bims-stacyt 2026-04-19 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2026–04–19
eight papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

Cancer cachexia: A tumor-driven disorder of whole-body homeostasis.
Optogenetic Control of the Integrated Stress Response Limits Glioblastoma Invasion.
GFRAL is required to mediate changes in systemic metabolism in response to mitochondrial stress in brown adipose tissue.
Hypoxic microenvironment in cancer: role in metabolic reprogramming.
Intrinsic Tumor Aggressiveness Dictates Hypoxia-Driven Metabolic Programs in Hepatocellular Carcinoma.
PBK-Loaded secretory autophagosomes drive radiotherapy-induced systemic adipose depletion via MAPK/ERK-PRKA/PKA-LIPE/HSL signaling: a therapeutic target for esophageal cancer cachexia.
Metabolite import by SLC33A1 is required for ATF6 activation during endoplasmic reticulum stress.
Fatty acids in the tumor microenvironment reprogram neutrophils to induce immunosuppression via adenosine.

Cancer Cell. 2026 Apr 16. pii: S1535-6108(26)00166-2. [Epub ahead of print]

Cancer cachexia: A tumor-driven disorder of whole-body homeostasis.

Yuqing Zhang, Ryan D Nipp, Tobias Janowitz, Yi-Ping Li, Denis C Guttridge, Min Li.

  Cancer cachexia is a systemic metabolic syndrome driven by tumor-induced disruption of whole-body homeostasis. Characterized by skeletal muscle atrophy and adipose tissue loss, cachexia leads to functional decline, impaired quality of life, reduced treatment tolerance, and poor survival across multiple malignancies. Emerging evidence indicates that cachexia arises from complex and dynamic interactions between tumors and host organ systems, including immune, metabolic, endocrine, and neural networks, that collectively reshape energy balance, immune function, and tissue integrity. Despite its profound clinical impact, effective therapies remain limited, reflecting incomplete mechanistic understanding and the absence of integrated clinical frameworks. Here, we review recent advances in cachexia biology, including tumor-host signaling, multiorgan metabolic remodeling, and neuroendocrine regulation. We further propose a tumor-centric framework in which cachexia represents a progressive collapse of systemic homeostasis and outline translational strategies to guide mechanism-informed therapeutic interventions.

Keywords:  adipose tissue loss; anorexia; cancer cachexia; energy balance; metabolic reprogramming; neuroendocrine regulation; skeletal muscle wasting; systemic inflammation; tumor-host interactions; whole-body homeostasis

DOI:  https://doi.org/10.1016/j.ccell.2026.03.012
Cell Biochem Funct. 2026 Apr;44(4): e70212

Optogenetic Control of the Integrated Stress Response Limits Glioblastoma Invasion.

Lisa K Månsson, Ethan Dickson, Lun Hao, Angela A Pitenis, Maxwell Z Wilson.

  The integrated stress response (ISR) is a highly conserved signaling network, allowing cells to adapt and respond to various stressors. With its aggressive spread and high recurrence rates, glioblastoma multiforme (GBM) is one of the toughest cancers to date, yet the role of the ISR is still to be well understood, whether activation may suppress or promote this disease, and drug-treatment of GBM has thus far shown inconclusive results. In this work, we use an optogenetic tool, opto-PKR, to specifically trigger ISR activation via light-induced oligomerizing PKR-kinases, offering high spatiotemporal and reversible control, while avoiding potential upstream damage or side effects from drugs. Using immunofluorescence and RNA-sequencing, we show that targeted ISR activation reaching levels where both adaptive (ATF4) and terminal responses (CHOP) are activated results in subsequent downregulation of genes associated with the extracellular environment and glial cell migration, further supported by ECM-stain and scratch assays. Next, we show inhibition of aggressive spread for ISR-activated GBM spheroids in collagen 3D culture. Photopatterning of ISR activation in spheroids demonstrates a cell-intrinsic effect at the tissue scale, and recovery studies indicate a tunable, non-ablative intervention space. These findings suggest a route to containment and motivate ISR-activating small molecule screening in GBM models.

Keywords:  3D Culture; Opto‐PKR; cancer; cell migration; therapeutics

DOI:  https://doi.org/10.1002/cbf.70212
J Mol Med (Berl). 2026 Apr 14. pii: 64. [Epub ahead of print]104(1):

GFRAL is required to mediate changes in systemic metabolism in response to mitochondrial stress in brown adipose tissue.

