bims-cagime 2026-01-04 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2026–01–04
33 papers selected by
Kıvanç Görgülü, Technical University of Munich

Lung Metastases in Pancreatic Cancer: Timing Their First Breath.
Adaptation to cystine limitation stress confers a targetable lipid metabolism vulnerability in pancreatic ductal adenocarcinoma.
FSP1 and histone deacetylases suppress cancer persister cell ferroptosis.
The cell biologist's guide to detecting and modulating membrane phospholipids.
Surface Morphometrics reveals local membrane thickness variation in organellar subcompartments.
Mechanistic insights make cancer cachexia a targetable syndrome.
TFEB coordinates autophagosome biogenesis and ribophagy during starvation via SQSTM1.
NF2 loss malignantly transforms human pancreatic acinar cells and enhances cell fitness under environmental stress.
Lipidomic changes in persister cancer cells drive enhanced ferroptosis sensitivity.
Netrin-1 Promotes Pancreatic Tumorigenesis and Innervation through NEO1.
p62 sorts Lupus La and selected microRNAs into breast cancer-derived exosomes.
Role of N-glycosylation as a determinant of ATG9A conformations and activity.
Spatial omics at the forefront: emerging technologies, analytical innovations, and clinical applications.
An interactive resource mapping the proteome and reactive cysteine landscape across the NCI-60 reveals cell and tissue-specific profiles.
Splice-switching ASOs targeting the AURKA 5' UTR collapse an SRSF1-AURKA-MYC oncogenic circuit in pancreatic cancer.
The membrane transition strongly enhances biopolymer condensation through prewetting.
Aspartate Transaminases Are Dispensable for Pancreatic Development and Pancreatic Cancer Progression.
Detection of Ferroptosis by Liperfluo and BODIPY™ 581/591 C11.
Repair of damaged lysosomes by TECPR1-mediated membrane tubulation during energy crisis.
A simple, anesthesia-free infusion technique for in vivo metabolic tracing.
Decrypting the impact of ferroptosis and cuproptosis in development of pancreatic ductal adenocarcinoma.
Trade-off between branching and polarity controls decision-making during cell migration.
Adaptive Cytoskeletal Responses to Extracellular Environment Viscosity Modulate Cell Migration.
Cell-DINO: Self-supervised image-based embeddings for cell fluorescent microscopy.
Spatial Mapping of PUFA Incorporation into Phospholipids with bisallylic deuteration.
Proximity Ligation Assay to Detect Protein-Protein Interaction in Cancer Cells.
CHAMP1 complex promotes heterochromatin assembly and reduces replication stress.
Methods for Measuring TNFα-Induced Autophagy in Cancer Cells.
DEAF1 - a transcriptional brake on muscle autophagy.
The Concise Guide to PHARMACOLOGY 2025/26: G protein-coupled receptors.
Multi-Organ Collection from Mouse Models for Aging Studies.
Biophysical adaptations of circulating tumor cells undergoing metastasis.
Loss of p62 Binding Allows TIF-IA Accumulation in Senescence, Which Promotes Phenotypic Changes to Nucleoli and the Senescence Associated Secretory Phenotype.

Cancer Res. 2026 Jan 02. 86(1): 7-9

Lung Metastases in Pancreatic Cancer: Timing Their First Breath.

Gianluca Mucciolo, Giulia Biffi.

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor survival rate. This is largely due to patients being diagnosed when the disease has already metastasized to other organs, most commonly the liver and lungs. For these patients, no effective treatment exists, and the 5-year survival rate is less than 5%. Despite its highly metastatic nature, the timing and mechanisms of metastasis formation in PDAC remain largely unknown. In this issue of Cancer Research, Lasse Opsahl and colleagues identify a role for premalignant pancreatic intraepithelial neoplasia (PanIN) lesions in lung premetastatic niche formation. By performing histology and single-cell RNA sequencing analyses of a KRASG12D inducible mouse model of PDAC, the authors identify pSTAT3+ fibroblasts in the lungs, but not the liver, upon PanIN formation. Notably, pSTAT3+ fibroblasts in the lungs are required for metastasis formation. Mechanistically, KRAS activation in the pancreatic epithelium and consequential IL6 release activate STAT3 in lung fibroblasts. Altogether, Lasse Opsahl and colleagues demonstrate that PanIN lesions prime the lungs to favor future malignant cell outgrowth before the development of a pancreatic tumor and that blocking the formation of this lung premetastatic niche impairs metastasis in mice. See related article by Lasse Opsahl et al., p. 22.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-4465
Nat Commun. 2025 Dec 31.

Adaptation to cystine limitation stress confers a targetable lipid metabolism vulnerability in pancreatic ductal adenocarcinoma.

Yunzhan Li, Zekun Li, Qin Li, Dongxiao Sun, Bo Ni, Mingjun Tan, Ashley E Shay, Min Wang, Chenyang Meng, Guangcong Shen, Boyang Fu, Yueying Shan, Shiqi Zhang, Rifah Rownak Tanshee, Tianxing Zhou, Yongjie Xie, Kun-Ming Chen, Bin Qiao, Yunkun Dang, Scot R Kimball, Guanshi Zhang, Girish H Rajacharya, Pankaj K Singh, Xiuchao Wang, Jihui Hao, Shengyu Yang.

Cystine/cysteine is critical for antioxidant response and sulfur metabolism in cancer cells and is one of the most depleted amino acids in the microenvironment of pancreatic ductal adenocarcinoma (PDAC). The effects of cystine limitation stress (CLS) on PDAC progression are poorly understood. Here we report that adaptation to CLS (CLSA) promotes PDAC cell proliferation and tumor growth through translational upregulation of the oxidative pentose phosphate pathway (OxPPP). OxPPP activates the de novo synthesis of nucleotides and fatty acids to support tumor growth. On the other hand, CLSA-mediated lipidomic reprogramming depends on triacylglycerides synthesis and lipid droplet formation to mitigate lipotoxicity. Through drug screening, we identify lomitapide as an inhibitor of CLSA PDAC tumor growth and a potent sensitizer of chemotherapy. Lomitapide inhibits triacylglycerides synthesis to interfere with CLSA and chemotherapy-induced lipidomic reprogramming. Taken together, we demonstrate that CLSA promotes PDAC tumor growth through metabolic reprogramming and lomitapide could be used to target the dysregulated lipid metabolism in PDAC.

DOI: https://doi.org/10.1038/s41467-025-68099-0
Sci Adv. 2026 Jan 02. 12(1): eaea8771

FSP1 and histone deacetylases suppress cancer persister cell ferroptosis.

Masayoshi Higuchi, August F Williams, Anna E Stuhlfire, Ariel H Nguyen, David A G Gervasio, Claire E Turkal, Suejean Chon, Matthew J Hangauer.

Cancer persister cells which survive oncogene targeted therapies are sensitized to ferroptosis, but mechanistic understanding of this vulnerability remains limited. Here, we found that while levels of iron, glutathione, and various ferroptosis-suppressing enzymes vary among persister cell types, ferroptosis suppressor protein 1 (FSP1) is down-regulated in multiple persister cell types, and persister cells which survive glutathione peroxidase 4 (GPX4) inhibition rely on residual FSP1 to survive. Furthermore, persister cells which survive GPX4 inhibition down-regulate oxidative phosphorylation, a key source of mitochondrial reactive oxygen species which are required for persister cell ferroptosis. We also found that persister cell treatment with histone deacetylase inhibitors induces reactive oxygen species and sensitizes multiple persister cell types to GPX4 inhibition. Together, these findings reveal that FSP1 and histone deacetylases suppress persister cell ferroptosis.

