bims-cagime 2026-02-08 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2026–02–08
28 papers selected by
Kıvanç Görgülü, Technical University of Munich

Combined targeted and epigenetic-based therapy enhances antitumor immunity by stabilizing GATA6-dependent MHCI expression in pancreatic ductal adenocarcinoma.
Apical and basolateral plasma membranes in epithelial cells have distinct lipidomes and biophysical properties.
Theoretical limits for sensing through phase separation.
Estrogen Shapes Fibroblast States to Limit Pancreatic Cancer Aggressiveness.
Exploiting a purine imbalance to target KRAS mutant pancreatic adenocarcinomas.
Activated ATF6α is a hepatic tumour driver restricting immunosurveillance.
Age-Driven Lipid Remodeling Activates Lysosome-Mediated Plasma Membrane Repair.
Tumour-brain crosstalk restrains cancer immunity via a sensory-sympathetic axis.
SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth.
KRAS Inhibitors in Pancreas Cancer: Facts and Hopes about the Immunotherapy We've All Been Waiting For.
Cullin-3 adaptor SHKBP1 inhibits SQSTM1/p62 oligomerization and Keap1 sequestration.
Emerging landscape of KRAS inhibitors in cancer treatment.
The Stmn1-lineage contributes to acinar regeneration but not to neoplasia upon oncogenic Kras expression.
Proteostasis of organelles in aging and disease.
An oncogenic KRAS-driven secretome involving TNFα promotes niche preparation prior to pancreatic cancer onset.
A Dual-Organelle Fluorescent Probe for Visualizing Intracellular Microviscosity Dynamics.
Condensates and Cell States: A New Paradigm for Understanding Tumor Biology.
A p53-controlled lysosomal recycling circuit fuels phospholipid synthesis.
Kras G12C- and G12D-driven lung cancers differ in oncogenic potency, immunogenicity, and relapse after Kras inhibition in mouse models.
Cyclic stretch induces autophagy-mediated focal adhesion remodeling and activates mitochondria.
Is survival influenced by metastatic site in synchronous metastatic pancreatic adenocarcinoma (PDAC)? A prospective real-world BACAP study.
Clinical and translational results from a phase 1 trial of gemcitabine/nab-paclitaxel with nivolumab/ipilimumab or hydroxychloroquine/ipilimumab in untreated metastatic pancreatic adenocarcinoma.
Brief pulses of high-level fluid shear stress enhance metastatic potential and rapidly alter the metabolism of cancer cells.
Paclitaxel drives TREM2+ macrophage expansion underlying its inferior therapeutic efficacy compared to Nab-paclitaxel.
Ionic Regulation of Mechanosurveillance and Metastasis via the MRTFA/KCNMB1 Axis.
Septins buffer actomyosin forces to protect the nucleus from genotoxic mechanical stress.
17.6% of patients in a German cohort with exocrine pancreatic cancer were diagnosed with a genetic tumor syndrome-a case for universal genetic testing?
Rational Design of a Dual-Locked Fluorescent Probe for Precise Imaging of Tumor via β-Galactosidase/Viscosity Activation.

Nat Commun. 2026 Feb 06.

Combined targeted and epigenetic-based therapy enhances antitumor immunity by stabilizing GATA6-dependent MHCI expression in pancreatic ductal adenocarcinoma.

JuanFei Peng, JiaJin Yang, Georgia Antonopoulou, Rui Fang, Bikash Adhikari, Markus Vogt, Elmar Wolf, Chong Sun, Shangce Du, Laura Godfrey, Aayush Gupta, Marija Trajkovic-Arsic, Nicole Teichmann, Barbara T Grünwald, Niklas Krebs, Katja Steiger, Carolin Mogler, Kristina Althoff, Xin Wang, Giovanni Giglio, Sven-Thorsten Liffers, Konstantinos Savvatakis, Rickmer Braren, Rita T Lawlor, Aldo Scarpa, Diana Behrens, Karl S Lang, Phyllis F Cheung, Jens T Siveke.

GATA6 promotes epithelial phenotypes and limits epithelial-to-mesenchymal (EMT) transition in pancreatic ductal adenocarcinoma (PDAC). Here we show that GATA6 defines a tumor cell state that induces MHCI expression and anti-tumor cytotoxicity upon therapy. In human PDAC, GATA6 expression correlates with immune cell infiltration, and spatial analysis reveals interaction between GATA6+ tumor cells and CD8+ T cells. In murine PDAC, MEK inhibition (MEKi) enriches antigenicity-related gene sets in GATA6high cells, while GATA6 knockout or degradation impairs MEKi-induced MHCI upregulation. High-GATA6 tumors respond to MEKi with increased MHCI, enhancing T-cell cytotoxicity, whereas GATA6 loss abolishes this effect. Treatment-induced EMT reduces GATA6+ populations and MHCI expression, which is restored by combining MEKi with HDAC inhibitors, enhancing GATA6+ tumor cells, MHCI, CD8+ T cell infiltration, tumor suppression, and survival. These findings suggest that therapeutic strategies promoting a GATA6-driven tumor cell state improve immune recognition of PDAC cells and potentiate anti-tumor cytotoxic effects.

DOI: https://doi.org/10.1038/s41467-026-69013-y
Proc Natl Acad Sci U S A. 2026 Feb 10. 123(6): e2521220123

Apical and basolateral plasma membranes in epithelial cells have distinct lipidomes and biophysical properties.

Carolyn R Shurer, Kandice R Levental, Ilya Levental.

  Epithelial cell polarization is essential for many physiological processes, including tissue morphogenesis, nutrient absorption, barrier integrity, and directional secretion. A defining feature of such polarization is the separation of plasma membrane (PM) lipids and proteins into distinct apical and basolateral compartments. It has long been suggested that the apical compartment is rich in glycolipids and cholesterol and that this composition arises through trafficking of self-assembled membrane domains (termed lipid rafts). However, neither the detailed composition nor the mechanisms of molecular sorting between epithelial cell PM compartments have been fully resolved. Particularly, the lipid profile of the basolateral membrane and consequently the lipid disparity between the apical and basolateral membrane remain undefined. We developed a method to separately isolate the apical and basolateral PM and used lipidomics and biophysical profiling to characterize the changes in membrane composition and properties between these compartments in polarized Madin-Darby canine kidney cells. We find that the apical membrane is enriched in cholesterol, saturated lipids, and glycolipids relative to the basolateral membrane and that its biophysical properties reflect a more ordered environment. Further, we evaluate the longstanding hypothesis that lipid rafts contribute to apical protein trafficking by assessing the relationship between transmembrane domain raft affinity and apical localization and find that lipid raft affinity only modestly influences apical versus basolateral sorting. These findings define the distinct compositional and biophysical features of apical and basolateral compartments of epithelial cells and suggest mechanistic evidence for their biogenesis.