Ayushi Sood, Joshua Peterson, Jayashree Jena, Vamsi Challa, Caden Washburn, Randy J Seeley, Renata O Pereira.

  Growth differentiation factor 15 (GDF15) is a cytokine induced in several tissues in response to stress. GDF15 suppresses food intake and increases energy expenditure via its actions on the glial-derived neurotrophic factor receptor α family-like specific receptor (GFRAL), located in the hindbrain. We recently showed that selective deletion of the mitochondrial fusion protein optic atrophy 1 (OPA1) in brown adipocytes (OPA1 BKO) leads to GDF15 secretion, partially mediating resistance to diet-induced obesity (DIO), and improving thermoregulation. To investigate whether GDF15 signaling through GFRAL is necessary to mediate these metabolic effects, we crossed OPA1 BKO mice with GFRAL global knockout mice (DKO). Under isocaloric conditions, DKO mice had similar body weight as control and OPA1 BKO mice. Upon high-fat diet feeding, DKO mice were partially resistant to DIO, but lacked the improvement in glucose homeostasis and insulin sensitivity observed in OPA1 BKO mice. Finally, DKO mice were susceptible to cold-induced hypothermia, suggesting a role for GFRAL in core body temperature regulation in the OPA1 BKO mice. Our data reveals a novel BAT-GDF15-GFRAL axis that modulates resistance to DIO and improves thermoregulation in mice in the context of mitochondrial stress. KEY MESSAGES: OPA1 deletion induces a BAT-GDF15-GFRAL axis to regulate systemic metabolic homeostasis. GDF15-signaling through GFRAL partially mediates resistance to DIO in mice lacking OPA1 in BAT. GFRAL mediates GDF15's effects on energy homeostasis in DIO OPA1 BKO mice. GDF15-GFRAL signaling is required to maintain core body temperature in cold-exposed OPA1 BKO mice.

Keywords:  Brown adipose tissue; GDF15; GFRAL; OPA1; Obesity; Thermoregulation

DOI:  https://doi.org/10.1007/s00109-026-02671-z
Front Oncol. 2026 ;16 1771365

Hypoxic microenvironment in cancer: role in metabolic reprogramming.

Niti Sureka, Rashi Maheshwari, Amit Agravat, Shweta Singhal, Shamsuz Zaman, Bhavika Rishi, Fouzia Siraj, Sufian Zaheer, Aroonima Misra.

  Hypoxia, a defining hallmark of solid tumors, arises from structurally and functionally abnormal vasculature, rapid cellular proliferation, and impaired perfusion, resulting in chronic and cycling oxygen deprivation within the tumor massThe hypoxic tumor microenvironment orchestrates extensive molecular reprogramming primarily through stabilization and activation of hypoxia-inducible factors (HIF-1α and HIF-2α), which regulate broad transcriptional networks governing metabolism, angiogenesis, stemness, invasion, and immune modulation. Under low oxygen tension, tumor cells shift toward aerobic glycolysis, enhance glutamine utilization, promote lipid synthesis and storage, suppress mitochondrial oxidative phosphorylation, and fine-tune redox balance through coordinated regulation of ROS-generating and antioxidant systems. These adaptations not only sustain proliferation and survival under metabolic stress but also facilitate epithelial-mesenchymal transition, extracellular matrix remodeling, and metastatic dissemination. Beyond malignant cells, hypoxia reprograms stromal compartments-including cancer-associated fibroblasts, endothelial cells, tumor-associated macrophages, and myeloid-derived suppressor cells-thereby establishing a metabolically cooperative, angiogenic, and profoundly immunosuppressive microenvironment. Hypoxia-induced acidosis, lactate accumulation, and HIF-driven cytokine signaling further impair cytotoxic T-cell and NK-cell activity, contributing to immune escape and resistance to radiotherapy, chemotherapy, and immunotherapy. Emerging evidence from single-cell multi-omics, spatial transcriptomics, metabolic imaging, and early-phase clinical trials targeting HIF signaling, angiogenic pathways, and metabolic enzymes has uncovered actionable vulnerabilities in hypoxia-driven malignancies. This review synthesizes the mechanistic foundations of hypoxia-induced metabolic reprogramming, its role in tumor progression and therapeutic resistance, and discusses innovative strategies aimed at exploiting hypoxia-associated metabolic dependencies to advance precision oncology.