DOI: https://doi.org/10.1126/sciadv.aea8771
J Cell Biol. 2026 Feb 02. pii: e202508058. [Epub ahead of print]225(2):

The cell biologist's guide to detecting and modulating membrane phospholipids.

Michael Worcester, Morgan M C Ricci, Claire C Weckerly, Jesus G Calixto, Gerald R V Hammond.

Molecular biology has benefited enormously from repurposed tools-many enzymes and antibodies evolved for other functions but are now essential for interrogating biological function by manipulating proteins or nucleic acids. In contrast, lipids have remained technically difficult to visualize or manipulate in cells. This review introduces tools that bring lipid biology into reach for molecular cell biologists, using familiar experimental approaches. We first describe adaptations of immunofluorescence and live-cell imaging of fluorescent molecules to track lipids. Then, we discuss tools for manipulating lipid levels, including pharmacologic inhibitors, synthetic biology platforms for inducible lipid generation or degradation, and optogenetic systems for precise temporal control. While some methods remain technically demanding, most tools are now broadly accessible. Our goal is to offer a practical framework for integrating lipid biology into mainstream cell biology experiments.

DOI: https://doi.org/10.1083/jcb.202508058
J Cell Biol. 2026 Mar 02. pii: e202505059. [Epub ahead of print]225(3):

Surface Morphometrics reveals local membrane thickness variation in organellar subcompartments.

Michaela Medina, Ya-Ting Chang, Hamidreza Rahmani, Mark Frank, Zidan Khan, Daniel Fuentes, Frederick A Heberle, M Neal Waxham, Benjamin A Barad, Danielle A Grotjahn.

Lipid bilayers form the basis of organellar architecture, structure, and compartmentalization in the cell. Decades of biophysical, biochemical, and imaging studies on purified or in vitro-reconstituted liposomes have shown that variations in lipid composition influence the physical properties of membranes, such as thickness and curvature. However, similar studies characterizing these membrane properties within the native cellular context have remained technically challenging. Recent advancements in cellular cryo-electron tomography (cryo-ET) imaging enable high-resolution, three-dimensional views of native organellar membrane architecture preserved in near-native conditions. We previously developed a "Surface Morphometrics" pipeline that generates surface mesh reconstructions to model and quantify cellular membrane ultrastructure from cryo-ET data. Here, we expand this pipeline to measure the distance between the phospholipid head groups of the membrane bilayer as a readout of membrane thickness. Using this approach, we demonstrate thickness variations both within and between distinct organellar membranes. We show that organellar membrane thickness positively correlates with other features, such as membrane curvedness, in cells. Further, we show that subcompartments of the mitochondrial inner membrane exhibit varying membrane thicknesses that are independent of whether the mitochondria are in fragmented or elongated networks. We also demonstrate that our technique, when applied to three-dimensional data, yields results that match existing measurements obtained from two-dimensional data of in vitro samples. Finally, we demonstrate that large membrane-associated macromolecular complexes exhibit distinct density profiles that correlate with local variations in membrane thickness. Overall, our updated Surface Morphometrics pipeline provides a framework for investigating how changes in membrane composition in various cellular and disease contexts affect organelle ultrastructure and function.

DOI: https://doi.org/10.1083/jcb.202505059
Nat Med. 2026 Jan 02.

Mechanistic insights make cancer cachexia a targetable syndrome.

Ed Reznik, Martin H Voss, A Ari Hakimi.

DOI: https://doi.org/10.1038/s41591-025-04109-4
Sci Adv. 2026 Jan 02. 12(1): eaea9302

TFEB coordinates autophagosome biogenesis and ribophagy during starvation via SQSTM1.

Maria Iavazzo, Laura Cinque, Sophie Levantovsky, Castrese Morrone, Jlenia Monfregola, Andrea Raimondi, Elena Polishchuk, Rossella De Cegli, Diego Carrella, Edoardo Nusco, Luigi Ferrante, Francesca Sacco, Lisa B Frankel, Christian Behrends, Carmine Settembre.

(Macro)autophagy is a conserved cellular degradation pathway that delivers substrates to lysosomes via autophagosomes. Among various physiological stimuli, nutrient starvation is the most potent inducer of autophagy. In response to starvation, transcription factor EB (TFEB) is activated and up-regulates a broad set of autophagy-related genes. However, the mechanisms by which TFEB promotes autophagosome biogenesis remain incompletely understood. Here, we demonstrate that TFEB-mediated transcriptional induction of sequestosome 1 (SQSTM1; p62) triggers the formation of SQSTM1-positive bodies that recruit essential autophagy factors, thereby initiating autophagosome biogenesis. Genetic disruption of TFEB-dependent SQSTM1 regulation markedly impairs starvation-induced autophagy, underscoring the critical role of the TFEB-SQSTM1 axis in the autophagic response to nutrient stress. Furthermore, we show that these SQSTM1 bodies contain ubiquitinated ribosomal proteins and that TFEB promotes ribosomal protein ubiquitination by inducing the E3 ubiquitin ligase ZNF598. Collectively, our findings uncover a transcriptionally coordinated mechanism that regulates both autophagosome biogenesis and substrate ubiquitination, facilitating efficient cargo clearance during starvation-induced autophagy.

DOI: https://doi.org/10.1126/sciadv.aea9302
J Clin Invest. 2026 Jan 02. pii: e194395. [Epub ahead of print]136(1):

NF2 loss malignantly transforms human pancreatic acinar cells and enhances cell fitness under environmental stress.

Yi Xu, Michael H Nipper, Angel A Dominguez, Chenhui He, Francis E Sharkey, Sajid Khan, Han Xu, Daohong Zhou, Lei Zheng, Yu Luan, Jun Liu, Pei Wang.

  Pancreatic ductal adenocarcinoma (PDAC) occurs as a complex, multifaceted event driven by the interplay of tumor-permissive genetic mutations, the nature of the cellular origin, and microenvironmental stress. In this study, using primary human pancreatic acinar 3D organoids, we performed a CRISPR-KO screen targeting 199 potential tumor suppressors curated from clinical PDAC samples. Our data revealed significant enrichment of a list of candidate genes, with neurofibromatosis type 2 associated gene (NF2) emerging as the top target. Functional validation confirmed that loss of NF2 promoted the transition of PDAC to an invasive state, potentially through extracellular matrix modulation. NF2 inactivation was found to enhance PDAC cell fitness under nutrient starvation. This adaptation not only reinforced the oncogenic state but also conferred therapeutic resistance. Additionally, we found that NF2 loss was associated with fibroblast heterogeneity and cancer-stroma communication in tumor evolution. These findings establish NF2 as a critical tumor suppressor in PDAC and uncover its role in mediating nutrient adaptation and drug resistance. Importantly, this study provides additional insights into drug resistance mechanisms and potential therapeutic targets in PDAC.

Keywords:  Cancer; Gastroenterology; Genetics; Oncology; Therapeutics; Tumor suppressors

DOI:  https://doi.org/10.1172/JCI194395
Ferroptosis Oxid Stress. 2025 ;pii: 202501. [Epub ahead of print]1(1):

Lipidomic changes in persister cancer cells drive enhanced ferroptosis sensitivity.

Eduard Reznik, Fereshteh Zandkarimi, Joleen M Csuka, Qiulin Zhu, Jenny Jin, Taruna Vani Neelakantan, Jiewen Zheng, Vasiliki Polychronidou, Mark Fongheiser, Ashley Brown, Baiyu Qiu, Megan Rodriguez, Lela DeVine, Prem S Subramaniam, Wei Gu, Andrea Califano, Brent R Stockwell.

