bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2025–12–21
thirty-two papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. c-Rel drives pancreatic cancer metastasis through fibronectin-integrin signaling-induced isolation stress resistance and EMT.
  2. Mechanotransduction by nuclear envelope tension.
  3. A cell-state axis underlying colonization in carcinomas with implications for metastasis risk prediction and interception.
  4. AMP-activated protein kinase-driven lipid droplet dynamics govern melanoma sensitivity to polyunsaturated fatty acid and iron-induced ferroptosis.
  5. Targeting PRDX6-dependent localization and function of GPX4 enhances ferroptosis-mediated tumor suppression.
  6. High-Dimensional Protein Analysis Uncovers Distinct Immunological and Stromal Features in Primary and Metastatic Pancreatic Ductal Adenocarcinoma.
  7. TBK1 Induces the Formation of Optineurin Filaments That Condensate with Polyubiquitin and LC3 for Cargo Sequestration.
  8. Hereditary chronic pancreatitis induced plasticity cooperates with mutant Kras in early pancreatic carcinogenesis.
  9. Early Detection of Cell Death Using Transmembrane Water Exchange Magnetic Resonance Imaging.
  10. Methods to analyze cell migration data: fundamentals and practical guidelines.
  11. Circulating Tumor Cell Infiltration of Major Vessels Influences Cancer Prognosis.
  12. AUTOPHAGIC punctum a self-sensing vacuole/lysosome: V-ATPase dysfunction activates selective autophagy.
  13. Intrinsic resistance to RAS inhibitors is driven by dysregulation of KRAS degradation.
  14. NRG1 fusion-positive solid tumors: clinical detection, genomic landscape, and real-world data in pancreatic cancer.
  15. Deprivation of EGFR signal causes senolysis in PDAC with CDK4/6 inhibition.
  16. Sleepyhead, deadly awakening: the dynamics of metastatic organotropism, tumor dormancy and therapeutic implications.
  17. Selecting the optimal cell migration assay: fundamentals and practical guidelines.
  18. Cuproptosis in cancer: from molecular mechanisms to therapeutic intervention.
  19. SpaceBar enables single-cell-resolution clone tracing with imaging-based spatial transcriptomics.
  20. Mitochondrial position responds to glucose stimulation in a model of the pancreatic beta cell.
  21. Computational prediction of human genetic variants in the mouse genome.
  22. Ferroptosis inhibitors: mechanisms of action and therapeutic potential.
  23. Serial Imaging of Tumour and microEnvironment (SITE) platform for live-cell ex vivo modelling of primary and metastatic cancer dynamics.
  24. Co-targeting KRAS and Exportin1 as an effective therapeutic strategy for KRASG12D mutant pancreatic ductal adenocarcinoma.
  25. Antibody-lectin chimeras for glyco-immune checkpoint blockade.
  26. Real-time cancer monitoring via leukocyte adhesion in a biomimetic microfluidic assay.
  27. Cell context-dependent in silico organelle localization in label-free microscopy images.
  28. Concurrent PIK3CA mutant promotes cachexia through inflammatory signaling in EGFR mutant lung cancer.
  29. Multicellular force coordination constructs microchannel networks for barrier-free metastasis across extracellular matrix.
  30. High fidelity of Claudin-18.2 expression in primary and matched metastatic (lymph nodes, peritoneum, and liver) pancreatic ductal adenocarcinoma: a foundation for targeted therapy.
  31. A clinical-stage oncology compound selectively targets drug-resistant cancers.
  32. Practical Trade-offs in 3D Cancer Imaging.
  1. Mol Cancer. 2025 Dec 15.
    c-Rel drives pancreatic cancer metastasis through fibronectin-integrin signaling-induced isolation stress resistance and EMT.
    D Bakırdöğen, K Görgülü, J Xin, L Richter, S Alcalá, L Ruiz-Cañas, C Dai, K J Frank, N Wu, K N Diakopoulos, H Ozturk, D Demircioğlu, K Peschke, R Ranjan, F Fusco, J Martinez-Useros, M J Fernandez-Aceñero, N F Chhabra, J C López-Gil, J Ai, D A Ruess, E Kaya-Aksoy, F Schmidt, L Kohlmann, A Berninger, H Yangin, F Schicktanz, K Steiger, I E Demir, R M Schmid, M Reichert, M Adli, M Lesina, B Sainz, H Algül.
      
    Keywords:  Anchorage independence; CD61; FN1; Fibronectin; Integrin β3; Metastasis; NF-κB; PDAC; c-Rel
    DOI:  https://doi.org/10.1186/s12943-025-02486-5
  2. Nucleus. 2026 Dec;17(1): 2600901
    Mechanotransduction by nuclear envelope tension.
    Sriivatsan G Rajan, Pere Roca-Cusachs, Philipp Niethammer.
      Mechanotransduction mediated by the tension in lipid membranes is a well-established paradigm. This has been studied largely in the context of the plasma membrane, but recent work shows that it applies also to endomembranes, and specifically to the nuclear envelope. Here, we review membrane tension-mediated mechanotransduction at the nuclear envelope by focusing on its two best characterized modes of action: the cytosolic phospholipase A2 (cPLA2) pathway, and nuclear pore dilation. We discuss the mechanisms involved and their physiological implications. Finally, we discuss how nuclear envelope tension can be controlled and measured, and how its properties enable mechanosensing with different context-dependency than that of the plasma membrane. These properties apply to cPLA2 and nuclear pore complexes but potentially also to many other mechanosensors yet to be discovered.
    Keywords:  Cytosolic phospholipase A2; YAP; mechanobiology; membrane; nuclear deformation; nuclear envelope; nuclear pore complex; nuclear transport; nucleus; tension
    DOI:  https://doi.org/10.1080/19491034.2025.2600901
  3. Cell Rep. 2025 Dec 15. pii: S2211-1247(25)01473-1. [Epub ahead of print]44(12): 116701
    A cell-state axis underlying colonization in carcinomas with implications for metastasis risk prediction and interception.
    Jesse S Handler, Zijie Li, Rachel K Dveirin, Jessica D Lin, Weixiang Fang, Shihan Wu, James E Forsmo, Hani Goodarzi, Elana J Fertig, Reza Kalhor.
      Metastasis to the liver drives mortality in pancreatic ductal adenocarcinoma (PDAC), yet mechanisms of colonization remain unclear. Using genomic barcoding, we developed a clonal competition model under immune surveillance, isolating murine PDAC subclones with high or low liver-colonization potential. Combined transcriptome and chromatin-accessibility analyses revealed a distinct "metastatic-potential axis," separate from the normal-to-PDAC and classical-basal axes. We established "MetScore" as a biomarker of this axis. MetScore distinguishes metastases from primary PDAC tumors in patients, predicts outcomes beyond classical-basal classifications, and generalizes across carcinoma subtypes, suggesting conserved colonization mechanisms. High-MetScore PDAC cells preferentially occupy immune cell-enriched niches, suggesting they remodel the metastatic microenvironment. Functional screening identified c-Fos as a positive mediator of colonization and a candidate anti-metastatic target. Collectively, we identify a cell-state axis underpinning PDAC liver colonization, introduce MetScore as a broadly applicable biomarker, and nominate actionable targets for peri-operative therapeutic intervention.