Keywords:  epithelial cells; lipid biophysics; lipidomics; membrane domains; protein sorting

DOI:  https://doi.org/10.1073/pnas.2521220123
Proc Natl Acad Sci U S A. 2026 Feb 10. 123(6): e2520040123

Theoretical limits for sensing through phase separation.

Henry Alston, Mason Rouches, Arvind Murugan, Aleksandra M Walczak, Thierry Mora.

  Biomolecular condensates form on timescales of seconds in cells upon environmental or compositional changes. Condensate formation is thus argued to act as a mechanism for sensing such changes and quickly initiating downstream processes, such as forming stress granules in response to heat stress and amplifying cyclic GMP-AMP synthase enzymatic activity upon detection of cytosolic DNA. Here, we study a dynamical model of droplet nucleation and growth to demonstrate how phase separation allows cells to discriminate small concentration differences on finite, biologically relevant timescales. We propose optimal sensing protocols, which use the sharp onset of phase separation. We show how, given experimentally measured rates, cells can achieve rapid and robust sensing of concentration differences of [Formula: see text] on a timescale of minutes, offering an alternative to classical biochemical mechanisms.

Keywords:  biological concentration sensing; cellular decision-making; droplet; liquid–liquid phase transition

DOI:  https://doi.org/10.1073/pnas.2520040123
Cancer Res. 2026 Feb 02. 86(3): 567-568

Estrogen Shapes Fibroblast States to Limit Pancreatic Cancer Aggressiveness.

Lisa Veghini, Vincenzo Corbo.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive desmoplastic stroma that profoundly influences tumor biology and therapeutic response. Cancer-associated fibroblasts (CAF), the major stromal component, exist as heterogeneous populations with both tumor-promoting and tumor-restraining functions. In this issue of Cancer Research, Manoukian and colleagues uncover a previously unrecognized hormonal axis in PDAC, demonstrating that estrogen signaling reprograms fibroblast identity and shapes the tumor microenvironment. Building on prior work identifying an inflammatory CAF subset marked by high OGN and CLEC3B expression (iCAF.1) and associated with favorable prognosis, the authors show that estrogen produced by cancer cells promotes this tumor-restraining phenotype while limiting myofibroblastic CAF activation. Reciprocally, CAF-derived branched-chain amino acids taken up by cancer cells via SLC25A44-mediated uptake fuel estrogen biosynthesis, creating a feedback loop that sustains the classical, less aggressive PDAC subtype. Collectively, these findings establish estrogen as a key modulator of CAF heterogeneity and highlight a novel mechanism of tumor-stroma cross-talk with potential therapeutic implications for stroma-directed interventions in pancreatic cancer. See related article by Manoukian et al., p. 571.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-4671
Gut. 2026 Feb 04. pii: gutjnl-2025-337940. [Epub ahead of print]

Exploiting a purine imbalance to target KRAS mutant pancreatic adenocarcinomas.

Jorge Mota-Pino, Oscar Fernandez-Capetillo.



Keywords:  BIOMARKERS; CHEMOTHERAPY; PANCREATIC CANCER

DOI:  https://doi.org/10.1136/gutjnl-2025-337940
Nature. 2026 Feb 04.

Activated ATF6α is a hepatic tumour driver restricting immunosurveillance.

Xin Li, Cynthia Lebeaupin, Aikaterini Kadianaki, Clementine Druelle-Cedano, Niklas Vesper, Charlotte Rennert, Júlia Huguet-Pradell, Borja Gomez Ramos, Chaofan Fan, Robert Stefan Piecyk, Laimdota Zizmare, Pierluigi Ramadori, Luqing Li, Lukas Frick, Menjie Qiu, Cangang Zhang, Luiza Martins Nascentes Melo, Vikas Prakash Ranvir, Peng Shen, Johannes Hanselmann, Jan Kosla, Mirian Fernández-Vaquero, Mihael Vucur, Praveen Baskaran, Xuanwen Bao, Olivia I Coleman, Yingyue Tang, Miray Cetin, Zhouji Chen, Insook Jang, Stefania Del Prete, Mohammad Rahbari, Peng Zhang, Timothy V Pham, Yushan Hou, Aihua Sun, Li Gu, Laura C Kim, Ulrike Rothermel, Danijela Heide, Adnan Ali, Suchira Gallage, Nana Talvard-Balland, Marta Piqué-Gili, Albert Gris-Oliver, Alessio Bevilacqua, Lisa Schlicker, Alec Duffey, Kristian Unger, Marta Szydlowska, Jenny Hetzer, Duncan T Odom, Tim Machauer, Daniele Bucci, Pooja Sant, Jun-Hoe Lee, Jonas Rösler, Sven W Meckelmann, Johannes Schreck, Sue Murray, M Celeste Simon, Sven Nahnsen, Almut Schulze, Ping-Chih Ho, Manfred Jugold, Kai Breuhahn, Jan-Philipp Mallm, Peter Schirmacher, Susanne Roth, Nuh Rahbari, Darjus F Tschaharganeh, Stephanie Roessler, Benjamin Goeppert, Bertram Bengsch, Geoffroy Andrieux, Melanie Boerries, Nisar P Malek, Marco Prinz, Achim Weber, Robert Zeiser, Pablo Tamayo, Peter Bronsert, Konrad Kurowski, Robert Thimme, Detian Yuan, Rafael Carretero, Tom Luedde, Roser Pinyol, Felix J Hartmann, Michael Karin, Alpaslan Tasdogan, Christoph Trautwein, Moritz Mall, Maike Hofmann, Josep M Llovet, Dirk Haller, Randal J Kaufman, Mathias Heikenwälder.

Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related mortality and there are limited therapies1. Although endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) are implicated in HCC, the involvement of the UPR transducer ATF6α remains unclear2. Here we demonstrate the function of ATF6α as an ER-stress-inducing tumour driver and metabolic master regulator restricting cancer immunosurveillance for HCC, in contrast to its well-characterized role as an adaptive response to ER stress3. ATF6α activation in human HCC is significantly correlated with an aggressive tumour phenotype, characterized by reduced patient survival, enhanced tumour progression and local immunosuppression. Hepatocyte-specific ATF6α activation in mice induced progressive hepatitis with ER stress, immunosuppression and hepatocyte proliferation. Concomitantly, activated ATF6α increased glycolysis and directly repressed the gluconeogenic enzyme FBP1 by binding to gene regulatory elements. Restoring FBP1 expression limited ATF6α-activation-related pathologies. Prolonged ATF6α activation in hepatocytes triggered hepatocarcinogenesis, intratumoural T cell infiltration and nutrient-deprived immune exhaustion. Immune checkpoint blockade (ICB)4 restored immunosurveillance and reduced HCC. Consistently, patients with HCC who achieved a complete response to immunotherapy displayed significantly increased ATF6α activation compared with those with a weaker response. Targeting Atf6 through germline ablation, hepatocyte-specific ablation or therapeutic hepatocyte delivery of antisense oligonucleotides dampened HCC in preclinical liver cancer models. Thus, prolonged ATF6α activation drives ER stress, leading to glycolysis-dependent immunosuppression in liver cancer and sensitizing to ICB. Our findings suggest that persistently activated ATF6α is a tumour driver, a potential stratification marker for ICB response and a therapeutic target for HCC.

DOI: https://doi.org/10.1038/s41586-025-10036-8
Res Sq. 2026 Jan 20. pii: rs.3.rs-8607320. [Epub ahead of print]

Age-Driven Lipid Remodeling Activates Lysosome-Mediated Plasma Membrane Repair.

Dorota Skowronska-Krawczyk, Emily Tom, Fangyuan Gao, Carolina Franco, Adrian Wong, Nathan Kemmerer, Zichen Wang, Qianlan Xu, Yinyin Zhuang, Samuel Du, Grazyna Palczewska, Krzysztof Palczewski, Itay Budin, Xiaoyu Shi, Vera Bonilha, Johannes Schöneberg, Karl Wahlin, Lauren Albrecht.

The abundance and stoichiometry of membrane lipid species vary across a cell's lifespan and metabolic state. In the retinal pigment epithelium (RPE), age-related alterations in lipid composition contribute to vision loss and diseases such as age-related macular degeneration (AMD), yet the molecular drivers of these changes remain unclear. Here, we show that age-dependent remodeling of the composition and biophysical properties of the plasma membrane compromises membrane integrity and function. Remarkably, rather than undergoing cell death, affected cells activate a lysosome-dependent plasma membrane repair program to preserve barrier integrity. While this adaptive response may protect RPE structure under metabolic stress, it also drives spatially polarized release of lysosomal contents that potentially can contribute to extracellular matrix remodeling and sub-RPE deposit formation during aging and AMD. Finally, we demonstrate that supplementation with the direct product of the aging-associated lipid elongase ELOVL2 alleviates these phenotypes, providing direct evidence for a critical role of ELOVL2-mediated PUFA elongation in healthy aging. Taken together, our results propose a model in which age-dependent decline in PUFA elongation disrupts the balance between membrane flexibility and stability, initiating a compensatory cycle of membrane stress and repair.

DOI: https://doi.org/10.21203/rs.3.rs-8607320/v1
Nature. 2026 Feb 04.

Tumour-brain crosstalk restrains cancer immunity via a sensory-sympathetic axis.

Haohan K Wei, Chuyue D Yu, Bo Hu, Xing Zeng, Hiroshi Ichise, Liang Li, Yu Wang, Ruiqi L Wang, Ronald N Germain, Rui B Chang, Chengcheng Jin.

Body-brain communication has emerged as a key regulator of tissue homeostasis1-5. Solid tumours are innervated by different branches of the peripheral nervous system and increased tumour innervation is associated with poor cancer outcomes6-8. However, it remains unclear how the brain senses and responds to tumours in peripheral organs, and how tumour-brain communication influences cancer immunity. Here we identify a tumour-brain axis that promotes oncogenesis by establishing an immune-suppressive tumour microenvironment. Combining genetically engineered mouse models with neural tracing, tissue imaging and single-cell transcriptomics, we demonstrate that lung adenocarcinoma induces innervation and functional engagement of vagal sensory neurons, a major interoceptive system connecting visceral organs to the brain. Mechanistically, Npy2r-expressing vagal sensory nerves transmit signals from lung tumours to brainstem nuclei, driving elevated sympathetic efferent activity in the tumour microenvironment. This, in turn, suppresses anti-tumour immunity via β2 adrenergic signalling in alveolar macrophages. Disruption of this sensory-to-sympathetic pathway through genetic, pharmacological or chemogenetic approaches significantly inhibited lung tumour growth by enhancing immune responses against cancer. Collectively, these results reveal a bidirectional tumour-brain communication involving vagal sensory input and sympathetic output that cooperatively regulate anti-cancer immunity; targeting this tumour-brain circuit may provide new treatments for visceral organ cancers.

DOI: https://doi.org/10.1038/s41586-025-10028-8
Nat Metab. 2026 Feb 06.

SLC6A6 imports taurine into mitochondria to sustain mitochondrial translation and tumour growth.

Liucheng Li, Jianwei You, Zi-Qing Chai, Xueshan Li, Xinlei Cai, Lin Wang, Fang Yang, Lingzhi Zhu, Wen Mi, Xinyi Xia, Haohang Yan, Fei Li, Juan Wang, Tong-Jin Zhao, Ligong Chen, Hongbin Ji, Pingyu Liu, Xiao-Long Zhou, Li Chen, Fuming Li.

Taurine plays a crucial role in mitochondrial translation. Mammalian cells obtain taurine via exogenous uptake mediated by the plasma membrane transporter SLC6A6 or via cytosolic biosynthesis. However, it remains unclear how taurine enters mitochondria and impacts cellular metabolism. Here we show that SLC6A6, but not exogenous taurine, is essential for mitochondrial metabolism and cancer cell growth. We discover that SLC6A6 also localizes to mitochondria and imports taurine for mitochondrial transfer RNA modifications. SLC6A6 deficiency specifically reduces mitochondrial taurine abundance and abrogates mitochondrial translation and cell proliferation. We identify protein kinase A as a regulator of SLC6A6 subcellular localization, as it promotes SLC6A6 presence at the plasma membrane while inhibiting its mitochondrial localization. Furthermore, we identify NFAT5 as a key regulator of mitochondrial function through SLC6A6 and demonstrate that targeting the NFAT5-SLC6A6 axis markedly impairs mitochondrial translation and tumour growth. Together, these findings suggest that SLC6A6 is a mitochondrial taurine transporter and an exploitable metabolic dependency in cancer.

DOI: https://doi.org/10.1038/s42255-026-01455-6
Clin Cancer Res. 2026 Feb 05.

KRAS Inhibitors in Pancreas Cancer: Facts and Hopes about the Immunotherapy We've All Been Waiting For.

Ben Z Stanger, Robert H Vonderheide.