   Aims: Unique in the broader category of drug-resistant cells, persister cancer cells (PSs) acquire their tolerance to compounds through reversible, chromatin-mediated changes, allowing them to 'persist' in the face of cancer therapeutic agents. PSs are implicated in minimal residual disease from which cancer relapse occurs, and given their established sensitivity to ferroptosis, PSs present a critical point through which identification and targeting of drug-resistant cancers may be possible. Ferroptosis sensitivity in drug-resistant cancers may be caused by the attainment of the persister state, or it may merely be correlative with this state and due instead to extended inhibition of oncogenic signaling or the induction of chemotherapy stress. Nonetheless, ferroptosis sensitivity has emerged as a common phenotype across multiple PS and drug-resistant cancer cell types. Identifying biomarkers for and drivers of ferroptosis sensitivity in drug-resistant and PS cells is therefore a high priority.
Methods: We derived PS cells from the lung carcinoma cell line PC9 (PSPC9), performed transcriptomic analysis, and subsequently lipidomics on the PC9/PSPC9 system. Additionally, we reverted PSPC9 cells to the ferroptosis-resistant parental state (PC9PS -> PC9) and assessed the resulting lipid changes. We generated two additional PS-like cell models: PS-like prostate carcinoma (PSLNCaP) from LNCaP cells and PS-like fibrosarcoma (PSHT1080) from HT1080 cells, with lipidomics analysis. Finally, we performed a mitochondrial elimination assay and assessed its effect on ferroptosis sensitivity.
Results: We observed enrichment of lipid and sugar metabolism gene expression in PSPC9; lipidomics revealed enrichment within PSPC9 for ferroptosis-driving diPUFA phospholipids (diPUFA-PL), as well as polyunsaturated free fatty acids (PUFA FFAs). Upon PSPC9 reversion to the ferroptosis-resistant parental state (PC9PS -> PC9), this lipid signature reverted. The LNCaP and HT1080 PS-like models individually showed features consistent with PS, including an increased labile-iron pool, reversibility, and enhanced ferroptosis sensitivity, and had lipid features consistent with those in PSPC9. Finally, mitochondrial elimination partially abrogated ferroptosis sensitivity and altered the PS lipid profile.
Conclusion: In summary, lipidomic changes dependent on the presence of mitochondria are key to the ferroptosis sensitivity of drug-tolerant persister cancer cells.

Keywords:  Polyunsaturated fatty acid; cancer; diPUFA; ferroptosis; lipids; mitochondria; persisters

DOI:  https://doi.org/10.70401/fos.2025.0003
Cancer Res. 2025 Dec 31.

Netrin-1 Promotes Pancreatic Tumorigenesis and Innervation through NEO1.

Hiroki Kobayashi, Yosuke Ochiai, Junya Arai, Masahiro Hata, Feijing Wu, Masaki Sunagawa, Tadashi Iida, Taisuke Baba, Ermanno Malagola, Takayuki Tanaka, Zhengyu Jiang, Ruth A White, Xiaofei Zhi, Jin Qian, Quin T Waterbury, Ruhong Tu, Biyun Zheng, Yi Zeng, Hualong Zheng, Puran Zhang, Shuang Li, Leah B Zamechek, Jonathan S LaBella, Takahiro Sugie, Atsushi Enomoto, Holger K Eltzschig, Carmine F Palermo, Iok In Christine Chio, Kenneth P Olive, Timothy C Wang.

Nerves can regulate tumorigenesis and cancer progression. However, clarification of the role of axon guidance molecules in tumorigenesis, innervation, and metastasis is required to better understand the tumor-promoting functions of nerves. Using murine KrasG12D-mutant pancreatic organoids, we screened axon guidance molecules and identified netrin-1 upregulation. Netrin-1 was also upregulated in vivo during pancreatic tumorigenesis in humans and mice. Mutant KRAS and β-adrenergic signaling upregulated netrin-1 and its receptor NEO1 in epithelial cells in part through the MAPK pathway. Ex vivo culture of celiac ganglia showed that netrin-1 promoted the axonogenesis of sympathetic neurons through nerve NEO1. In the Pdx1-Cre;LSL-KrasG12D/+ model, knockout of Ntn1, which encodes netrin-1, decreased sympathetic innervation and the development of pancreatic intraepithelial neoplasia. Treatment of pancreatic tumor organoids with recombinant netrin-1 enhanced cell growth, epithelial-mesenchymal transition (EMT), and cancer stemness with the upregulation of ZEB1 and SOX9 through NEO1-mediated activation of focal adhesion kinase (FAK). In Pdx1-Cre;LSL-KrasG12D/+;LSL-Trp53R172H/+ mice, Ntn1 knockout reduced innervation, FAK phosphorylation, and the features of EMT and stemness to extend mouse survival. In a liver metastasis model of pancreatic ductal adenocarcinoma (PDAC), treatment with a netrin-1-neutralizing antibody or tumoral knockout of Neo1 reduced ZEB1 and SOX9 and decreased tumor progression. In contrast, netrin-1 overexpression promoted innervation and the progression of PDAC liver metastasis. These data suggest that the netrin-1/NEO1 axis is a key regulator of PDAC progression, directly influencing cancer cell stemness and EMT, while indirectly promoting tumor growth through nerves. Inhibiting the netrin-1 pathway could represent a potential therapeutic approach for PDAC.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2243
J Cell Biol. 2026 Mar 02. pii: e202503087. [Epub ahead of print]225(3):

p62 sorts Lupus La and selected microRNAs into breast cancer-derived exosomes.

Jordan Matthew Ngo, Justin Krish Williams, Morayma Mercedes Temoche-Diaz, Abinayaa Murugupandiyan, Randy Schekman.

Exosomes are multivesicular body-derived extracellular vesicles that are secreted by metazoan cells. Exosomes have utility as disease biomarkers, and exosome-mediated miRNA secretion has been proposed to facilitate tumor growth and metastasis. Previously, we demonstrated that the Lupus La protein (La) mediates the selective incorporation of miR-122 into metastatic breast cancer-derived exosomes; however, the mechanism by which La itself is sorted into exosomes remains unknown. Using unbiased proximity labeling proteomics, biochemical fractionation, superresolution microscopy, and genetic tools, we establish that the selective autophagy receptor p62 sorts La and miR-122 into exosomes. We then performed small RNA sequencing and found that p62 depletion reduces the exosomal secretion of tumor suppressor miRNAs and results in their accumulation within cells. Our data indicate that p62 is a quality control factor that modulates the miRNA composition of exosomes. Cancer cells may exploit p62-dependent exosome cargo sorting to eliminate tumor suppressor miRNAs and thus to promote cell proliferation.

DOI: https://doi.org/10.1083/jcb.202503087
Protein Sci. 2026 Jan;35(1): e70390

Role of N-glycosylation as a determinant of ATG9A conformations and activity.

Mattia Utichi, Matteo Lambrughi, Henri-Baptiste Marjault, Christian B Borg, Sergio Esteban Echeverría, Kenji Maeda, Nicholas M I Taylor, Anders Gorm Pedersen, Elisa Fadda, Marja Jäättelä, Elena Papaleo.