    Keywords:  CP: Cancer; PDAC metastasis; c-Fos; carcinoma metastasis pathways; intratumoral heterogeneity; lineage barcoding; metastasis biomarker; metastatic potential; pancreatic cancer; tumor cell fate; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2025.116701
  4. Nat Commun. 2025 Dec 17. 16(1): 11252
    AMP-activated protein kinase-driven lipid droplet dynamics govern melanoma sensitivity to polyunsaturated fatty acid and iron-induced ferroptosis.
    Sahar Motamedi, Nina Ravoet, Jonas Dehairs, Frank Vanderhoydonc, Abril Escamilla-Ayala, Malgorzata A Sliwinska, Shuncong Wang, Jakub Idkowiak, Stefaan Soenen, Patrizia Agostinis, Jean-Christophe Marine, Johannes V Swinnen.
      Ferroptosis, a regulated form of cell death driven by lipid peroxidation, holds promise for targeting treatment-resistant cancer cells. Using a panel of melanoma cell lines, we uncover variability in the timing of ferroptosis onset upon exposure to iron and polyunsaturated fatty acids (PUFAs). This heterogeneity is linked to differences in PUFA sequestration into lipid droplets (LDs) and their subcellular distribution, particularly near lipid-metabolizing organelles such as mitochondria. In late-onset models, ferroptosis is delayed by peripheral LD retention and triggered by nutrient deprivation and AMP-activated protein kinase (AMPK) activation, which promotes LD trafficking toward mitochondria. Early responders bypass this mechanism. Our findings identify nutrient status and LD dynamics as key modulators of PUFA- and iron-induced ferroptosis, offering insights for therapeutic exploitation in cancer.
    DOI:  https://doi.org/10.1038/s41467-025-66113-z
  5. Mol Cell. 2025 Dec 18. pii: S1097-2765(25)00940-2. [Epub ahead of print]85(24): 4602-4620.e9
    Targeting PRDX6-dependent localization and function of GPX4 enhances ferroptosis-mediated tumor suppression.
    Yameng Hu, Ziwen Li, Man Li, Xingui Wu, Shuxia Zhang, Miaoling Tang, Ruyuan Yu, Meisongzhu Yang, Xin Chen, Libing Song, Guido Kroemer, Valerian E Kagan, Hülya Bayir, Rui Kang, Jinbao Liu, Daolin Tang, Jun Li.
      Inducing lipid peroxidation-dependent ferroptosis is a promising anticancer strategy; however, the development of resistance poses a considerable challenge. This study identifies peroxiredoxin 6 (PRDX6) as a crucial modulator of glutathione peroxidase 4 (GPX4), affecting its localization and functional roles, thus contributing to ferroptosis resistance. PRDX6, endowed with phospholipase A2 activity, catalyzes the conversion of peroxy-phospholipids to lysophospholipids and oxidized fatty acids. Through targeted structural mutations and biochemical analyses, we demonstrate that PRDX6 binds to GPX4 via a C47 disulfide bond, facilitating GPX4's membrane translocation and enhanced production of hydroxy fatty acids. Combining the inhibition of PRDX6 with ferroptosis inducers increases lipid peroxidation, effectively suppressing tumor growth in liver and ovarian cancer mouse models, including patient-derived models. Furthermore, high PRDX6 expression correlates with shorter progression-free survival across multiple human cancer types. Collectively, our findings delineate a PRDX6-dependent mechanism in ferroptosis defense, offering new perspectives for targeted cancer therapy.
    Keywords:  PRDX6; cancer therapy; lysophospholipids; membrane translocation of GPX4
    DOI:  https://doi.org/10.1016/j.molcel.2025.11.023
  6. Cancer Res. 2025 Dec 19.
    High-Dimensional Protein Analysis Uncovers Distinct Immunological and Stromal Features in Primary and Metastatic Pancreatic Ductal Adenocarcinoma.
    Emily Greene, Natalie K Horvat, Deon Bryant Doxie, Vaunita Cohen Parihar, Jayden Kim, Cameron J Herting, Erin E Grundy, Ayana T Ruffin, Alyssa M Krasinskas, Shishir K Maithel, Juan M Sarmiento, Mihir M Shah, Mohammad Y Zaidi, Maria Diab, Olatunji B Alese, Kavita Dhodapkar, Haydn T Kissick, Bassel F El-Rayes, Chrystal M Paulos, Gregory B Lesinski.
      Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor type with poor patient outcomes. Most patients present with metastatic disease, which generally has reduced immune infiltration compared to primary tumors. Further work to elucidate the specific cellular features of metastatic PDAC is needed to guide the development of future immunotherapy strategies. Here, we investigated the hypothesis that PDAC tumors harbor distinct immunologic and stromal features depending on their anatomical site. Multiplex immunohistochemistry (mIHC), spatial analysis, and single-cell mass cytometry (CyTOF) uncovered dominant immune and stromal cell populations in tumors derived from 27 primary and 26 liver metastases. Metastatic liver tumors from PDAC patients contained reduced T cell infiltration, fibroblast populations, and collagen accumulation than primary lesions, while CD68+ cells, often co-expressing CCR2, were more abundant. Spatial analyses revealed distinct immune cell communities in primary and metastatic PDAC, whereby CK19+ cells clustered differentially with α-SMA+, CD3+, and CD68+ cells, depending on the tumor site. When comparing tumor-associated regions, the proportion of peritumoral CK19- cells remained consistent, but their composition varied by disease site. CD8+ T cells were significantly less frequent in metastatic tumors, while both CD4+ and CD8+ T cells present in primary tumors expressed more transcription factors (TFs) associated with suppressive properties, including FoxP3 and RORγt. CyTOF revealed that T cells co-expressed multiple inhibitory checkpoint receptors, most notably LAG-3 and PD-1. This report reveals that primary and metastatic tumors from PDAC patients harbor vastly distinct immunologic and stromal features at the protein level.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-1697
  7. Adv Sci (Weinh). 2025 Dec 17. e09927
    TBK1 Induces the Formation of Optineurin Filaments That Condensate with Polyubiquitin and LC3 for Cargo Sequestration.
    Maria G Herrera, Lena Kühn, Lisa Jungbluth, Verian Bader, Laura J Krause, David Kartte, Elias Adriaenssens, Sascha Martens, Jörg Tatzelt, Carsten Sachse, Konstanze F Winklhofer.
