor-suppressing and tumor-promoting states, providing mechanistic insight into therapy-induced tumor progression.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-4574
  7. Int J Mol Sci. 2026 Feb 09. pii: 1677. [Epub ahead of print]27(4):
    Upregulation of Parathyroid Hormone Receptor 1 (PTH1R) in Non-Mechanostimulated Osteocytes Under High-Glucose Conditions Promotes a Macrophage Pro-Inflammatory and Osteoclastogenic Phenotype via IL-6 Secretion.
    Irene Tirado-Cabrera, Joan Pizarro-Gomez, Eduardo Martin-Guerrero, Celia Méndez-Rodríguez, Teresita Bellido, Arancha R Gortazar, Juan A Ardura.
      Diabetes mellitus disrupts bone homeostasis, inducing bone fragility, through mechanisms involving chronic inflammation and altered cellular signaling. Osteocytes, the primary mechanosensory cells in bone, play a pivotal role in regulating bone remodeling via the secretion of factors that influence both osteoclast and osteoblast activity. We investigated the impact of high glucose on osteocytic parathyroid hormone receptor type 1 (PTH1R) expression and its downstream effects on interleukin-6 (IL-6) secretion, macrophage polarization, and osteoclastogenesis. Using both in vitro and ex vivo bone models, we demonstrate that elevated glucose levels in static conditions without mechanical stimulation induce the overexpression of PTH1R in osteocytes. PTH1R upregulation in turn enhances osteocytic IL-6 secretion associated with the promotion of a pro-inflammatory macrophage M1 phenotype (increased tumor necrosis factor (TNF)-α/CD206 and inducible nitric oxide synthase (iNOS)/CD206 ratios) and the upregulation of the pro-osteoclastogenic markers tartrate-resistant acid phosphatase (TRAP) and receptor activator of nuclear factor kappa-Β (RANK). Neutralization of IL-6 in the osteocytic secretome attenuated macrophage inflammatory gene overexpression, underscoring IL-6's critical role in this regulatory axis. Our findings reveal that a high-glucose environment triggers osteocytic dysregulation of PTH1R-mediated signaling pathways, amplifying inflammatory and osteoclastogenic activity in bone via IL-6. This osteocyte-macrophage crosstalk may contribute to the increased bone resorption and impaired regeneration observed in diabetic bone disease. Targeting PTH1R upregulation and the IL-6 signaling pathway in osteocytes could represent a novel therapeutic approach to mitigating bone complications associated with diabetes.
    Keywords:  IL-6; PTH1R; diabetes; high glucose; inflammation; macrophage; osteocyte; static osteocyte
    DOI:  https://doi.org/10.3390/ijms27041677
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