  Here, we investigate the effects of glycosylation at position N99 on the structural dynamics and lipid scrambling activity of ATG9A, a key autophagy protein, using microsecond all-atom molecular dynamics simulations. ATG9A is an integral membrane protein involved in autophagosome biogenesis, and glycosylation at N99 has previously been implicated in intracellular trafficking, although its precise role remains unclear. The simulations reveal that the hydrophilic central cavity of ATG9A supports lipid reorientation and partial trans-bilayer movements, consistent with experiments on its lipid scrambling activity. We propose that N-glycosylation at N99 enhances cooperative interactions between protomers, facilitating lipid insertion and translocation within the central cavity. These findings suggest a mechanism by which glycosylation may influence lipid redistribution across the phagophore membrane during autophagy. To test this hypothesis, we generate N99 variants (ATG9AN99A and ATG9AN99D) lacking N-glycosylation. These mutants show no significant changes in autophagy flux, suggesting that N99 glycosylation may not be essential for bulk autophagic processing. However, the analysis of autophagosome size indicates that the variants fail to rescue the enlarged vesicle phenotype of ATG9A-KO cells, unlike wild-type ATG9A. Thus, glycosylation might fine-tune ATG9A function, influencing vesicle morphology through conformational dynamics and lipid transport. We also observe asymmetric protomer conformations in ATG9A, in contrast to the symmetric structures obtained from cryo-EM, suggesting that structural heterogeneity could be further explored with experimental methods. Overall, our study highlights the importance of including glycosylation in computational models of membrane proteins and provides mechanistic insight into lipid transport during autophagy, with potential implications for other lipid scramblases and flippases.

Keywords:  ATG9A; autophagy; glycosylation; membranes; molecular dynamics; post‐translational modifications

DOI:  https://doi.org/10.1002/pro.70390
Cancer Cell. 2025 Dec 31. pii: S1535-6108(25)00543-4. [Epub ahead of print]

Spatial omics at the forefront: emerging technologies, analytical innovations, and clinical applications.

Yunhe Liu, Yibo Dai, Linghua Wang.

  Spatial omics transforms our understanding of cancer by revealing how tumor cells and the microenvironment are organized, interact, and evolve within tissues. Here, we synthesize advances in spatial technologies that map tumor ecosystems with unprecedented fidelity. We highlighted analytical breakthroughs-including multimodal integration and emerging spatial foundation models-that resolve functional niches and spatial communities, converting spatial patterns into mechanistic insights. We summarize how spatially organized features, from immune hubs to microbiota and neural interfaces, shape tumor evolution and clinical outcomes. We then outline how spatial approaches illuminate precancer biology, metastatic adaptation, and therapy response. Bridging discovery and translation, we provide a practical roadmap for incorporating spatial readouts into clinically oriented study design. We conclude by discussing persistent challenges in standardization and scalability and how high-plex spatial discoveries may be distilled into scalable, AI-enabled, clinically deployable assays, positioning spatial omics as a cornerstone of next-generation predictive and precision oncology.

Keywords:  AI; ML; TME; artificial intelligence; cell-cell interaction; cellular neighborhood; computational pathology; machine learning; molecular imaging; multi-omics; multimodal data integration; proteomics; spatial biomarkers; spatial heterogeneity; spatial niche; spatial omics; transcriptomics; tumor microenvironment

DOI:  https://doi.org/10.1016/j.ccell.2025.12.009
Cell Chem Biol. 2025 Dec 31. pii: S2451-9456(25)00396-4. [Epub ahead of print]

An interactive resource mapping the proteome and reactive cysteine landscape across the NCI-60 reveals cell and tissue-specific profiles.

José L Montaño, Vishnu R Tejus, Vee Xu, Andrew C Condon, Andrew K Ecker, Andreas Langen, Kevin K Leung, Balyn W Zaro.

  The NCI-60 cancer cell line panel is one of the most extensively characterized and publicly accessible resources in cancer research. Here, we expand this platform by generating a comprehensive proteomic and cysteine reactivity atlas using shotgun proteomics and quantitative chemoproteomics. We quantified over 12,000 proteins and identified more than 36,000 reactive cysteines, including over 10,000 hyperreactive sites, across the panel. Our analyses reveal widespread heterogeneity in cysteine reactivity, while conserved hyperreactive cysteines strongly correlate with functional roles. Tissue-specific cysteine reactivity occurred independently of protein abundance, highlighting context-dependent regulation. To enable exploration and integration with existing datasets, we developed an interactive online database that allows users to visualize protein and cysteine coverage and design custom cell line panels. Together, these data and tools illuminate the landscape of cysteine reactivity in cancer and provide a foundational resource to advance future studies in protein function, redox biology, and covalent drug discovery.

Keywords:  NCI-60; chemical proteomics; cysteine reactivity; mass spectrometry

DOI:  https://doi.org/10.1016/j.chembiol.2025.12.003
Mol Cell. 2025 Dec 30. pii: S1097-2765(25)00978-5. [Epub ahead of print]

Splice-switching ASOs targeting the AURKA 5' UTR collapse an SRSF1-AURKA-MYC oncogenic circuit in pancreatic cancer.

Alexander J Kral, Lu Jia, GeunYoung Sim, Ledong Wan, Yuma Ishigami, Adrian R Krainer.

  Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy, driven by oncogenic KRAS mutations and dysregulated oncogenes, including SRSF1, MYC, and Aurora kinase A (AURKA). Although KRAS-targeted therapies are in development, resistance mechanisms underscore the need to identify alternative vulnerabilities. Here, we uncover an SRSF1-AURKA-MYC oncogenic circuit, wherein SRSF1 regulates AURKA 5' UTR alternative splicing, enhancing AURKA protein expression; AURKA positively regulates SRSF1 and MYC post-translationally, independently of its kinase activity; and MYC transcriptionally upregulates both SRSF1 and AURKA. Elevated SRSF1 in tumor cells promotes inclusion of an Alu-derived exon in the AURKA 5' UTR, resulting in splicing-dependent mRNA accumulation and exon-junction-complex deposition. Modulating 5' UTR splicing with splice-switching antisense oligonucleotides (ASOs) collapses the oncogenic circuit, reducing PDAC cell viability and triggering apoptosis. Our findings identify AURKA alternative splicing as a critical regulatory node and highlight a potential therapeutic strategy that simultaneously targets SRSF1, AURKA, and MYC oncogenes.

Keywords:  ASOs; AURKA; Alu exonization; Aurora kinase A; MYC signaling; PDAC; RNA splicing; SRSF1; antisense oligonucleotides; oncogenic circuit; pancreatic ductal adenocarcinoma; splicing-dependent gene expression; therapeutic splicing modulation

DOI:  https://doi.org/10.1016/j.molcel.2025.12.004
Nat Chem Biol. 2026 Jan 02.

The membrane transition strongly enhances biopolymer condensation through prewetting.

Yousef Bagheri, Mason N Rouches, Benjamin B Machta, Sarah L Veatch.

Biopolymers that separate into condensed and dilute phases in solution also prewet membranes when one or more components couple to membrane lipids. Here we demonstrate that this prewetting transition becomes exquisitely sensitive to lipid composition when membranes have compositions near the boundary of liquid-ordered/liquid-disordered phase coexistence in both simulation and in reconstitution when polyelectrolytes are coupled to model membranes. In cells, we use an optogenetic tool to characterize prewetting at both the plasma membrane (PM) and the endoplasmic reticulum (ER) and find that prewetting is potentiated or inhibited by perturbations of membrane composition. Prewetting can also mediate membrane adhesion, with avidity dependent on membrane composition, as demonstrated in cells through the potentiation or inhibition of ER-PM contact sites. The strong correspondence of results in simulation, reconstitution and cells reveals a new role for membrane lipids in regulating the recruitment and assembly of soluble proteins.

DOI: https://doi.org/10.1038/s41589-025-02082-0
bioRxiv. 2025 Dec 19. pii: 2025.12.17.694916. [Epub ahead of print]

Aspartate Transaminases Are Dispensable for Pancreatic Development and Pancreatic Cancer Progression.

Julia Ugras, Noah Nelson, Samuel A Kerk, Damien Sutton, Lin Lin, Peter Sajjakulnukit, Teresa Dombrowski, Gillian Davidson, Brooke Lavoie, Dominik Awad, Alberto Olivei, Wei Yan, Christopher Strayhorn, Megan Radyk, Matthew Perricone, Marina Pasca di Magliano, Filip Bednar, Timothy Frankel, Yatrik M Shah, Costas A Lyssiotis.

Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related deaths in the United States. This is due in part to the limited availability of effective treatment options for patients, highlighting a significant need for new targets and approaches. Deregulated metabolism is a hallmark feature of PDA that has gained attention as a promising inroad for therapy. The aspartate transaminases ( g lutamate o xaloacetate transaminases, cytosolic GOT1 and mitochondrial GOT2) have several important metabolic functions, including maintaining energy and redox balance and generating aspartate, an essential building block in protein and nucleotide biosynthesis. Previous studies of GOT proteins in preclinical tumor transplant models have yielded conflicting results regarding the requirement of GOT1 and GOT2 for PDA tumor growth. To assess the role of GOT proteins in tumor development and tumor maintenance, we generated conditional knockout mice for Got1 and Got2 and crossed these into pancreas-specific models. Whereas loss of either Got does not impact pancreas development, double Got1 and Got2 knockout results in markedly reduced pancreas size and cellularity without overtly impacting endocrine or exocrine function. In genetically engineered cancer models, single Got loss does not impact lesion formation, tumor size, animal survival, or the composition of the tumor microenvironment. Identical results were also observed in orthotopic allograft mouse models. Together, these findings add to a growing body of work illustrating the adaptability of metabolism in cancer. They also emphasize the importance of model selection, the use of multiple independent models, and the in vivo context when studying the role of metabolic programs in cancer.

DOI: https://doi.org/10.64898/2025.12.17.694916
Methods Mol Biol. 2026 ;2983 135-142

Detection of Ferroptosis by Liperfluo and BODIPY™ 581/591 C11.

Cristina Aguilar Flores, Wan Seok Yang.

  Ferroptosis is a unique form of regulated cell death characterized by the toxic buildup of lipid peroxides in plasma membranes. Uncontrolled ferroptosis has been linked to various pathological conditions, including cancer progression, neurodegeneration, kidney damage, ischemia/reperfusion injury, and T-cell immunity. In this article, we present a method for detecting ferroptosis by measuring lipid peroxides in cellular membranes with the Liperfluo and BODIPY-C11 probes. The potential role of ferroptosis in immune-modulatory cells can also be assessed using this approach.

Keywords:  BODIPY-C11; Erastin, RSL3; Ferroptosis; Liperfluo; Lipid peroxides

DOI:  https://doi.org/10.1007/978-1-0716-4901-5_13
Cell Res. 2026 Jan 02.

Repair of damaged lysosomes by TECPR1-mediated membrane tubulation during energy crisis.

Hanmo Chen, Chaojun Zhang, Yuhui Fu, Linsen Li, Xiaoyu Qiao, Shen Zhang, Hanyan Luo, She Chen, Xiaoxia Liu, Qing Zhong.

Lysosomes are essential for cellular homeostasis, serving as degradative organelles that recycle nutrients. Whether and how lysosomes maintain membrane integrity under energy stress is poorly understood. Here, we found that the uptake of lipid droplets by lysosomes during glucose starvation provokes disruption of lysosomal membranes. We identified tectonin beta-propeller repeat-containing protein 1 (TECPR1) as a critical mediator of lysosomal repair during glucose starvation or LLOMe-induced lysosomal membrane permeabilization. TECPR1 is recruited to damaged lysosomes via interaction with PI4P on damaged lysosomal membranes. It interacts with KIF1A to facilitate tubule formation from damaged lysosomes, enabling the removal of damaged membrane components and promoting lysosomal repair. Our in vitro reconstituted tubulation process provided further evidence that TECPR1 coordinates with KIF1A to drive tubulation from PI4P-enriched giant unilamellar vesicles. TECPR1-mediated lysosomal repair is essential for maintaining lipid metabolism and cellular survival during an energy crisis, as TECPR1 deficiency exacerbates starvation-induced liver damage in a high-fat diet-induced MAFLD mouse model. Our findings demonstrate a previously unrecognized role of TECPR1 in lysosomal repair, revealing its critical contributions to energy stress adaptation and liver protection. This work provides new insight into mechanisms of lysosomal repair and their implications for metabolic and lysosome-related disorders.

DOI: https://doi.org/10.1038/s41422-025-01193-6
bioRxiv. 2025 Dec 19. pii: 2025.12.17.694756. [Epub ahead of print]

A simple, anesthesia-free infusion technique for in vivo metabolic tracing.

Yumi Kim, Samantha Caldwell, Meredith Long, Dominique Abrahams, Margi Baldwin, Gina M DeNicola.

Accurate metabolic flux analysis requires tracer delivery that preserves physiological metabolism. Current methods may distort metabolism through anesthesia, surgical stress, or complex procedures. We demonstrate that isoflurane anesthesia profoundly alters serum and tissue metabolism across multiple pathways. Glycolytic and TCA cycle intermediates, sulfur and aromatic amino acid metabolites, acylcarnitines, and nucleotide pools decreased, while branched-chain amino acids, their ketoacids, ketone bodies, and fatty acids increased. These coordinated changes were suggestive of mitochondrial complex I inhibition and reduced oxidative catabolism, leading to shifts in metabolite pool sizes that compromise isotopologue-based flux interpretation. We established a tail vein catheterization method completed in minutes under brief anesthesia that enables multi-hour tracer infusion in awake, freely moving mice. This method achieved steady-state labeling of cystine and downstream products comparable to jugular infusion without supraphysiologic cystine accumulation. This platform provides a practical, physiologically accurate method for in vivo steady-state isotope tracing.

DOI: https://doi.org/10.64898/2025.12.17.694756
Comput Biol Chem. 2025 Dec 25. pii: S1476-9271(25)00531-6. [Epub ahead of print]121 108867

Decrypting the impact of ferroptosis and cuproptosis in development of pancreatic ductal adenocarcinoma.

Deepyaman Das, Arunima Maiti, Sayan Saha, Sounetra Choudhury, Sumit Mukherjee, Debabrata Ghosh Dastidar, Nilabja Sikdar.

  Pancreatic cancer (PanCa) is a devastating disease with very low survival rate. Ferroptosis and cuproptosis, regulated forms of cell death, resulting from the accumulation of iron and copper ions, respectively are gaining increasing attention for their roles in tumor development. These non-apoptotic cell death forms would be worth to explore in the context of PanCa, as it is a difficult disease to treat and often become resistant to apoptosis inducing conventional therapeutic modes. So, targeting the transcription factors (TFs) regulating both these cell death pathways are critical for pancreatic ductal adenocarcinoma (PDAC) therapeutics because they control the cellular mechanisms that execute these specialized, non-apoptotic forms of cell death. Therefore, using differentially expressed genes (DEGs) from RNA-Seq and TCGA data, we first rebuilt the protein-protein interaction network (PPIN) for PDAC (PPINPDAC). We then identified 71 strongly connected clusters within the PPINPDAC. Functional enrichment of these clusters revealed that key cell death mechanisms are compromised in this cancer. Next, we discovered that 37 deregulated clusters of PDAC are regulated by 10 ferroptotic and 1 cuproptotic transcription factors (FerrTFs and CuprTF), respectively. NFE2L2 was found to be both FerrTF and CuprTF. Using various clinicopathological parameters for PDAC, we screened 4 critical TFs among the 10 TFs viz. NFE2L2, TP53, ZEB1, and HIF1A which might be critical for disease progression. Lastly, drugs epigallocatechin gallate (EGCG) and protodioscin (PTN) were identified as promising therapeutic candidates against the 4 TFs using molecular docking and simulation studies. This preliminary investigation pinpoints possible TFs of ferroptosis and cuproptosis in PDAC and develops countermeasures against them.