      Optineurin is an autophagy receptor that plays an important role in the selective degradation of mitochondria, protein aggregates, and intracellular pathogens. It recognizes ubiquitylated cargo by its ubiquitin-binding in ABIN and NEMO (UBAN) domain and recruits the autophagic machinery through its LC3-interacting region (LIR) domain. Phosphorylation of Optineurin by TANK-binding kinase 1 (TBK1) increases the binding of Optineurin to both ubiquitin chains and lipidated microtubule-associated protein light chain 3 (LC3). Optineurin has been reported to form foci at ubiquitylated cargo, but the underlying mechanism and how these foci are linked to selective autophagy has remained largely unknown. This study shows that phosphorylation of Optineurin by TBK1 induces the formation of filaments that phase separate upon binding to linear polyubiquitin. LC3 anchored to unilamellar vesicles co-partitions into Optineurin/polyubiquitin condensates, resulting in the local deformation of the vesicle membrane. Thus, the condensation of filamentous Optineurin with ubiquitylated cargo promotes the nucleation of cargo and its subsequent alignment with LC3-positive nascent autophagosomes, suggesting that co-condensation processes ensure directionality in selective autophagy.
    Keywords:  Optineurin; TBK1; autophagy; phase separation; ubiquitin
    DOI:  https://doi.org/10.1002/advs.202509927
  8. Gut. 2025 Dec 19. pii: gutjnl-2025-335947. [Epub ahead of print]
    Hereditary chronic pancreatitis induced plasticity cooperates with mutant Kras in early pancreatic carcinogenesis.
    Tanvi Vikrant Inamdar, Ferdinand Krannich, Nico Hesselbarth, Atul Verma, Teresa Vauti, Mariami Helena Jasaszwili, Ghanem El Kassem, Jasmine Hillmer, Tom Kaune, Michael Boettcher, Ivonne Regel, Heidi Griesmann, Irene Esposito, Markus Glaß, Monika Hämmerle, Patrick Michl, Helmut Laumen, Jonas Rosendahl.
       BACKGROUND: Chronic pancreatitis (CP) is a risk factor for pancreatic cancer, with inherited cases conferring a markedly increased risk. The underlying mechanisms driving malignant transformation by CP remain poorly understood.
    OBJECTIVE: Combining a recently developed mouse model of CP carrying the human carboxypeptidase A1 (CPA1) p.N256K mutation with the established KrasG12D pancreatic cancer model, we characterised mechanisms linking chronic inflammation to early pancreatic carcinogenesis.
    DESIGN: We crossed Cpa1 N256K mice (Cpa1) with Ptf1aCre;KrasLSL-G12D (KC). In Cre, Cpa1, KC and KC-Cpa1 mice, we performed phenotypical characterisation at five early time points and in an ageing cohort. Assessment of histology combined with both RNA-sequencing and single-cell RNA-sequencing was performed to analyse metaplasia, preneoplastic lesions and cellular heterogeneity.
    RESULTS: KC-Cpa1 pancreata displayed a stark increase in remodelling, fibrosis and formation of metaplastic lesions as compared with KC. Cpa1N256K induced extensive plasticity in both the acinar and ductal compartment, including an early acinar-to-ductal metaplasia state in acinar cells characterised by an upregulation of endoplasmic reticulum stress markers and an inflammatory ductal phenotype (iDucts). We characterised the complex cell-cell communication networks underlying both pancreatic inflammation and early carcinogenesis, revealing disease-specific signalling between ductal cells, granulocytes and fibroblasts.
    CONCLUSIONS: The humanised KC-Cpa1 mouse model reveals the interplay of inflammation in hereditary CP and carcinogenesis. Cpa1N256K -induced plasticity in acinar and ductal cells, inflammation and cell-cell interaction networks cooperate with KrasG12D in early pancreatic carcinogenesis.
    Keywords:  Pancreatic Cancer; Pancreatic Damage; Pancreatic Disease; Pancreatitis
    DOI:  https://doi.org/10.1136/gutjnl-2025-335947
  9. Adv Sci (Weinh). 2025 Dec 17. e13317
    Early Detection of Cell Death Using Transmembrane Water Exchange Magnetic Resonance Imaging.
    Athanasia Kaika, Luca Nagel, Ulrike Höckendorf, Bangwen Xie, Geoffrey J Topping, Mathias Schillmaier, Irina Beer, Frits H A van Heijster, Julian Rauch, Tristan A Kuder, Sandra Sühnel, Bernd Erber, Christian Lohrmann, Simone Ballke, Thomas Metzler, Katja Steiger, Philipp J Jost, Natalia P Ivleva, Philipp Paprottka, Jonathan Nadjiri, Kevin M Brindle, Wolfgang A Weber, Franz Schilling.
      Cell death plays a key role in cancer progression and treatment. After its onset, cell membrane integrity is often compromised. Here, it is shown in cells, animals and humans that the transmembrane water exchange rate, measured using magnetic resonance filter-exchange spectroscopy (FEXSY) or imaging (FEXI), and quantified by the apparent exchange rate (AXR), is an early biomarker of cell death. AXR measurements detect the onset of cell death in vivo earlier than diffusion-weighted MRI (DWI) and in vitro with similar sensitivity as flow cytometry. 13C magnetic resonance imaging (MRI) measurements of the malate/fumarate ratio (MFR), following injection of hyperpolarized [1,4-13C2]fumarate, in tumors displaying diffuse necrosis, are correlated with AXR. AXR detects early treatment response in colorectal and lymphoma tumor models while the apparent diffusion coefficient (ADC) measured by DWI remains unchanged. AXR measurements in human uterine fibroids show sensitivity to post-treatment changes soon after embolization, demonstrating clinical translatability of the method.
    Keywords:  MRI; cell death; diffusion; transmembrane water exchange
    DOI:  https://doi.org/10.1002/advs.202513317
  10. Nat Methods. 2025 Dec 18.
    Methods to analyze cell migration data: fundamentals and practical guidelines.
    Pei-Hsun Wu, Jude M Phillip, Wenxuan Du, Andre Forjaz, Praful R Nair, Denis Wirtz.
      Cell migration assays provide invaluable insights into fundamental biological processes. In a companion Review, we describe commercial and custom in vitro and in vivo assays to measure cell migration and provide guidelines on how to select the most appropriate assay for a given biological question. Here, we describe the fundamental principles of how to compute-from the raw data generated by these assays-quantitative cell migration parameters that help determine the biophysical nature of the cell migration, such as cell speed, mean-squared displacement, diffusivity, persistence, speed and anisotropy, and how to quantify cell heterogeneity, with practical guidance. We also describe new imaging and computational technologies, including AI-based methods, which have helped establish fast, robust and accurate tracking of cells and quantification of cell migration. Taken together, these Reviews offer practical guidance for cell migration assays from conception to analysis.
    DOI:  https://doi.org/10.1038/s41592-025-02935-5
  11. Cancer Discov. 2025 Nov 28. OF1
    Circulating Tumor Cell Infiltration of Major Vessels Influences Cancer Prognosis.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2025-103
  12. Autophagy. 2025 Dec 18.
    AUTOPHAGIC punctum a self-sensing vacuole/lysosome: V-ATPase dysfunction activates selective autophagy.