Oncogenic RAS drives an immunosuppressive tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC). Inhibition of RAS signaling, as is now possible with an ever-increasing pharmaceutical portfolio, not only directly blocks tumors cells but also reverses immunosuppression, enabling infiltration of cytotoxic T cells and major alteration of the tumor microenvironment. In preclinical studies, the full anti-tumor effects of RAS inhibitors depend on T cells such that regressions in mice lacking T cells (or cross-presenting dendritic cells) are less deep and less durable than those in T cell-replete mice. Moreover, RAS inhibitors given with immune checkpoint blockade and immune agonists produce even more potent anti-tumor effects, especially in tumors with some amount of baseline T cell infiltration. These findings set the stage for testing RAS inhibitors and immunotherapy in combination for pancreatic ductal carcinoma (PDAC), which is otherwise refractory to immunotherapy. Other immune partners might include vaccines, bispecific antibodies, and cell therapy. A major clinical opportunity eventually would be combining RAS inhibitors and immunotherapy in the adjuvant, neo-adjuvant, and interception settings, provided this new class of drugs is developed keeping its immune modulatory power in mind.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-0821
J Cell Biol. 2026 Apr 06. pii: e202501207. [Epub ahead of print]225(4):

Cullin-3 adaptor SHKBP1 inhibits SQSTM1/p62 oligomerization and Keap1 sequestration.

Lin Luan, Xiaofu Cao, Zijun Xia, Shivanshi Vaid, Manuel D Leonetti, Jeremy M Baskin.

SQSTM1/p62 is a master regulator of the autophagic and ubiquitination pathways of protein degradation and the antioxidant response. p62 functions in these pathways via reversible assembly and sequestration of additional factors into cytoplasmic phase-separated structures termed p62 bodies. The physiological roles of p62 in these various pathways depend on numerous mechanisms for regulating p62 body formation and dynamics that are incompletely understood. Here, we identify a new mechanism for regulation of p62 oligomerization and incorporation into p62 bodies by SHKBP1, a cullin-3 E3 ubiquitin ligase adaptor, that is independent of its potential functions in ubiquitination. We map an SHKBP1-p62 protein-protein interaction outside of p62 bodies that limits p62 assembly into p62 bodies and affects the antioxidant response involving sequestration of Keap1 and nuclear translocation of Nrf2. These studies provide a non-ubiquitination-based mechanism for an E3 ligase adaptor in regulating p62 body formation and cellular responses to oxidative stress.

DOI: https://doi.org/10.1083/jcb.202501207
Cancer Cell. 2026 Jan 29. pii: S1535-6108(26)00010-3. [Epub ahead of print]

Emerging landscape of KRAS inhibitors in cancer treatment.

Jakob M Riedl, Hiroyuki Matsubara, Reid McNeil, Parasvi S Patel, Ferran Fece de la Cruz, Doga C Gulhan, Ryan B Corcoran.

  Alterations in KRAS, NRAS, and HRAS occur in roughly 20% of patients with cancer, making RAS one of the most intensively studied oncogenic targets. The discovery of mutant-selective KRASG12C inhibitors has provided a proof-of-concept for RAS-directed therapies, heralding a new era in the treatment of RAS-driven cancers. Yet, the efficacy of first-generation KRASG12C inhibitors is limited by the rapid emergence of resistance. Novel classes of (K)RAS inhibitors with distinct mechanisms of action and broader target coverage hold promise to overcome resistance and extend the benefits of RAS-targeted therapies to a wider patient population. In this review, we summarize clinical evidence for KRASG12C inhibitors across tumor types and delineate key mechanisms of resistance. We further discuss the rapidly evolving landscape of next-generation (K)RAS inhibitors, with particular emphasis on their target selectivity, mechanisms of action, preliminary clinical efficacy, and the therapeutic opportunities and challenges inherent to each class.

Keywords:  KRAS; KRAS G12C; KRAS inhibitor; colorectal cancer; drug resistance; non-small cell lung cancer; pancreatic cancer

DOI:  https://doi.org/10.1016/j.ccell.2026.01.001
Cell Mol Gastroenterol Hepatol. 2026 Jan 28. pii: S2352-345X(26)00021-4. [Epub ahead of print] 101743

The Stmn1-lineage contributes to acinar regeneration but not to neoplasia upon oncogenic Kras expression.

Shakti Dahiya, Jorge R Arbujas, Arian Hajihassani, Sara Amini, Michael Wageley, Klara Gurbuz, Zhibo Ma, Celina Copeland, Mohamed Saleh, George K Gittes, Bon-Kyoung Koo, Kathleen E DelGiorno, Farzad Esni.

   BACKGROUND & AIMS: The exocrine pancreas has a limited regenerative capacity, but to what extent all acinar cells are involved in this process is unclear. Nevertheless, the heterogenous nature of acinar cells suggests that cells exhibiting higher plasticity might play a more prominent role in acinar regeneration. In that regard, Stmn1-expressing acinar cells have been identified as potential facultative progenitor-like cells in the adult pancreas. Here, we studied Stmn1-progeny under physiological conditions, during regeneration, and in the context of KrasG12D expression.
METHODS: We followed the fate of Stmn1-progenies both under baseline conditions, following caerulein-induced acute or chronic pancreatitis, pancreatic duct ligation, and in the context of KrasG12D expression.
RESULTS: The Stmn1-lineage contributes to baseline acinar cell turnover under physiological conditions. Furthermore, these cells rapidly proliferate and repopulate the acinar compartment in response to acute injury in an ADM-independent manner. Moreover, acinar regeneration during chronic pancreatitis progression is in conjunction with a decline in the proliferative capacity of the Stmn1-lineage. Interestingly, newly generated acinar cells display increased susceptibility to additional injury during recurrent acute pancreatitis (RAP). Finally, given their inability to form ADMs, the Stmn1-lineage fails to form PanINs upon oncogenic Kras expression.
CONCLUSIONS: Our findings establish the Stmn1-lineage as a pivotal subpopulation for acinar regeneration. The ability of these cells to restore acinar tissue in an ADM-independent manner distinguishes them as a critical regenerative population. This study presents a new paradigm for acinar regeneration and repair in the context of pancreatitis and neoplasia.

Keywords:  ADM; Acinar cells; Neoplasia; Pancreas; Regeneration; Stmn1

DOI:  https://doi.org/10.1016/j.jcmgh.2026.101743
FEBS J. 2026 Feb 04.

Proteostasis of organelles in aging and disease.

Yara Nabawi, Cansu Doğan, Dunja Petrović, Gülce Perçin, Seda Koyuncu, David Vilchez.