Keywords:  Cuproptosis; Ferroptosis; Pancreatic Ductal Adenocarcinoma; Pancreatic cancer; Protein-Protein Interaction Network; Transcription Factors

DOI:  https://doi.org/10.1016/j.compbiolchem.2025.108867
Sci Adv. 2026 Jan 02. 12(1): eads2734

Trade-off between branching and polarity controls decision-making during cell migration.

Jiayi Liu, Javier Boix-Campos, Jonathan E Ron, Johan M Kux, Magdalena E M Oremek, Adriano G Rossi, Nir S Gov, Pablo J Sáez.

Motile cells often face microenvironmental constraints and obstacles that force them to extend multiple protrusions. However, the analysis of shape dynamics during directional decision-making has been restricted to single junctions. Here, we combined live-cell imaging and a coarse-grained model to study the migratory behavior of highly branched cells while simultaneously facing several junctions. The theoretical model predicts that the choice of a new direction is determined by the competition between the cellular protrusions in the form of seesaw oscillations. We found that macrophages and endothelial cells display different regimes moving on hexagonal networks, despite sharing a mesenchymal (i.e., adhesion-dependent) migratory strategy. The model describes the motility of both cell types and reveals a trade-off between branching and speed: Having many protrusions allows local microenvironmental exploration for directional cues, but long-range migration efficiency improves with fewer protrusions. Collectively, our data highlight the relevance and provide insights for the regulation of shape dynamics during cell navigation in complex geometries.

DOI: https://doi.org/10.1126/sciadv.ads2734
ACS Nano. 2025 Dec 30.

Adaptive Cytoskeletal Responses to Extracellular Environment Viscosity Modulate Cell Migration.

Zhongya Lin, Xindong Chen, Xi-Qiao Feng.

  Cell migration is a pivotal process in metastasis, allowing cancer cells to invade surrounding tissues and disseminate to distant organs. While extracellular environment (ECE) viscosity serves as a critical modulator of cell motility, its regulatory mechanisms remain unclear. This study presents a mechanobiological model to investigate how ECE viscosity modulates cancer cell migration by regulating some key processes, including actin polymerization, retrograde flow, and adhesion adaptations. Our results reveal a biphasic response: a moderate increase in ECE viscosity enhances actin filament network density and adhesion strength, thereby accelerating migration, whereas excessively high viscosity hinders movement due to too large mechanical resistance. Furthermore, we identify a short-term migration memory phenomenon where cancer cells exposed to high-viscosity environments retain elevated migration speeds after transitioning to low-viscosity conditions. This memory effect is sustained by the continued assembly of cytoskeletal proteins, such as actin monomers and Arp2/3. These analyses reveal an adaptive mechano-chemo-biological mechanism by which cancer cells integrate and respond to mechanical cues from their viscous environment to optimize migration and advance the understanding of cancer cell migration in various tissue environments.

Keywords:  actin dynamics; cell migration; mechanobiology; memory mechanism; viscosity

DOI:  https://doi.org/10.1021/acsnano.5c11355
PLoS Comput Biol. 2025 Dec 29. 21(12): e1013828

Cell-DINO: Self-supervised image-based embeddings for cell fluorescent microscopy.

Théo Moutakanni, Camille Couprie, Seungeun Yi, Michael Doron, Zitong S Chen, Nikita Moshkov, Elouan Gardes, Mathilde Caron, Hugo Touvron, Armand Joulin, Piotr Bojanowski, Wolfgang M Pernice, Juan C Caicedo.

Accurately quantifying cellular morphology at scale could substantially empower existing single-cell approaches. However, measuring cell morphology remains an active field of research, which has inspired multiple computer vision algorithms over the years. Here, we show that DINOv2, a vision-transformer based, self-supervised algorithm, has a remarkable ability for learning rich representations of cellular morphology without manual annotations or any other type of supervision. We apply DINOv2 to cell phenotyping problems, and compare the performance of resulting models, called Cell-DINO models, on a wide variety of tasks across two publicly available imaging datasets of diverse specifications and biological focus. Compared to supervised and other self-supervised baselines, Cell-DINO models demonstrate improved performance, especially in low annotation regimes. For instance, to classify protein localization using only 1% of annotations on a challenging single-cell dataset, Cell-DINO performs 70% better than a supervised strategy, and 24% better than another self-supervised alternative. The results show that Cell-DINO can support the study of unknown biological variation, including single-cell heterogeneity and relationships between experimental conditions, making it an excellent tool for image-based biological discovery.

DOI: https://doi.org/10.1371/journal.pcbi.1013828
J Lipid Res. 2025 Dec 31. pii: S0022-2275(25)00234-2. [Epub ahead of print] 100971

Spatial Mapping of PUFA Incorporation into Phospholipids with bisallylic deuteration.

Junji Obi, Kuniyuki Kano, Yuta Shimanaka, Shukichi Haisa, Nozomu Kono, Junken Aoki.

  Mass spectrometry (MS) imaging using stable isotope-labeled fatty acids provides a groundbreaking approach to precisely localizing exogenous fatty acids and their metabolites in vivo. However, challenges persist, particularly with fatty acids labeled with fixed isotopic numbers, which can lead to spectral interferences and limit the number of metabolites that can be detected. In this study, we employed a bisallylic deuteration method to synthesize dihomo-γ-linolenic acid (DGLA) isotopes with m/z values ranging from +4 to +8 Da relative to endogenous DGLA, which allowed us to meticulously dissect DGLA metabolism in mice using LC-QTof-MS and MS imaging. Our strategy enabled the clear selection of m/z values for phospholipids enriched with deuterated DGLA (D-DGLA) and deuterated ARA (D-ARA) derived from D-DGLA, all while maintaining low background noise. This precision facilitated the successful visualization of D-DGLA and D-ARA-containing phospholipids in lung tissue, revealing their distinct localization compared to endogenous phospholipids. Our findings highlight bisallylic deuteration as a powerful tool for elucidating the in vivo dynamics of exogenous polyunsaturated fatty acids (PUFAs) through MS imaging techniques.

Keywords:  Bisallylic deuteration; Dihomo-γ-linolenic acid (DGLA); Mass spectrometry (MS) imaging; Phospholipids; Polyunsaturated fatty acids (PUFAs)

DOI:  https://doi.org/10.1016/j.jlr.2025.100971
Methods Mol Biol. 2026 ;2983 249-256

Proximity Ligation Assay to Detect Protein-Protein Interaction in Cancer Cells.

Patricia Rozario, Yan Zhu.

  Combining immunoassays with nucleic acid-based amplification and detection, the proximity ligation assay (PLA) is a useful tool for immunofluorescent detection, visualization, and quantification of individual proteins, protein modifications, and protein-protein interactions in fixed cells and tissue samples. Here, we present a detailed procedure for detecting protein-protein interactions in cancer cells with a commercially available Naveni® in situ proximity ligation technology to assist the researcher in successfully performing the experiments.

Keywords:  In situ assays; Protein; Protein interaction; Proximity ligation assay

DOI:  https://doi.org/10.1007/978-1-0716-4901-5_21
Proc Natl Acad Sci U S A. 2026 Jan 06. 123(1): e2525144122

CHAMP1 complex promotes heterochromatin assembly and reduces replication stress.

Feng Li, Amira Elbakry, Felix Y Zhou, Tianpeng Zhang, Ramya Ravindranathan, Huy Nguyen, Aleem Syed, Lifang Sun, Sirisha Mukkavalli, Roger A Greenberg, Alan D D'Andrea.