    Yuxiang Huang, Daniel J Klionsky.
      Macroautophagy/autophagy has long been viewed as being strictly dependent on vacuolar or lysosomal acidity, with the vacuolar-type H+ -translocating ATPase (V-ATPase) functioning mainly as a proton pump that sustains degradation. Our recent paper overturns this paradigm, revealing that loss of V-ATPase activity paradoxically induces a selective autophagy program in nutrient-replete Saccharomyces cerevisiae. Vacuolar deacidification triggers a signaling cascade through the Gcn2-Gcn4/ATF4 integrated stress response, which drives Atg11-dependent ribophagy even when TORC1 remains active. This "V-ATPase-dependent autophagy" operates as a self-corrective feedback loop: when the vacuole's degradative capacity falters, it signals its own dysfunction to restore homeostasis. Tryptophan and NAD+ metabolism modulate this response, linking metabolic balance to autophagy induction. This discovery reframes the vacuole/lysosome from a passive endpoint to an active sensor of cellular integrity. It also challenges the use of V-ATPase inhibitors such as bafilomycin A1 as neutral autophagy flux blockers, because inhibition itself can stimulate autophagy induction. Collectively, these findings position the V-ATPase as a bidirectional regulator - both gatekeeper and sentinel - governing how cells translate organelle stress into adaptive autophagy.
    Keywords:  ATF4/Gcn4; NAD+ metabolism; V-ATPase; ribosome biogenesis; selective autophagy; tryptophan metabolism
    DOI:  https://doi.org/10.1080/15548627.2025.2604345
  13. Nat Commun. 2025 Dec 15.
    Intrinsic resistance to RAS inhibitors is driven by dysregulation of KRAS degradation.
    Tonci Ivanisevic, Yan Ma, Emiel Van Boxel, Wout Magits, Benoit Lechat, Zeynep Koçberber, Phillipp Willnow, Sarah-Maria Fendt, Greetje Vande Velde, Raj Sewduth, Anna A Sablina.
      Activating mutations in KRAS occur in approximately 30% of lung adenocarcinomas. Despite advances in RAS-targeted therapies, intrinsic resistance limits their long-term efficacy. Here, we identify elevated levels of wild-type KRAS (WT-KRAS) protein as a key driver of intrinsic resistance in KRAS-mutant lung tumors. KRAS accumulation results from impaired LZTR1-mediated degradation, triggered either by LZTR1 loss or pharmacological RAS inhibition. Stabilized WT-KRAS activates the mTOR/HIF1α pathway by promoting lysosomal recruitment of the SLC3A2/SLC7A5 amino acid transporter complex, reprogramming lysosomal amino acid sensing. Shallow deletions of LZTR1, present in up to 40% of KRAS-mutant lung adenocarcinomas, are associated with increased mTOR activity and may contribute to therapeutic resistance to RAS inhibitors. Co-inhibition of mTOR or the SLC3A2/SLC7A5 complex using dactolisib or JPH203 restores sensitivity to KRAS inhibitors in vitro and in vivo. These findings support combinatorial targeting of mTOR signaling or amino acid transport to overcome intrinsic resistance in KRAS-mutant lung cancer.
    DOI:  https://doi.org/10.1038/s41467-025-67109-5
  14. J Natl Cancer Inst. 2025 Dec 13. pii: djaf361. [Epub ahead of print]
    NRG1 fusion-positive solid tumors: clinical detection, genomic landscape, and real-world data in pancreatic cancer.
    Alison M Schram, Soo-Ryum Yang, Genessa Kahn, Rogelio Velasco, Matteo Repetto, Richard Kinh Gian Do, Sara DiNapoli, Purvil Sukhadia, Megan Troxel, Kerem Ozcan, Zeynep Tarcan, Marc Ladanyi, James J Harding, Alexander Drilon, Olca Basturk, Eileen M O'Reilly.
       BACKGROUND: NRG1 fusions are unique oncogenic drivers that activate the HER3/HER2/PI3K pathway. The FDA granted Accelerated Approval to a HER2/HER3 antibody, zenocutuzumab, for treatment of NRG1 fusion-positive (NRG1+) non-small-cell lung and pancreatic cancer (PDAC). The optimal detection methods and clinicopathologic features of patients with NRG1+ cancer have not been systematically studied. We review NRG1+ cancer and focus on outcomes in PDAC.
    METHODS: NRG1+ patients at Memorial Sloan Kettering were identified using institutional databases. Clinicopathologic data were extracted from the medical record. NRG1+ PDAC cases underwent review of radiology, pathology, treatment data, and assessment of progression-free and overall survival.
    RESULTS: Out of 76,531 patients, 48 NRG1+ cases were identified. The most common tumor types were lung (60%), PDAC (21%), and breast (10%). Approximately half (46%) received HER2 and/or HER3-directed therapy. Patients were identified by RNA (n = 34), DNA (n = 11), or both (n = 3). RNA was superior to DNA for fusion identification. Twenty-one fusion partners were detected, most commonly CD74 (40%) and ATP1B1 (10%). Lung cancers were otherwise driver-negative and PDAC were KRAS wild-type. NRG1+ PDAC exhibited distinct histopathologic and clinical features. Median age was 48.5 years, median PFS on 1st-line chemotherapy was 12.6 months (n = 7; 95% CI 2.9-NR), and median OS from diagnosis was 39.6 months (n = 9; 95% CI 23.2-NR).
    CONCLUSIONS: NRG1 fusions are a newly described clinically actionable target in solid tumors. We report the landscape of NRG1+ cancers and highlight the importance of RNA testing. NRG1+ PDAC is enriched in younger patients with KRAS wild-type disease and has a unique biology.
    DOI:  https://doi.org/10.1093/jnci/djaf361
  15. Cell Death Differ. 2025 Dec 18.
    Deprivation of EGFR signal causes senolysis in PDAC with CDK4/6 inhibition.
    Yuanyuan Zhang, Susumu Kohno, Keqi Gao, Mahadi Hasan, Tomohisa Baba, Zixue Zhang, Nao Sankoda, Hai Yu, Junjian Pan, Noriko Gotoh, Makoto Nakanishi, Yasuhiro Yamada, Jindan Sheng, Takiko Daikoku, Yoshikazu Johmura, Chiaki Takahashi.