  To maintain proteome integrity within distinct subcellular compartments, cells rely on tightly regulated proteostasis mechanisms, including protein synthesis, folding, trafficking, and degradation. Disruption of these processes leads to the accumulation of damaged proteins and structural changes that progressively compromise organelle function, contributing to aging and age-associated disorders, such as neurodegeneration, cancer, and metabolic dysfunction. Here, we discuss recent insights into how proteostasis influences the integrity and function of specific organelles, including the nucleus, mitochondria, endoplasmic reticulum, Golgi apparatus, and lysosomes, as well as membraneless organelles, such as stress granules, processing bodies, the nucleolus, and nuclear speckles. We further discuss how dysfunction in these systems contributes to different hallmarks of aging and disease progression, highlighting potential therapeutic strategies aimed at maintaining organelle homeostasis to promote healthy aging.

Keywords:  aging; cellular stress responses; membraneless organelles; membrane‐bound organelles; neurodegenerative diseases; organelle dysfunction; protein aggregation; proteostasis; stress granules

DOI:  https://doi.org/10.1111/febs.70439
Mol Cancer. 2026 Feb 03.

An oncogenic KRAS-driven secretome involving TNFα promotes niche preparation prior to pancreatic cancer onset.

Chantal Allgöwer, Medhanie A Mulaw, James Nagai, Sandra Wiedenmann, Elena Anne Ringel, Benedetta Ferrara, Lorenzo Piemonti, Tengku Ibrahim Maulana, Luisa T Ferreira, Adam Flinders, Claudia Teufel, Leon Reichardt, Paul B Lopatta, Dharini Srinivasan, Anton Lahusen, Thomas Seufferlein, Nadine Therese Gaisa, Annika Beck, Jessica Lindenmayer, Michael K Melzer, Eleni Zimmer, Elodie Roger, Sandra Heller, J-Mathias Löhr, Stefan Liebau, Peter Loskill, Yuan-Na Lin, Paolo Riccardo Camisa, Claus Jorgensen, Stefano Crippa, Matthias Meier, Meike Hohwieler, Ivan G Costa, Markus Breunig, Alexander Kleger.

DOI: https://doi.org/10.1186/s12943-025-02541-1
J Fluoresc. 2026 Feb 05.

A Dual-Organelle Fluorescent Probe for Visualizing Intracellular Microviscosity Dynamics.

Kaiwen Zheng, Xiang Wang, Haijiao Xie.

  Intracellular microviscosity is a key physicochemical parameter that influences molecular diffusion, signal transduction, and organelle function. However, fluorescence probes capable of selectively visualizing viscosity dynamics with high sensitivity and biological compatibility remain limited. Here, we report a dihydroxanthene-based viscosity-responsive fluorescent probe, ZKW, constructed with a D-π-A push-pull architecture and an o-bromophenyl molecular rotor. ZKW displays a pronounced viscosity-dependent fluorescence enhancement at 580 nm upon 550 nm excitation, originating from restricted intramolecular rotation and suppressed TICT processes. The probe exhibits good selectivity toward viscosity with negligible interference from polarity, pH, reactive species, metal ions, amino acids, or proteins, along with acceptable photostability and low cytotoxicity. Colocalization studies revealed preferential mitochondrial accumulation with partial lysosomal distribution, enabling simultaneous visualization of viscosity variations in these organelles. Using multiple cellular stress models-including LPS stimulation, oleic-acid treatment, nystatin exposure, and erastin-induced ferroptosis-ZKW effectively reported viscosity elevations at the subcellular level. These results establish ZKW as a robust and versatile tool for probing microviscosity heterogeneity in living cells and for facilitating studies of viscosity-associated physiological and pathological processes.

Keywords:  Cellular stress; Fluorescent probe; Intracellular microviscosity; Live-cell imaging; Lysosome; Mitochondria

DOI:  https://doi.org/10.1007/s10895-026-04714-7
Biophys J. 2026 Jan 31. pii: S0006-3495(26)00084-6. [Epub ahead of print]

Condensates and Cell States: A New Paradigm for Understanding Tumor Biology.

Ruth Nussinov, Hyunbum Jang.

  Traditionally, cells have been classified by their type. Identifying cell types was deemed vital for understanding biological processes. More recently, cell type classification has been recognized as not good enough. Cells have many transient states that depend on their spatial environment and vary over time. The current cell states description recognizes that a cell is dynamic, varying over developmental time, location, senescence, and disease. While cell states refer to the functional behavior of the cells, biomacromolecular condensates are now recognized as the membraneless structures within them, which by concentrating functionally related proteins, make the function happen. Here, we (i) clarify the molecular basis of the current separation between cell types and states and point to the merit of the "cell states", which make the classical "cell types" distinction expendable; (ii) discuss how fundamental physical principles evolved the functionally specific, conformationally biased biomacromolecular condensates; and (iii) consider the pharmacology of cell states and condensates. Recent reports highlighted condensates as drug targets. However, drugs designed to dismantle condensates can be toxic due to lack of specificity-unlike cell states, which are controlled by targetable specific epigenetics players. Especially (iv), we consider transitioning primary cancer cells, linking cell states and condensates to tumor proliferation. We suggest that original cancer cells transitioning to other tissues are primarily influenced by cell states,supported by their multi-condensates structuring. The high genetic homogeneity of untreated cancers-within primary tumors and metastases-underscores the significance of the transient nature of cell states.

Keywords:  allosteric; allostery; cell types; drugs; epigenetics; metastases; spatial microenvironment; tumor proliferation

DOI:  https://doi.org/10.1016/j.bpj.2026.01.052
Nat Cell Biol. 2026 Jan 30.

A p53-controlled lysosomal recycling circuit fuels phospholipid synthesis.

DOI: https://doi.org/10.1038/s41556-025-01868-7
Sci Transl Med. 2026 Feb 04. 18(835): eadq6647

Kras G12C- and G12D-driven lung cancers differ in oncogenic potency, immunogenicity, and relapse after Kras inhibition in mouse models.

Hai-Cheng Huang, Qing Deng, Lei Guo, Teresa Gorria, Federica Pecci, Daniella Yang, Scott Rodig, Luis De Las Casas, Jill Hallin, James G Christensen, Mark M Awad, Lin Xu, Biagio Ricciuti, Esra A Akbay.