  Replication stress (RS) is a major driver of genomic instability and a hallmark of cancer cells. Although dynamic heterochromatin remodeling has been implicated in RS response, the precise mechanisms remain unclear. The CHAMP1 complex, composed of CHAMP1, POGZ, HP1α, and the H3K9 methyltransferase SETDB1, is known to regulate heterochromatin assembly at multiple genomic sites. Interestingly, upon RS, the CHAMP1 complex is transiently recruited to stalled replication forks, where it facilitates H3K9me3 deposition and establishes a repressive chromatin environment. The complex is required for stabilization of replication forks, and it shields forks from MRE11-mediated degradation. The complex also reduces RS at specific chromosomal sites, such as the heterochromatin-rich telomeric sites in tumor cells which use the ALT pathway of telomere maintenance. Loss of the CHAMP1 complex results in increased micronuclei formation and heightened sensitivity to RS. Loss of the complex also leads to a compensatory increase in other pathways which reduce RS, such as the FA pathway and the ATR/CHK1 pathway. Notably, CHAMP1 deficiency induces synthetic lethality with FANCM inhibition in ALT-positive tumor cells, and the CHAMP1 complex is essential for the survival of CCNE1-amplified ovarian cancers. These findings uncover a heterochromatin-based mechanism of replication fork stabilization and suggest that CHAMP1 may represent a candidate therapeutic vulnerability in cancers with elevated RS.

Keywords:  CHAMP1; H3K9me3; POGZ; SETDB1; replication stress

DOI:  https://doi.org/10.1073/pnas.2525144122
Methods Mol Biol. 2026 ;2983 143-158

Methods for Measuring TNFα-Induced Autophagy in Cancer Cells.

Sheyda Najafi, Ehab M Abo-Ali, Vikas V Dukhande.

  Autophagy is an evolutionarily conserved cellular mechanism in eukaryotes that plays an important role in the maintenance of cellular homeostasis. The autophagy process maintains protein homeostasis by recycling damaged organelles and degrading many long-lived or damaged proteins through lysosomes in coordination with the ubiquitin-proteasome system. Cytokines are low molecular weight secreted proteins that regulate a broad range of biological activities. For instance, pro-inflammatory cytokines such as tumor necrosis factor-α (TNFα) induce inflammation, autophagy, and apoptotic cell death. In this chapter, we discuss experimental techniques such as immunoblotting and fluorescence microscopy that can be utilized to measure autophagy in response to TNFα treatment.

Keywords:  Apoptosis; Autophagy; Bafilomycin A1; Chloroquine; Fluorescence microscopy; Immunoblotting; LC3; TNFα; p62

DOI:  https://doi.org/10.1007/978-1-0716-4901-5_14
Autophagy. 2025 Dec 31. 1-2

DEAF1 - a transcriptional brake on muscle autophagy.

Wen Xing Lee, Kah Yong Goh, Sze Mun Choy, Hong-Wen Tang.

  Macroautophagy/autophagy protects muscle from proteotoxic stress and maintains tissue homeostasis, yet skeletal muscle relies on it more than most organs. Adult fibers endure constant mechanical strain and require continuous turnover of long-lived proteins, while muscle stem cells (MuSCs) depend on autophagy to remain quiescent, activate after injury, and regenerate effectively. How autophagy is transcriptionally regulated in muscle has been unclear. We identified DEAF1 as a transcriptional brake on autophagy. In MuSCs, DEAF1 controls activation and regeneration and becomes aberrantly elevated with age, promoting protein aggregate formation and cell death. In muscle fibers, DEAF1 is chronically induced during aging, suppressing autophagy and driving functional decline. Exercise reverses DEAF1 induction, restoring autophagy and muscle function. These findings reveal DEAF1 as a key regulator linking autophagy to regeneration and aging, highlighting a therapeutically tractable axis for preserving muscle health.

Keywords:  Autophagy; DEAF1; muscle; muscle stem cell; regeneration

DOI:  https://doi.org/10.1080/15548627.2025.2610451
Br J Pharmacol. 2025 Dec;182 Suppl 1 S24-S151

The Concise Guide to PHARMACOLOGY 2025/26: G protein-coupled receptors.

Stephen P H Alexander, Anthony P Davenport, Eamonn Kelly, Alasdair J Gibb, Alistair A Mathie, Chloe J Peach, Emma L Veale, Jane F Armstrong, Elena Faccenda, Simon D Harding, Christopher Southan, Jamie A Davies, Maria Pia Abbracchio, George R Abraham, Alexander Agoulnik, Wayne Alexander, Khaled Al-Hosaini, Magnus Bäck, Jillian G Baker, Nicholas M Barnes, Ross Bathgate, Jean-Martin Beaulieu, Annette G Beck-Sickinger, Maik Behrens, Kirstie A Bennett, Kenneth E Bernstein, Bernhard Bettler, Nigel J M Birdsall, Victoria A Blaho, Pascal Bonaventure, Francois Boulay, Corinne Bousquet, Hans Bräuner-Osborne, Andrew J Brown, Geoffrey Burnstock, Marta Busnelli, Girolamo Caló, Vanni Caruso, Justo P Castaño, Kevin J Catt, Stefania Ceruti, Paul Chazot, Nan Chiang, Bice Chini, Arthur Christopoulos, Jerold Chun, Antonia Cianciulli, Olivier Civelli, Lucie H Clapp, Réjean Couture, Helen M Cox, Zsolt Csaba, Claes Dahlgren, Frank M Dautzenberg, Gordon Dent, Steven D Douglas, Pascal Dournaud, Margarita L Dubocovich, Satoru Eguchi, Emanuel Escher, Edward J Filardo, Tung Fong, Huamei Fu Forsman, Marta Fumagalli, Raul R Gainetdinov, Michael L Garelja, Marc de Gasparo, Florence Gbahou, Craig Gerard, Marvin Gershengorn, Michelle Glass, David E Gloriam, Fernand Gobeil, Theodore L Goodfriend, Cyril Goudet, Lukas Grätz, Karen J Gregory, Christian Gruber, Andrew L Gundlach, Jörg Hamann, Julien Hanson, Deborah S Hartman, Richard L Hauger, Debbie L Hay, Akos Heinemann, Laura Heitman, Deron R Herr, Morley D Hollenberg, Nicholas D Holliday, Birgitte Holst, Mastgugu Horiuchi, Daniel Hoyer, László Hunyady, Ahsan Husain, Adriaan P IJzerman, Tadashi Inagami, Paul A Insel, Kenneth A Jacobson, Laura H Jacobson, Robert T Jensen, Ralf Jockers, Deepa Jonnalagadda, Sadashiva Karnik, Klemens Kaupmann, Jacqueline Kemp, Charles Kennedy, Yasuyuki Kihara, Julia Kinsolving, Takio Kitazawa, Pawel Kozielewicz, Hans-Jürgen Kreienkamp, Jyrki P Kukkonen, Luxmichan Laishram, Tobias Langenhan, Christopher J Langmead, Dan Larhammar, Katie Leach, Davide Lecca, John D Lee, Susan E Leeman, Jérôme Leprince, Rob Leurs, Xaria X Li, Ines Liebscher, Stephen J Lolait, Amelie Lupp, Robyn Macrae, Janet J Maguire, Davide Malfacini, Maurice Manning, Davide Marangon, Kirill Martemyanov, Jean Mazella, Craig A McArdle, Shlomo Melmed, Martin C Michel, Laurence J Miller, Vincenzo Mitolo, Bernard Mouillac, Christa E Müller, Philip M Murphy, Jean-Louis Nahon, Richard R Neubig, Tony Ngo, Xavier Norel, Duuamene Nyimanu, Anne-Marie O'Carroll, Stefan Offermanns, Maria Antonietta Panaro, Marc Parmentier, Nicole Perry-Hauser, Roger G Pertwee, Jean-Philippe Pin, Eric R Prossnitz, Helena Chengxue Qin, Mark Quinn, Stefano Raffaele, Rithwik Ramachandran, Manisha Ray, Rainer K Reinscheid, Alejandro Romeral Buzón, Philippe Rondard, Mette M Rosenkilde, G Enrico Rovati, Chiara Ruzza, Gareth J Sanger, Nicole Scholz, Torsten Schöneberg, Gunnar Schulte, Stefan Schulz, Deborah L Segaloff, Charles N Serhan, Arun K Shukla, Khuraijam Dhanachandra Singh, Craig M Smith, Nicola J Smith, Claudia Stäubert, Leigh A Stoddart, Yukihiko Sugimoto, Roger Summers, Valerie P Tan, David M Thal, Walter Wally Thomas, Pieter B M W M Timmermans, Kalyan Tirupula, Lawrence Toll, Giovanni Tulipano, Hamiyet Unal, Thomas Unger, Celine Valant, Patrick Vanderheyden, David Vaudry, Hubert Vaudry, Joseph G Verbalis, Jean-Pierre Vilardaga, Christopher S Walker, Ji Ming Wang, Donald T Ward, Hans-Jürgen Wester, Gary B Willars, Tom Lloyd Williams, Trent M Woodruff, Huixian Wu, Cheng Yang, Chengcan Yao, Richard D Ye, Nathan Zaidman.