      Approved KRAS inhibitors have shown limited therapeutic benefit over standard chemotherapy in PDAC and often encounter acquired resistance due to additional genetic alterations. RAS and RB1 functionally antagonize each other, which explains why RB1 is rarely mutated in KRAS-driven tumors. In PDAC cells, CDK4/6 inhibition induced cellular senescence accompanied by partial apoptosis. However, additional treatment with a senolytic agent or an ERK inhibitor promoted more efficient tumor cell elimination. While CDK4/6 inhibition downregulated KRAS activity, it concurrently upregulated EGFR signaling in a SASP and JNK-dependent manner. Deprivation of EGFR signaling after CDK4/6 inhibition triggered apoptosis in senescent cells in a manner similar to the treatment with a senolytic agent. In contrast, specific inhibition of KRAS induced modest enhancement of EGFR activity and SASP in a JNK-independent manner. Collectively, our study proposes that the CDK4/6 inhibitor may achieve greater therapeutic efficacy when combined with the EGFR inhibitor than KRAS inhibitor monotherapy.
    DOI:  https://doi.org/10.1038/s41418-025-01634-0
  16. Front Oncol. 2025 ;15 1701031
    Sleepyhead, deadly awakening: the dynamics of metastatic organotropism, tumor dormancy and therapeutic implications.
    Soumyajit Sarkar, Suresh P K.
      As per the global mortality-related data, metastasis and tumor-related relapse are the major determinants of cancer-related deaths. This phenomenon is largely driven by tumor dormancy - a state in which disseminated tumor cells (DTCs) persist in a non-proliferative phase. These dormant cells evade immune surveillance and resist conventional therapies, contributing to late relapse and metastatic outgrowth. Dormancy is maintained through intricate crosstalk between cancer cells and the microenvironment, involving extracellular matrix components, and various cellular signaling pathways. However, changes in these microenvironmental cues can disrupt this balance and reactivate dormant cells, leading to their proliferation and metastatic colonization. The undetectability of dormant DTCs complicate therapeutic targeting, underscoring the need to elucidate the molecular and epigenetic mechanisms that regulate dormancy maintenance and escape. This review explores the key signaling mechanisms and microenvironmental influences that regulates the tumor dormancy. Furthermore, we discuss emerging therapeutic strategies aimed at eradicating dormant cancer cells - either by maintaining dormant state, reactivating and sensitizing dormant cells to chemotherapy, or directly eliminating dormant populations. A deeper understanding of dormancy biology holds promise for developing innovative interventions to prevent recurrence and improve long-term patient survival.
    Keywords:  cancer recurrence; microenvironmental signaling; organotropism; therapeutic approaches; tumor dormancy
    DOI:  https://doi.org/10.3389/fonc.2025.1701031
  17. Nat Methods. 2025 Dec 18.
    Selecting the optimal cell migration assay: fundamentals and practical guidelines.
    Wenxuan Du, Praful R Nair, Andre Forjaz, Jude M Phillip, Pei-Hsun Wu, Denis Wirtz.
      Cell migration is a key cellular process that drives major developmental programs. To mimic and mechanistically understand cell migration in these different contexts, different assays have been developed. However, owing to the lack of practical guidelines, these different cell migration assays are often used interchangeably. This and the inherent dynamic nature of cell migration, which often requires sophisticated live-cell microscopy, may have caused cell migration to be notably less well understood than equally important cell functions, such as cell differentiation or proliferation. In this Review, we describe commonly used custom and commercial in vitro and in vivo cell migration assays and provide a comprehensive practical guide and decision tree outlining how to choose and implement an assay that best suits the biological question at hand. We hope this guidance spurs biological insights into this complex process and encourages future methods development.
    DOI:  https://doi.org/10.1038/s41592-025-02890-1
  18. Trends Cancer. 2025 Dec 18. pii: S2405-8033(25)00309-7. [Epub ahead of print]
    Cuproptosis in cancer: from molecular mechanisms to therapeutic intervention.
    Dadi Jiang, Li Zhuang, Albert C Koong, Boyi Gan.
      Cuproptosis, a recently discovered form of regulated cell death triggered by copper overload, is distinguished by the aggregation of lipoylated mitochondrial proteins and destabilization of iron-sulfur cluster proteins. Given the altered copper metabolism and metabolic dependencies of cancer cells, cuproptosis might represent a unique vulnerability with therapeutic potential. In this review we summarize current knowledge of copper homeostasis, the molecular mechanisms of cuproptosis and its roles in cancer biology. We highlight therapeutic strategies that harness cuproptosis, including copper ionophores, nanomedicine, and rational combination therapies, and discuss challenges such as systemic toxicity, resistance mechanisms, and biomarker development. Finally, we outline key questions and future directions for translating cuproptosis into the clinic.
    Keywords:  cancer therapy; copper; cuproptosis; protein lipoylation; regulated cell death
    DOI:  https://doi.org/10.1016/j.trecan.2025.12.002
  19. Nat Methods. 2025 Dec 18.
    SpaceBar enables single-cell-resolution clone tracing with imaging-based spatial transcriptomics.
    Grant Kinsler, Caitlin Fagan, Haiyin Li, Jessica Kaster, Maggie Dunne, Robert J Vander Velde, Ryan H Boe, Sydney Shaffer, Meenhard Herlyn, Arjun Raj, Yael Heyman.
      Imaging-based spatial transcriptomics methods allow for the measurement of spatial determinants of cellular phenotypes but are incompatible with random barcode-based clone-tracing methods, preventing the simultaneous detection of clonal and spatial drivers. Here we report SpaceBar, which enables simultaneous clone tracing and spatial gene expression profiling with standard imaging-based spatial transcriptomics pipelines. Our approach uses a library of 96 synthetic barcode sequences that combinatorially labels each cell. Thus, SpaceBar can distinguish between clonal dynamics and environmentally driven transcriptional regulation in complex tissue contexts.
    DOI:  https://doi.org/10.1038/s41592-025-02968-w
  20. Biophys J. 2025 Dec 18. pii: S0006-3495(25)00767-2. [Epub ahead of print]
    Mitochondrial position responds to glucose stimulation in a model of the pancreatic beta cell.
    Luis Perez, Xue Wen Ng, Michael Mohs, David W Piston, Shankar Mukherji.
      The compartmentalization of eukaryotic cells into membrane-bound organelles with specific subcellular positioning enables precise spatial and temporal control of cellular functions. Although functionally significant mitochondrial localization has been demonstrated in cells such as neurons, it remains unclear how general these cell principles are. Here, we examine the spatial organization of mitochondria within MIN6 pancreatic beta cells under variable glucose conditions. We observe glucose-dependent redistributions of mitochondria, favoring peripheral localization at elevated glucose levels. Our results, formalized into a stochastic model of mitochondrial trafficking, suggest that active mitochondrial transport along microtubules and PKA signaling activity, but not ATP synthesis, are critical regulators of this redistribution. These results suggest that environmentally responsive mitochondrial subcellular positioning may represent a general regulatory mechanism in even nonpolarized cell types.
    DOI:  https://doi.org/10.1016/j.bpj.2025.11.018
  21. Nat Biotechnol. 2025 Dec 18.
    Computational prediction of human genetic variants in the mouse genome.
    Kexin Dong, Samuel I Gould, Minghang Li, Francisco J Sánchez Rivera.