Keywords:  Warburg effect; hypoxia; hypoxia-inducible factors (HIFs); immune evasion; metabolic reprogramming; mitochondrial metabolism; tumor microenvironment (TME)

DOI:  https://doi.org/10.3389/fonc.2026.1771365
Int J Mol Sci. 2026 Mar 27. pii: 3069. [Epub ahead of print]27(7):

Intrinsic Tumor Aggressiveness Dictates Hypoxia-Driven Metabolic Programs in Hepatocellular Carcinoma.

Fabiola Milosa, Nicolò Giglioli, Rosina Maria Critelli, Francesco Dituri, Grazia Serino, Serena Mancarella, Erica Villa.

  Hypoxia, a hallmark of hepatocellular carcinoma (HCC), regulates metabolic reprogramming, tumor progression, and therapy resistance. Although hypoxia-induced glycolytic changes are recognized, it remains unclear how intrinsic tumor aggressiveness influences the magnitude and plasticity of metabolic and transcriptional responses to oxygen deprivation. In this study, we investigated the effects of chronic hypoxia (1% O2 for 48 h) in spheroids generated from two immortalized (HepG2, Hep3B) and two patient-derived HCC cell lines with distinct aggressiveness (HLC19, HLC21). The metabolic activity, energetic status, proliferation, and expression of hypoxia- and metabolism-related genes were assessed, with oxygen levels monitored to validate experimental conditions. It has resulted that immortalized HCC spheroids displayed similar metabolic and transcriptional responses to hypoxia, with enhanced glycolytic activity but limited phenotypic plasticity. Primary HCC spheroids exhibited aggressiveness-dependent differences. Aggressive HLC19 cells showed a pre-established glycolytic phenotype, stable ATP levels, sustained proliferation, and minimal transcriptional remodeling under hypoxia. Less aggressive HLC21 cells relied on the delayed glycolytic activation and induction of hypoxia-responsive genes to maintain viability. Clustering analyses indicated that metabolic strategies, rather than absolute activity, aligned with tumor aggressiveness. These findings suggest that intrinsic tumor aggressiveness shapes hypoxia-driven metabolic programs in HCC and supports the relevance of patient-derived 3D models for studying metabolic adaptation.

Keywords:  glycolysis; hepatocellular carcinoma; hypoxia; metabolic reprogramming; patient-derived spheroids; tumor aggressiveness

DOI:  https://doi.org/10.3390/ijms27073069
Autophagy. 2026 Apr 16.

PBK-Loaded secretory autophagosomes drive radiotherapy-induced systemic adipose depletion via MAPK/ERK-PRKA/PKA-LIPE/HSL signaling: a therapeutic target for esophageal cancer cachexia.

Zhikai Li, Yibin Jia, Xin Chen, Guoyu Li, Zhuo Li, Hongjiao Wang, Tingting Yang, Anjing Chen, Jianbo Wang.

  Radiotherapy, while a cornerstone treatment for esophageal squamous cell carcinoma (ESCC), is paradoxically associated with significant weight loss that portends poor patient outcomes. The mechanisms driving this metabolic complication remain elusive. Here, we identified adipose depletion - rather than muscle atrophy - as the primary contributor to radiotherapy-induced weight loss in ESCC. We demonstrated that secretory autophagosomes (SAPs) released post-irradiation mediate systemic fat loss through integrated in vitro and in vivo studies. Proteomic profiling revealed enrichment of PBK (PDZ binding kinase) in radiation-induced SAPs, with functional studies establishing PBK as the master regulator of adipocyte lipolysis. Mechanistically, SAP-delivered PBK activated MAPK1/ERK2 (mitogen-activated protein kinase 1), triggering a downstream PRKA/PKA-LIPE/HSL signaling cascade that increases lipolytic rate. Clinically, elevated circulating SAPs levels predicted severe fat loss and reduced median survival in a ESCC cohort. Critically, pharmacological inhibition of PBK with OTS-514 rescued adipose mass in preclinical models while enhancing tumor radiosensitivity. Our work redefines radiotherapy-induced cachexia as an adipose-centric process orchestrated by SAPs, unveils PBK as a therapeutic target, and provides actionable biomarkers for early intervention. These findings bridge the gap between localized radiotherapy and systemic metabolic sequelae, offering a dual-strategy approach to improve both survival and quality of life in ESCC patients.