The development of allele-specific KRAS inhibitors underscores the importance of understanding the distinct tumor biology associated with common KRAS mutations, G12D and G12C, in genetically engineered mouse models (GEMMs) of non-small cell lung cancer (NSCLC) and patient samples. Lung tumors driven by the most common KRAS mutation, G12C, show delayed onset and slower progression compared with those driven by KRAS G12D in patients and mice. G12C tumors display lower proliferation and increased immune cell engagement, the latter of which is consistent with observations in patient tumors. Allele-specific KRAS G12C/D inhibitors effectively suppress the growth of respective autochthonous lung tumors. However, G12D-driven tumors relapse more rapidly than G12C-driven tumors in autochthonous models, reflecting greater intrinsic aggressiveness. Given this aggressive clinical behavior, we focused on elucidating the mechanism of action and strategies to potentiate KRASG12D inhibition in nonimmunogenic and immunogenic lung cancer models. G12D inhibition enhances tumor antigen presentation, activates T cells, and enables antigen-specific cytotoxicity, leading to efficacy with immune checkpoint blockade combination. This combination induces durable immune memory in immunogenic models but not in nonimmunogenic settings. Our findings underscore key differences between KRAS G12D and G12C mutations in shaping lung cancer biology, reveal distinct resistance dynamics under long-term targeted therapy, and uncover immune-mediated mechanisms specific to KRASG12D inhibition with direct clinical and translational relevance.

DOI: https://doi.org/10.1126/scitranslmed.adq6647
Life Sci Alliance. 2026 Apr;pii: e202503347. [Epub ahead of print]9(4):

Cyclic stretch induces autophagy-mediated focal adhesion remodeling and activates mitochondria.

Lukas Lövenich, Bahareh Rahimi, Henrique Baeta, Maithreyan Kuppusamy, Moritz Walkenbach, Frederik Rastfeld, Georg Dreissen, Ronald Wein, Jörg Höhfeld, Rudolf Merkel, Pitter F Huesgen, Bernd Hoffmann.

Mammalian cells are continuously exposed to internally generated or externally applied mechanical stimuli. Mechanosensitive proteins enable cells to sense mechanical stress and induce protective mechanisms like autophagy and cytoskeletal reorientation. However, how these contribute to cellular and tissue adaptations remains largely unknown. Here, we studied the response of rat smooth muscle cells (A7r5) to uniaxial cyclic stretch. Stretching induced autophagy and adaptive actin fiber reorientation. Inhibiting autophagy using chloroquine or expressing a Bag3 (T285D-S289D) phosphosite mutant that impairs chaperone-assisted selective autophagy (CASA) delayed reorientation. Proteomic analysis revealed a depletion of cytoskeletal and focal adhesion proteins after stretching, which was attenuated by autophagy inhibition. Stretching caused a reduction in focal adhesion (FA) size, and the remodeled FAs reoriented perpendicularly to the strain direction. Concurrently, prolonged stretching activated mitochondria, and inhibiting mitochondrial ATP synthesis slowed actin reorientation, suggesting that mitochondrial activity supports the mechanoresponse. Our findings highlight the role of autophagy and mitochondria in the structural remodeling of cells upon adaptation to mechanical stress.

DOI: https://doi.org/10.26508/lsa.202503347
ESMO Gastrointest Oncol. 2025 Jun;8 100144

Is survival influenced by metastatic site in synchronous metastatic pancreatic adenocarcinoma (PDAC)? A prospective real-world BACAP study.

BACAP Consortium

   Background: Advanced pancreatic ductal adenocarcinoma (PDAC) carries a dismal prognosis with a 5-year survival rate of 3%. While treated as an even population, previous retrospective studies suggested significantly different survival rates for patients with lung-only metastases when compared with other patients. This study aims to explore prospectively the difference in survival outcome based on initial site of metastases in synchronous metastatic PDAC.
Patients and methods: This is a prospective observational study including all adult patients with synchronous metastatic PDAC in BACAP (national Anatomo-Clinical Database on Pancreatic Adenocarcinoma). Data regarding patients' demographics, tumor characteristics and survival outcomes were analyzed.
Results: Overall, 559 patients were included (52.8% male, mean age 69 years) of which 26 (4.7%), 65 (11.6%), 299 (53.5%) and 169 (30.2%) patients had lung-only, peritoneal-only, liver-only and multi-site metastases at diagnosis, respectively. The median overall survival (OS) was significantly different according to metastatic site (P < 0.001) with a median OS for lung-only, peritoneum-only, liver-only and multi-site of 12.6 months [95% confidence interval (CI) 9.7-16.9 months], 8.6 months (95% CI 5.4-11.5 months), 7.9 months (95% CI 6.5-8.9 months) and 4.5 months (95% CI 3.9-5.8 months), respectively. The median progression-free survival (PFS) was also significantly different according to metastatic site (P < 0.01) with a median PFS of 6.3 months (95% CI 2.7-9.1 months), 5.1 months (95% CI 3.7-6.2 months), 4.7 months (95% CI 3.3-5.7 months) and 3.2 months (95% CI 2.6-4.1 months), respectively.
Conclusions: Patients with lung-only metastases represented 4.7% of synchronous metastatic PDAC patients and exhibited improved survival. These results suggest that a subset of patients with synchronous metastatic PDAC could benefit from more aggressive locoregional treatments.

Keywords:  lung-only metastases; metastatic site; pancreatic cancer; survival

DOI:  https://doi.org/10.1016/j.esmogo.2025.100144
J Immunother Cancer. 2026 Jan 30. pii: e012864. [Epub ahead of print]14(1):

Clinical and translational results from a phase 1 trial of gemcitabine/nab-paclitaxel with nivolumab/ipilimumab or hydroxychloroquine/ipilimumab in untreated metastatic pancreatic adenocarcinoma.

Eileen M O'Reilly, Christopher R Cabanski, Jaclyn P Lyman, Zev A Wainberg, George A Fisher, Robert A Wolff, Andrew H Ko, Mark H O'Hara, Christine N Spencer, Jia Xin Yu, Diane M Da Silva, Lacey J Padrón, Jamie Arnott, Justin Fairchild, Jonni S Moore, Brandon Peng, William A Hoos, Jill O'Donnell-Tormey, Silvia Boffo, Ute Dugan, Alec C Kimmelman, Ravi K Amaravadi, Robert H Vonderheide.