      The design of genetically engineered mouse models would benefit from a computational pipeline to predict mouse genetic variants that mirror the sequence and functional effects of human disease variants. Here we present H2M (human-to-mouse), which achieves this by integrating mouse-to-human and paralog-to-paralog variant mapping analyses with genome-editing tools. We provide a database containing >3 million human-mouse equivalent mutation pairs and base-editing and prime-editing libraries to engineer 4,944 variant pairs.
    DOI:  https://doi.org/10.1038/s41587-025-02925-0
  22. Cell Mol Life Sci. 2025 Dec 19. 82(1): 441
    Ferroptosis inhibitors: mechanisms of action and therapeutic potential.
    Kun Duo, Xiaona Feng, Xiaofang Tian, Fang Wang, Yaxing Zhao, Jianqiang Yu, Yue Liu, Yuan He, Zhenyu Cai.
      Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation. It plays a crucial role in various pathological conditions, including neurodegenerative diseases, cancer, ischemia-reperfusion injury, and organ failure. This review systematically explores the key mechanisms underlying ferroptosis, including polyunsaturated fatty acid-containing phospholipid (PUFA-PL) peroxidation, iron metabolism, and mitochondrial dysfunction. Additionally, we summarize major endogenous ferroptosis defense systems, including the SLC7A11-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis, the ferroptosis suppressor protein 1 (FSP1)-ubiquinol (CoQH₂) system, the mitochondrial dihydroorotate dehydrogenase (DHODH)-CoQH₂ pathway, and the guanosine triphosphate cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4) pathway, which act as critical brakes on ferroptosis. Furthermore, we discuss various small-molecule inhibitors targeting ferroptosis, categorized by their mechanisms of action, including iron chelators, lipid peroxidation inhibitors, antioxidants, and regulatory pathway modulators. Recent advances in pharmacological strategies and their potential therapeutic applications are also highlighted.
    Keywords:  Ferroptosis; Iron metabolism; Lipid peroxidation; Mitochondrial dysfunction; Small-molecule inhibitors
    DOI:  https://doi.org/10.1007/s00018-025-05958-5
  23. bioRxiv. 2025 Nov 25. pii: 2025.09.08.674915. [Epub ahead of print]
    Serial Imaging of Tumour and microEnvironment (SITE) platform for live-cell ex vivo modelling of primary and metastatic cancer dynamics.
    Vaibhav Murthy, Rawan Makkawi, Francis Anderson, Carol Halsey, Elise Manalo-Hall, Sanjay Srikanth, Gabriella Tangkilisan, Ting Zheng, James McGann, Marc R Birtwistle, Jeremy Copperman, Alexander E Davies.
      Understanding cancer initiation and progression is extremely challenging, in part due to experimental limitations in measuring and interpreting key signalling and tumour-microenvironment (TME) interactions that determine changes in cell and tissue behaviours over time. Here we developed SITE (Serial Imaging of Tumour and microEnvironment), a spatially-and temporally integrated, modular, ex vivo platform enabling quantitative analysis of TME interaction dynamics, signalling, and cell fate at single cell and tissue scales. Applied to modelling primary and lung metastatic breast cancer, SITE revealed tissue-specific TME interactions and ERK signalling patterns linked to distinct single-cell behaviours. We found that the earliest steps in tumour establishment and metastatic seeding involved active cell protrusion and the establishment of a multicellular niche interfacing tumour and host. Experimental and mathematical modelling showed that ERK signalling was co-influenced by these interactions, where cancer cluster formation increased signalling via the establishment of local signalling circuits. Disruption of these signalling circuits led to tissue-specific impacts on cancer intrinsic and TME interaction dynamics. Here, we modelled breast cancer as a test case, demonstrating the broad utility of SITE for quantitative exploration of TME interaction dynamics‒ closing a significant gap in experimental capabilities between in vivo models and in vitro systems.
    DOI:  https://doi.org/10.1101/2025.09.08.674915
  24. bioRxiv. 2025 Nov 25. pii: 2025.11.21.689857. [Epub ahead of print]
    Co-targeting KRAS and Exportin1 as an effective therapeutic strategy for KRASG12D mutant pancreatic ductal adenocarcinoma.
    Husain Yar Khan, Mohammed Najeeb Al Hallak, Amro Aboukameel, Sahar F Bannoura, Md Hafiz Uddin, Adeeb A Aboukameel, Fulya Koksalar Alkan, Ahmet B Caglayan, Hilmi K Alkan, Bin Bao, Hugo Jimenez, Allan M Johansen, Callum McGrath, Grayson Barker, Khalil Choucair, Miguel Tubon, Eliza Beal, Steve Kim, Rafic Beydoun, Gregory Dyson, Yang Shi, Misako Nagasaka, Azeddine Atfi, Hasan Korkaya, Muhammad Wasif Saif, Philip A Philip, Bassel El-Rayes, Herbert Chen, Anthony F Shields, Ramzi M Mohammad, Boris C Pasche, Asfar S Azmi.
       Background: Several KRASG12D inhibitors (KRASG12Di) are under clinical evaluation for pancreatic ductal adenocarcinoma (PDAC). However, as seen with other first generation KRAS inhibitors, resistance may limit their long-term efficacy, necessitating combination strategies to enhance therapeutic outcomes. Exportin 1 (XPO1), a nuclear transport protein overexpressed in PDAC, represents a therapeutic vulnerability in KRAS-mutant cancers. Here, we demonstrate that the second-generation XPO1 inhibitor Eltanexor synergizes with MRTX1133 to enhance its efficacy in multiple PDAC models.
    Methods: We generated KRASG12Di-resistant PDAC cells and assessed their response to Eltanexor. The antiproliferative effects of MRTX1133 and Eltanexor combinations were evaluated in 2D and 3D in vitro PDAC models. The in vivo efficacy of the combination was tested in KRASG12D-mutant human and murine PDAC xenograft and allograft models.
    Results: Eltanexor sensitized MRTX1133-resistant PDAC cells to growth inhibition. In both 2D and 3D culture models, the combination of Eltanexor and MRTX1133 significantly reduced cell viability. Mechanistically, the combination treatment suppressed key KRAS downstream signaling molecules, including p-ERK, mTOR, p-4EBP1, DUSP6, and cyclin D1. Kinome analysis further revealed reduced MAPK-related kinase activity. Combining subtherapeutic doses of Eltanexor and MRTX1133 resulted in significant tumor regression and prolonged survival in PDAC xenograft and immunocompetent orthotopic allograft models. Moreover, maintenance therapy with Eltanexor prevented tumor relapse, yielding a durable antitumor response.
    Conclusion: This study demonstrates that Eltanexor overcomes resistance to MRTX1133 and enhances its efficacy in PDAC. The combination regimen may provide a durable therapeutic response while reducing the required dose of KRASG12D inhibitors, potentially delaying resistance and improving patient outcomes.