Keywords:  Cachexia; PDZ binding kinase; esophageal squamous cell carcinoma; lipolysis; radiation-induced abscopal effect; secretory autophagosomes

DOI:  https://doi.org/10.1080/15548627.2026.2661313
Life Sci Alliance. 2026 Jun;pii: e202603679. [Epub ahead of print]9(6):

Metabolite import by SLC33A1 is required for ATF6 activation during endoplasmic reticulum stress.

Ginto George, Heather P Harding, Richard Kay, David Ron, Adriana Ordoñez.

The transcription factor ATF6α has a central role in adapting mammalian cells to ER stress via the unfolded protein response (UPR), prompting efforts to identify ATF6α modulators. Here, an unbiased genome-wide CRISPR-Cas9 screen performed in Chinese Hamster Ovary cells revealed that proteolytic processing of the ATF6α precursor to its active form was impaired in cells lacking the ER-resident solute carrier SLC33A1, a transporter previously implicated in acetyl-CoA import, sialylation, and Nε-lysine protein acetylation. Cells lacking SLC33A1 constitutively trafficked the ATF6α to the Golgi but exhibited impaired Golgi processing and activating proteolysis. IRE1α signalling was derepressed by SLC33A1 deficiency consistent with selective loss of ATF6α-mediated negative feedback in the UPR. Slc33a1-deleted cells accumulated unmodified sialylated N-glycans, precursors to acetylated glycans, likely reflecting impaired glycan processing. Deletion of ER-localised acetyltransferases NAT8 and NAT8B, which catalyse protein Nε-lysine acetylation in the secretory pathway, did not replicate the ATF6α processing defects observed in Slc33a1-deficient cells. Together, our findings highlight a role of SLC33A1-mediated metabolite transport in the post-ER ATF6α maturation, linking small-molecule metabolism to branch-specific signalling in the UPR.

DOI: https://doi.org/10.26508/lsa.202603679
bioRxiv. 2026 Apr 06. pii: 2026.04.02.716169. [Epub ahead of print]

Fatty acids in the tumor microenvironment reprogram neutrophils to induce immunosuppression via adenosine.

Rashi Singhal, Nina W Zhang, Zheng Hong Lee, Hannah N Bell, Prarthana J Dalal, Sumeet Solanki, Wesley Huang, Ryan Rebernick, Peter Sajjakulnukit, Himani Jasewicz, Roshan Kumar, Nikhil K Kotla, Amanda Huber, Anitha Vijay Mallappa, Subhash B Arya, Shogo Takahashi, Carlos Ichiro Kasano-Camones, Eileen Carpenter, Marina Pasca di Magliano, James J Moon, Carole A Parent, Frank J Gonzalez, Andrew D Patterson, Michael D Green, Weiping Zou, Elena M Stoffel, Costas A Lyssiotis, Yatrik M Shah.

As solid tumors progress, the tumor microenvironment (TME) becomes increasingly immunosuppressive, impairing cytotoxic T-cell activity and limiting the efficacy of the immune checkpoint blockade. However, the mechanistic drivers of this immunosuppression remain poorly understood. Here, we identify a tumor-derived lipid-neutrophil-adenosine axis as a critical regulator of immune suppression in advanced colorectal cancer (CRC). We show that fatty acids enriched in tumor interstitial fluid reprogram neutrophils to generate adenosine via PPARα activation, leading to T-cell suppression. Using AB928, a dual A2aR/A2bR adenosine receptor antagonist currently in clinical trials, we restored T-cell proliferation, effector function, and tumor-killing capacity in vitro and in vivo. Importantly, AB928 synergized with anti-PD-1 therapy to enhance survival in an autochthonous model of metastatic CRC. Our findings define a metabolic immune evasion mechanism in the TME and provide a rationale for targeting neutrophil-derived adenosine signaling to improve immunotherapy responses in CRC and other solid tumors.

DOI: https://doi.org/10.64898/2026.04.02.716169