   BACKGROUND: Patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) often respond to cytotoxic therapy, but early disease progression is typical. Responses to immunotherapy alone are rare. Recent advances in chemoimmunotherapy combinations offer promise. We report results from cohorts A and B of REVOLUTION, an adaptive platform trial designed to evaluate the safety and antitumor activity of chemoimmunotherapy combinations in untreated mPDAC.
METHODS: REVOLUTION (NCT04787991) is an open-label, exploratory platform trial. Patients were assigned to enrolling cohorts in a non-randomized fashion. All patients received gemcitabine (1,000 mg/m2), nab-paclitaxel (125 mg/m2), and two doses of ipilimumab (1 mg/kg), administered intravenously. In addition, cohort A received nivolumab (360 mg intravenously every 3 weeks) and cohort B received hydroxychloroquine (600 mg orally two times a day). The primary endpoint was safety. Secondary endpoints included objective response rate (ORR), disease control rate, duration of response, progression-free survival, and overall survival (OS). Exploratory endpoints included pharmacodynamic changes and associations between biomarkers and clinical outcomes.
RESULTS: Both cohorts enrolled 15 patients. Grade 3-4 treatment-related adverse events occurred in 60% and 53% of patients in cohorts A and B, respectively. One grade 5 event occurred in cohort B, which exhibited more frequent dose modifications and non-compliance. Cohort A demonstrated an ORR of 33% (5/15) and a 12-month OS rate of 65.5% (95% CI 35.7% to 84.0%), with higher baseline levels of programmed cell death protein-1 (PD-1)+CD39+ central memory CD4+ T cells associated with prolonged survival. Cohort B demonstrated an ORR of 40% (6/15) and a 12-month OS rate of 53.9% (95% CI 24.3% to 76.3%). Cohort A showed increases in activated and proliferating CD4+ and CD8+ T cells, regulatory T cells, and circulating soluble PD-1 and Th1-associated cytokines. Cohort B exhibited delayed but sustained increases in activated CD4+ T cells and pharmacodynamic evidence of autophagy inhibition.
CONCLUSIONS: REVOLUTION cohorts A and B demonstrated encouraging antitumor activity in patients with mPDAC. In cohort B, hydroxychloroquine-related tolerability issues contributed to early discontinuations and reduced drug exposure. These findings highlight the potential and limitations of current chemoimmunotherapy approaches. Although neither cohort will be expanded, the results reinforce the continued promise of chemoimmunotherapy in mPDAC and the importance of refining these strategies.

Keywords:  Biomarker; Chemotherapy; Combination therapy; Immunotherapy; Solid tumor

DOI:  https://doi.org/10.1136/jitc-2025-012864
Cell Rep. 2026 Feb 03. pii: S2211-1247(25)01680-8. [Epub ahead of print]45(2): 116908

Brief pulses of high-level fluid shear stress enhance metastatic potential and rapidly alter the metabolism of cancer cells.

Amanda N Pope, Devon L Moose, Guy O Hudson, Hank R Weresh, Marion R Dykstra, Aabha Y Joshi, Patrick Breheny, Eric B Taylor, Michael D Henry.

  Circulating tumor cells (CTCs) face challenges to their survival, including mechanical and oxidative stresses that are different from cancer cells in solid primary and metastatic tumors. The impact of adaptations to the fluid microenvironment of the circulation on the outcome of the metastatic cascade is not well understood. Here, we find that cancer cells exposed to brief pulses of high-level fluid shear stress (FSS) exhibit enhanced invasiveness and anchorage-independent proliferation in vitro and enhanced metastatic colonization/tumor formation in vivo. Cancer cells exposed to FSS rapidly alter their metabolism in a manner that promotes survival by providing energy for cytoskeletal remodeling and contractility as well as reducing equivalents to counter oxidative stress associated with cell detachment. Thus, exposure to FSS may provide CTCs with an unexpected survival benefit that promotes metastatic colonization.

Keywords:  CP: cancer; CP: cell biology; circulating tumor cells; fluid shear stress; metabolism; metastasis; oxidative stress

DOI:  https://doi.org/10.1016/j.celrep.2025.116908
Nat Commun. 2026 Feb 03.

Paclitaxel drives TREM2+ macrophage expansion underlying its inferior therapeutic efficacy compared to Nab-paclitaxel.

Yuqi Xing, Ruiqi Zhong, Qianchen Li, Xinwei Duan, Moyang Xu, Miao Yu, Chenying Liu, Junming He, Yi Sun, Yunling Wang, Xiaojing Guo, Yunfei Xu, Hongnan Mo, Fei Ma, Hongquan Zhang, Jun Zhan.

Paclitaxel and nab-paclitaxel differ in therapeutic efficacy and modulation of the tumor immune microenvironment, yet the molecular basis remains poorly defined. Here, based on a meta-analysis, we first show that treatment with nab-paclitaxel results in a higher overall response rate and pathological complete response compared to paclitaxel in female patients with breast cancer. Notably, TREM2 expression in macrophages is elevated in primary tumors of paclitaxel- but not nab-paclitaxel-treated female patients. In metastatic breast cancer, TREM2+ macrophage infiltration is increased in primary tumors. In breast cancer models in female mice, paclitaxel, but not nab-paclitaxel, promotes lung metastasis by recruiting TREM2+ macrophages to primary tumors. Mechanistically, paclitaxel enhances the ATF3-FGF2 axis in breast cancer cells; secreted FGF2 activates the EGR1-TREM2-EMT cytokine axis in macrophages. Genetic ablation of Trem2 or pharmacologic targeting with antisense oligonucleotides suppress paclitaxel-induced breast cancer lung metastasis in vivo. Collectively, our findings demonstrate that paclitaxel, but not nab-paclitaxel, stimulates TREM2 expression and expands TREM2+ macrophages, suggesting that TREM2 targeting could enhance paclitaxel efficacy while limiting metastasis.

DOI: https://doi.org/10.1038/s41467-026-69060-5
bioRxiv. 2026 Jan 14. pii: 2026.01.13.699089. [Epub ahead of print]

Ionic Regulation of Mechanosurveillance and Metastasis via the MRTFA/KCNMB1 Axis.

Alexa M Gajda, Mohamed Haloul, Vinay Pai, Keyvan Mollaeian, Khushi J Patel, Raymundo Rodriguez-Lopez, Katie M Beverley, Mark A Sanborn, Kihak Lee, Caitlyn C Castillo, Stephanie M Wilk, Beata M Wolska, Faruk Hossen, Eron N Mendenhall, James C Lee, Irena Levitan, Jalees Rehman, Ekrem Emrah Er.

Cellular stiffness profoundly impacts cancer metastasis at multiple levels, but mechanisms that regulate cancer cells' stiffness remain poorly understood. Here, we identified potassium efflux and KCNMB1, an auxiliary subunit of the large conductance potassium efflux (BK) channels, as regulators of cellular stiffness downstream of myocardin related transcription factor A (MRTFA). In primary pericytes, KCNMB1 knockdown increased cellular stiffness, which is consistent with the role of potassium efflux in promoting relaxation during excitation-contraction coupling. In a striking contrast, however, KCNMB1 knockdown decreased cellular stiffness in cancer cells. Softer cancer cells were resistant to NK cell mediated cytotoxicity and the low KCNMB1 expression was associated with worse survival in breast cancer patients. Importantly, pharmacological activation of BK channels reduced metastatic burden in mice and improved lysis of cancer cells by cytotoxic T-lymphocytes. These results highlight the unique ionic regulation of stiffness in cancer cells and point to BK channel agonism as a new therapeutic approach in cancer.