    Statement of Translational Relevance: PDAC remains one of the deadliest malignancies, with limited effective therapies and dismal survival rates. The emergence of KRASG12D-selective inhibitors, such as MRTX1133, marks a critical advance for nearly 40% of PDAC patients harboring this oncogenic driver. However, inevitable emergence of adaptive or acquired resistance to KRAS inhibitors remains a major barrier to achieving durable clinical benefit. This study uncovers XPO1 inhibition as a rational and synergistic strategy to augment the antitumor efficacy of MRTX1133. By enhancing KRASG12D inhibitor activity and potentially reducing the required therapeutic dose, this combination approach offers a novel means to delay or overcome resistance. These findings provide a strong preclinical rationale for clinical trials evaluating KRAS inhibitors in combination with XPO1 inhibitors and may significantly improve outcomes for a substantial subset of PDAC patients who currently lack effective targeted treatment options.
    DOI:  https://doi.org/10.1101/2025.11.21.689857
  25. Nat Biotechnol. 2025 Dec 16.
    Antibody-lectin chimeras for glyco-immune checkpoint blockade.
    Jessica C Stark, Melissa A Gray, Itziar Ibarlucea-Benitez, Marta Lustig, Annalise Bond, Brian Cho, Ishika Govil, Tran Luu, Megan J Priestley, Tim S Veth, Wesley J Errington, Bence Bruncsics, Mikaela K Ribi, Leo A Williams, Casim A Sarkar, Simon Wisnovsky, Nicholas M Riley, Meghan A Morrissey, Thomas Valerius, Jeffrey V Ravetch, Carolyn R Bertozzi.
      Despite the curative potential of checkpoint blockade immunotherapy, many patients remain unresponsive to existing treatments. Glyco-immune checkpoints, which involve interactions of cell-surface glycans with lectin, or glycan-binding, immunoreceptors, have emerged as prominent mechanisms of immune evasion and therapeutic resistance in cancer. Here, we describe antibody-lectin chimeras (AbLecs), a modular system for glyco-immune checkpoint blockade. AbLecs are bispecific antibody-like molecules comprising a cell-targeting antibody domain and a lectin 'decoy receptor' domain that directly binds glycans and blocks their ability to engage inhibitory lectin receptors. AbLecs potentiate cancer cell destruction by primary human immune cells in vitro and reduce tumour burden in a humanized, immunocompetent mouse model, outperforming most existing therapies and combinations tested. By targeting a distinct axis of immunological regulation, AbLecs synergize with blockade of established immune checkpoints. AbLecs can be readily designed to target numerous tumours and immune cell subsets as well as glyco-immune checkpoints, thus representing a potential modality for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41587-025-02884-6
  26. Biosens Bioelectron. 2025 Dec 12. pii: S0956-5663(25)01188-1. [Epub ahead of print]295 118311
    Real-time cancer monitoring via leukocyte adhesion in a biomimetic microfluidic assay.
    Brian Choi, Seyong Kwon, Min Seok Lee, Amanzhol Kurmashev, Joo H Kang.
      Cancer progression involves cell adhesion molecules (CAMs), which facilitate the recruitment of leukocytes and metastatic tumor cells to distant organs by mediating adhesion with endothelial cells. While CAM-mediated tumor dissemination is well studied, the diagnostic potential of CAM ligand-expressing activated leukocytes as biomarkers reflecting the host's inflammatory response to cancer remains relatively unexplored. This study presents a microfluidic device that assesses cancer-driven leukocyte activation in a 4T1 breast cancer mouse model by quantifying leukocyte adhesion to CAM-coated microchannels under physiological flow conditions. In a 4T1 mouse model, inflammation induces upregulation of CAM ligands that enhance selectin-mediated adhesion between leukocytes and endothelial cells. The proportion of leukocytes expressing CAM ligands correlates with cancer progression, accompanied by an approximately 40-fold enhancement in leukocyte adhesion within a vascular endothelium-mimicking microchannel coated with CAMs following implantation of 4T1 cells in mice. Quantification of leukocyte adhesion in this system discriminates experimental conditions corresponding to primary tumor growth, chemotherapeutic response, and postsurgical recurrence or metastasis in the 4T1 mouse model. These findings establish leukocyte adhesion profiling in a biomimetic microfluidic assay as a functional biomarker of cancer-driven inflammation in vivo and support its potential as a complementary tool for translational cancer monitoring.
    Keywords:  Biomimetics; Cancer diagnosis; Cancer prognosis; Cell adhesion molecules; Leukocyte capture
    DOI:  https://doi.org/10.1016/j.bios.2025.118311
  27. Nat Methods. 2025 Dec 19.
    Cell context-dependent in silico organelle localization in label-free microscopy images.
    Nitsan Elmalam, Assaf Zaritsky.
      The in silico labeling prediction of organelle fluorescence from label-free microscopy images has the potential to revolutionize our understanding of cells as integrated complex systems. However, out-of-distribution data caused by changes in the intracellular organization across cell types, cellular processes or perturbations can lead to altered label-free images and impaired in silico labeling. Here we demonstrate that incorporating biological meaningful cell contexts, via a context-dependent model that we call CELTIC, enhanced in silico labeling prediction and enabled the downstream analysis of out-of-distribution data such as cells undergoing mitosis and cells located at the edge of the colony. These results suggest a link between cell context and intracellular organization. Using CELTIC to generate single-cell images transitioning between different contexts enabled us to overcome intercell variability toward the integrated characterization of organelles' alterations in cellular organization. The explicit inclusion of context has the potential to harmonize multiple datasets, paving the way for generalized in silico labeling foundation models.
    DOI:  https://doi.org/10.1038/s41592-025-02960-4
  28. Nat Commun. 2025 Dec 16.
    Concurrent PIK3CA mutant promotes cachexia through inflammatory signaling in EGFR mutant lung cancer.
    Meiting Yue, Zhen Qin, Shijie Tang, Xinlei Cai, Yikai Zhao, Chen Yang, Liang Chen, Luonan Chen, Hongbin Ji.
      PIK3CA mutation is frequently concurrent with known oncogenic drivers such as EGFR mutation in lung cancer, raising an interesting question about its real function. Cachexia is a systemic disease arising from tumor-organ crosstalk, significantly contributing to cancer-related mortality. Through integrative study of genetically engineered mouse models (GEMMs) and clinical data, we find concurrent PIK3CA mutant preferentially drives cachexia in EGFR-mutant lung cancer, promoting malignant progression instead of cancer initiation. PIK3CA mutant-mediated cachexia can be overcome by osimertinib (Osi) treatment in Osi-sensitive GEMM. In contrast, chemotherapy, routinely used in clinic for those relapsed from Osi therapy, fails to ameliorate cachexia in Osi-resistant GEMM despite notable tumor suppression. PIK3CA mutant-driven cachexia is mediated through NF-κB activation and can be dampened by combined aspirin treatment. This work provides insights into PIK3CA mutant biological function and mechanisms behind its clinical impacts, and proposes a potential strategy for clinical management.