The Concise Guide to Pharmacology 2025/26 marks the seventh edition in this series of biennial publications in the British Journal of Pharmacology. Presented in landscape format, the guide provides a comparative overview of the pharmacology of drug target families. The concise nature of the Concise Guide refers to the style of presentation, being clear, accessible, and well-structured, rather than the scope of the content, which spans approximately 500 pages. The Concise Guide summarises the key pharmacological properties of around 1900 human drug targets, and nearly 7000 interactions, involving around 4400 ligands. While the content is a substantially condensed version of the more detailed information and links available at the www.guidetopharmacology.org website, the printed guide serves as a permanent, citable, point-in-time record, that remains stable despite ongoing updates to the online database. The full contents of this publication can be found at https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.70230. The Concise Guides provide expert-curated recommendations of 'Gold Standard' selective pharmacological tools, available either commercially or as donations, which enable the identification of individual drug targets or families of drug targets. While the Concise Guide offers a more streamlined overview, more comprehensive information, including detailed pharmacological profiles and links to multiple online databases, is available through the Guide to Pharmacology website. The 2025/26 edition of the Concise Guide is based on material current as of mid-2025, and supersedes all previous editions, including the 2023/24 Guide, and earlier Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), and as such provides official IUPHAR classification and nomenclature for human drug targets, where applicable. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. Each section includes nomenclature guidance, concise summaries, information of the best available pharmacological tools, key references, and suggestions for further reading.

DOI: https://doi.org/10.1111/bph.70230
J Vis Exp. 2025 Dec 12.

Multi-Organ Collection from Mouse Models for Aging Studies.

Fredrick Biancardi, Neda Keyhanvar, Anastasia Zhurikhina, Sabrina Jang, Hanna Lucie Martens.

Aging is a systemic and multifactorial biological process that progressively affects nearly all organs and tissues, leading to structural, cellular, and molecular alterations. This protocol outlines a standardized and reproducible approach for evaluating age-related anatomical and morphological changes in mice through comprehensive organ collection for subsequent histological and molecular analyses. Using young (2-3 months old) and aged (20-24 months old) mice, we detail step-by-step procedures for gross anatomical dissection and systematic harvesting of major organs for downstream sectioning, histological staining, and microscopic evaluation. The protocol enables the collection of a broad range of organs and tissues (including the brain, eyes, esophagus, thymus, heart, aorta, lungs, lymph nodes, liver, pancreas, stomach, small intestine, colon, spleen, kidney, bladder, skin, skeletal muscle, bone, and adipose tissue) from a single animal. By maximizing data yield per subject, this workflow supports ethical animal use through reduction, enhances reproducibility across studies, and facilitates integrative analyses of organismal aging.

DOI: https://doi.org/10.3791/69128
Biophys Rep. 2025 Dec 31. 11(6): 423-432

Biophysical adaptations of circulating tumor cells undergoing metastasis.

Lanfeng Liang, Xiao Song, Shida Wang, Chwee Teck Lim.

  Circulating tumor cells (CTCs) are cancerous cells that break away from the primary tumor, enter the bloodstream, and travel to another part of the body. Research into CTCs, particularly their biological phenotypes and molecular mechanisms, has provided critical insights into metastasis and potential therapeutic targets. From a biophysical or mechanobiological perspective, CTCs must undergo biomechanical adaptations to navigate the processes of intravasation, circulation, arrest, and extravasation. These adaptations enable them to interact with blood components and survive in the circulatory system for hours or even days, ultimately facilitating metastatic progression. As research on metastasis within the bloodstream advances, this review explores the mechanobiology of CTCs, emphasizing the cellular and molecular mechanisms that regulate their suspension and adhesion states. Understanding these dynamic behaviors will offer deeper insights into CTC biology and the metastatic cascade.

Keywords:  Circulating tumor cells; Mechanical adaptation; Mechanobiology; Physical stresses

DOI:  https://doi.org/10.52601/bpr.2025.250018
Aging Cell. 2026 Jan;25(1): e70334

Loss of p62 Binding Allows TIF-IA Accumulation in Senescence, Which Promotes Phenotypic Changes to Nucleoli and the Senescence Associated Secretory Phenotype.

Hazel C Thoms, Tyler S Brant, Katie Duckett, Yizheng Yang, Jinxi Dong, Hongfei Wang, Freya Derby, Oluwatumilara F Akeke, Faizah Al-Alayeen, Amy Newell, Piotr Manasterski, Aishwarya Gopalakrishnan, Derek Mann, Fraser R Millar, Alex Von Kriegsheim, Juan Carlos Acosta, Fiona Oakley, Lesley A Stark.

  A key characteristic of senescent and ageing cells is a reduction in number and increase in size of nucleoli. Although a number of pathways have been suggested, the mechanisms underlying this altered nucleolar phenotype, and the downstream consequences, remain poorly understood. The PolI complex component, TIF-IA, has previously been implicated in regulating this characteristic nucleolar phenotype in response to stress. Here we explored the role of TIF-IA in senescence and ageing. We show that TIF-IA accumulation, particularly in the nucleus and nucleolus, is an early response to oncogene- and therapy-induced senescence (OIS and TIS) in vitro. Using multiple mouse models, we also demonstrate accumulation of TIF-IA in response to senescence induction and ageing in vivo. We demonstrate that TIF-IA accumulation is not required for cell cycle arrest but that in OIS and TIS, it is essential for phenotypic changes to nucleoli, the senescence-associated secretory phenotype (SASP) and establishment of stable senescence. We demonstrate that in proliferating cells, TIF-IA binds the cargo receptor, p62 (SQSTM1), and that accumulation in senescence occurs as a consequence of ATM activation, which disrupts this interaction. Finally, we show that TIF-IA accumulation causes an increase in reactive oxygen species (ROS) levels. Together, these results establish TIF-IA accumulation as a key regulator of the nucleolar phenotype and the SASP in senescence and uncover a novel, p62-dependent mechanism driving this process. These findings offer significant new insights into nucleolar size regulation in senescence and ageing, and suggest a potential relationship with the inflammatory phenotype.

Keywords:  ATM; DNA damage; PolI complex; ROS; inflammation; nucleolar; nucleolus; p62; senescence

DOI:  https://doi.org/10.1111/acel.70334