DOI: https://doi.org/10.64898/2026.01.13.699089
bioRxiv. 2026 Jan 21. pii: 2026.01.21.700789. [Epub ahead of print]

Septins buffer actomyosin forces to protect the nucleus from genotoxic mechanical stress.

Franklin Mayca-Pozo, Sarah M Butts, Andrew W Schaefer, Cristina Montagna, Elias T Spiliotis.

Invasively migrating cells thread their nucleus through confined interstitial spaces. How cells protect the nucleus from intracellular forces is poorly understood. Here, we show that the septin cytoskeleton buffers the actomyosin forces that power nuclear movement. Septin filaments comprising SEPT9, a septin amplified in breast cancer, align with perinuclear actomyosin cables which exhibit higher tensile stress during 3D confined migration through narrower pores. SEPT9 depletion amplifies actin stress during confined migration and after myosin II hyper-activation in non-migrating cells causing actin and nuclear envelope ruptures. Following confined migration, DNA breaks, nuclear blebs, micronuclei and cell death increase in SEPT9-depleted cells, phenotypes rescued by the oncogenic SEPT9 isoform 1. Clinicogenomic data reveal that SEPT9 amplification associates with lower genomic alteration in aggressive breast tumors and higher patient mortality. We propose that septins are a mechanoprotective element of the cytoskeleton, and SEPT9 amplification enhances tumor cell survival by preventing nuclear damage.

DOI: https://doi.org/10.64898/2026.01.21.700789
ESMO Gastrointest Oncol. 2025 Sep;9 100218

17.6% of patients in a German cohort with exocrine pancreatic cancer were diagnosed with a genetic tumor syndrome-a case for universal genetic testing?

D William, M Bermúdez, A Kübler, C Kahlert, M Distler, J Weitz, S Uhrig, M Fröhlich, B Hutter, D Aust, G Baretton, P Wimberger, K Kast, C Meisel, L Gieldon, J Porrmann, J Wagner, M Arlt, M Franke, J Fischer, K Hackmann, S Kreutzfeldt, A Mock, C E Heilig, D B Lipka, M-V Teleanu, R F Schlenk, B Brors, D Hübschmann, N Paramasivam, D Richter, K Beck, K Pfütze, I Buchhalter, W Weichert, T Herold, K Spiekermann, P J Jost, U Keilholz, F Klauschen, S Bauer, J T Siveke, T Kindler, M Boerries, A L Illert, M Bitzer, K Schulze-Osthoff, P Schirmacher, A Stenzinger, P Horak, C Heining, G Folprecht, S Fröhling, H Glimm, E Schröck, A Jahn.

   Background: Yields for (likely) pathogenic germline variants (PGVs) in cancer predisposition genes (CPGs) in pancreatic cancer (PCA) cases range from 5% to 10% in initial literature to 15% to 20% in recent literature. PGVs can impact therapy recommendations and cancer surveillance for individuals and families.
Patients and methods: We retrospectively evaluated prospective cancer predisposition testing in 125 patients with exocrine PCA from a single-center clinical genetics clinic (n = 41) and a multicenter precision oncology program (n = 84) within 64 genes, including 14 established PCA risk genes. Associations with clinical and somatic molecular parameters, as well as therapy recommendations, were assessed.
Results: PGVs were identified in 21.6% of patients (n = 27/125) across 14 CPGs. A genetic tumor syndrome was diagnosed in 17.6% of patients (n = 22/125). Existing inclusion criteria for germline testing [European Society for Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN)] would have missed up to 23.8% of PGV carriers (n = 5/21). Age of onset was not associated with PGV yield. A meta-analysis of 10 other PCA cohorts showed a median PGV yield of 14.1%.In a precision oncology program, 10.7% (n = 9/84) of PCA patients received treatment recommendations supported by PGVs. Genetic testing was carried out on relatives of 73.3% of PGV-positive patients (n = 11/15), with one family demonstrating PGV confirmation in 7 of 13 tested relatives.
Conclusions: These findings support ASCO and NCCN recommendations for germline testing in all PCA patients. We suggest offering large-panel genetic diagnostics early in clinical management, regardless of clinical parameters, with ongoing evaluation and adjustment of the gene panel.

Keywords:  familial pancreatic cancer; genetic tumor syndromes; germline testing; hereditary cancer; pancreatic adenocarcinoma; parallel germline and tumor testing; targeted therapy

DOI:  https://doi.org/10.1016/j.esmogo.2025.100218
Anal Chem. 2026 Feb 05.

Rational Design of a Dual-Locked Fluorescent Probe for Precise Imaging of Tumor via β-Galactosidase/Viscosity Activation.

Xiaoyi Zhang, Jiaoru Chen, Bo Wei, Lu Wang, Lingfeng Xie, Xueling Ding, Shilong Zhu, Dezhong Guan, Jinpei Zhou, Mian Wang, Huibin Zhang.

Fluorescence imaging is widely applied in oncology owing to its cost-effectiveness, noninvasiveness, and real-time imaging capability. Many activatable fluorescent probes targeting tumor biomarkers, such as β-galactosidase (β-gal) and viscosity, have been developed. However, the reliance on a single-response mechanism limits their ability to capture the dynamic alterations within tumors during cancer progression and chemotherapy. In this study, we rationally designed and developed ZW-gal, a dual-locked near-infrared (NIR) probe activated by both β-gal activity and viscosity. ZW-gal exhibited favorable photophysical properties, such as a large Stokes shift (125 nm), rapid enzymatic activation (within 2 min), and a strong viscosity-dependent fluorescence enhancement (up to 24.6-fold). Leveraging this dual-responsiveness, ZW-gal successfully distinguished cancer from normal cells, visualized doxorubicin-induced cancer cell senescence, and monitored cell death. In a mouse model of liver cancer, ZW-gal enabled precise tumor localization and identified senescent tumors. Moreover, through in situ spraying, ZW-gal provided real-time surgical navigation, facilitating complete tumor resection. Building on these advantages, ZW-gal represents a powerful tool with broad potential to advance both basic cancer research and personalized clinical applications.

DOI: https://doi.org/10.1021/acs.analchem.5c07416