    DOI:  https://doi.org/10.1038/s41467-025-67345-9
  29. Sci Adv. 2025 Dec 19. 11(51): eadz4291
    Multicellular force coordination constructs microchannel networks for barrier-free metastasis across extracellular matrix.
    Huan Gao, Bo Cheng, Guorui Jin, Yulong Han, Qi Tian, Yan Zhou, Xiwen Zhao, Yan Liu, Chunyu Cao, Lizhe Zhu, Juan Zhang, Lin Wang, Binghe Xu, Hui Guo, Min Lin, Jin Yang, Feng Xu.
      The extracellular matrix (ECM) acts as a primary physical barrier to cancer metastasis. While individual cancer cells can remodel ECM to create microchannel-like paths of least resistance, this cell-centric view overlooks the coordinated dynamics of multicellular communication. Here, we reveal that cancer cells collaboratively reprogram ECM to construct interconnected microchannel networks functioning as "superhighways" for barrier-free metastasis. Combining live-cell imaging, atomic force microscopy, and optical tweezers, we decode that the indispensable step in microchannel network construction is organized cross-convergence of adjacent channels. The convergence is precisely directed by mechanical bridges composed of aligned collagen bundles between adjacent channels, which transmit orientation cues to induce multicellular force coordination. Integrating single-cell sequencing and off-lattice agent-based model, we identify mechanically responsive leader cells enriched for integrin-RhoA/YAP signaling and matrix metalloproteinase 14, which sense bridge cues and initiate cross-convergence. Collectively, our findings unveil a self-organized metastatic network and its mechanobiological mechanisms, offering a previously unidentified framework and potential therapeutic insights for cancer metastasis.
    DOI:  https://doi.org/10.1126/sciadv.adz4291
  30. Hum Pathol. 2025 Dec 11. pii: S0046-8177(25)00301-6. [Epub ahead of print]168 106014
    High fidelity of Claudin-18.2 expression in primary and matched metastatic (lymph nodes, peritoneum, and liver) pancreatic ductal adenocarcinoma: a foundation for targeted therapy.
    Carlotta Franzina, Michele Bevere, Samantha Bersani, Paola Mattiolo, Carlotta Ceccon, Paola Piccoli, Giuseppe Malleo, Rita T Lawlor, Roberto Salvia, Michele Milella, Matteo Fassan, Aldo Scarpa, Claudio Luchini.
      Claudin-18.2 (CLDN18.2) is a tight-junction protein that can be expressed in various neoplasms, including pancreatic ductal adenocarcinoma (PDAC). Anti-CLDN18.2 targeted therapies have already been approved for CLDN18.2-positive gastric cancer and are currently being tested in clinical trials for PDAC. This study aims to define the expression patterns and concordance rate of CLDN18.2 in primary and matched metastatic PDAC. Whole-slide immunohistochemistry for CLDN18 was performed on primary PDAC and matched metastases, and was assessed by cell percentage (range: 0-100 %) and intensity of CLDN18-positivity (scores 0, 1+, 2+, and 3+), and also using the H-score. Tumor positivity for CLDN18 was determined if ≥ 75 % of tumor cells exhibited 2+/3+ staining. The study's cohort was composed of 20 patients with PDAC and concomitant lymph node metastases (LNM), 30 patients with PDAC and matched peritoneal metastases (PM), and 12 patients with PDAC and concomitant liver metastases (LIVM). The mean value of the percentages of 2+/3+ cells for primary tumors was 46.5 %, for LNM was 60 %, for PM was 31 %, and for LIVM was 22 %. The mean value of the H-score for primary tumors was 123.9, for LNM was 183, for PM was 89.1, and for LIVM was 54.6. The correspondence rate between primary PDAC and the matched metastatic sites was: 70.0 % for PDAC/LNM, 93.3 % for PDAC/PM, and 100.0 % for PDAC/LIVM. This study shows a high rate of correspondence of CLDN18-positivity between primary PDAC and different metastatic sites, providing a strong rationale for further exploring and testing anti-CLDN18.2 therapeutic strategies in this lethal malignancy.
    Keywords:  CLDN18; CLDN18.2; Claudin; Metastases; Metastasis; PDAC; Pancreatic cancer
    DOI:  https://doi.org/10.1016/j.humpath.2025.106014
  31. bioRxiv. 2025 Nov 30. pii: 2025.11.26.690878. [Epub ahead of print]
    A clinical-stage oncology compound selectively targets drug-resistant cancers.
    Kaitlin Long, Debanjan Bhattacharjee, Samuel H Newman-Stonebraker, Simon Suhr, Brandon Q Mercado, Anthony Tighe, Luciano Romero, Sarah L Thompson, Erin L Sausville, Kristen M John, Linda Julian, Sanat Mishra, Olaf Klingbeil, Punya Gupta, Uditi Bhatt, Allen C Gao, Sara Ricardo, Christopher R Vakoc, Beat C Bornhauser, Steven M Corsello, Stephen S Taylor, Patrick L Holland, Jason M Sheltzer.
      Re-evaluating existing clinical compounds can uncover previously unrecognized mechanisms that reshape a drug's therapeutic potential. The small molecule Procaspase-Activating Compound 1 (PAC-1) entered oncology testing as a proposed activator of caspase-driven apoptosis. Here, we show that PAC-1-driven cytotoxicity occurs in the absence of executioner caspase expression, demonstrating that its anti-cancer activity occurs via an alternative mechanism. We provide genetic, biochemical, and biophysical evidence demonstrating that PAC-1 functions as a highly selective iron chelator that eliminates cancer cells by disrupting iron homeostasis. Unexpectedly, we discovered that expression of the key chemotherapy-resistance pump MDR1 confers marked hypersensitivity to PAC-1 treatment. While PAC-1 is only weakly effluxed by MDR1 under basal conditions, this process is potentiated when PAC-1 is bound to iron. Consequently, PAC-1 induces progressive iron depletion and selective cytotoxicity in otherwise drug-resistant MDR1-expressing cancer cells. Together, these findings redefine PAC-1's mechanism-of-action and establish a framework for exploiting multidrug resistance as a therapeutic vulnerability through targeted iron starvation.
    DOI:  https://doi.org/10.1101/2025.11.26.690878
  32. Cancer Res. 2025 Dec 15.
    Practical Trade-offs in 3D Cancer Imaging.
    Lucie Dequiedt, Ashley L Kiemen.
      Three-dimensional imaging is increasingly shaping cancer research. This piece highlights key technical considerations when considering adopting 3D over traditional 2D imaging methods, emphasizing its unique ability to capture complex and heterogeneous tumor architecture. We also discuss the importance of multi-omics integration and how virtual staining workflows can address scalability issues. Finally, we propose hybrid strategies that balance 2D and 3D imaging for well-rounded understanding of inter- and intra-tumoral heterogeneity, underscoring the complimentary value of both modalities in advancing cancer research.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3336
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