bims-cagime 2026-05-03 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2026–05–03
39 papers selected by
Kıvanç Görgülü, Technical University of Munich

Heterogeneity in the management of patients with locally advanced pancreatic cancer: current surgeons' perspective and lessons for the future.
Diet-induced phospholipid remodeling dictates ferroptosis sensitivity and tumorigenesis in the pancreas.
GLIS3 marks a neural-like progenitor cell state that drives metastasis in pancreatic ductal adenocarcinoma.
ATG9A-mediated plasma membrane repair is linked to Vps13A and regulated by glycosylation.
Techniques for monitoring and isolating lipid droplets in cell death.
Metabolic Salvage and Acyl-chain Remodeling Support Glycosphingolipid Synthesis with the PDAC Tumor Microenvironment.
Evaluation of lipid peroxidation as a marker of ferroptosis in colon cancer cells.
Activated T cell extracellular vesicle DNA transfer enhances antigen presentation and anti-tumor immunity.
KRAS Signaling Inhibition Induces a Targetable Metabolic Dependency on Lipophagy-Dependent Fatty Acid Oxidation in Pancreatic Cancer.
Fingerprinting the Metabolic and Lipidomic Landscapes of Pancreatic Ductal Adenocarcinoma with MALDI Imaging.
When tissue tension creates a mutagenic niche.
Overexpression of autophagy genes activates lipophagy in Arabidopsis.
The Vitamin D3 Analog Calcipotriol Attenuates Pancreatic Cancer Malignancy via Downregulating Thrombospondin 1 in Pancreatic Stellate Cells.
Ras promotes macropinocytic nutrient uptake by suppressing the albumin recycling receptor FcRn.
In Silico Transcriptomic Analysis Suggests That Nickel Exposure Upregulates NINJ1 Expression: Implications for Lytic Cell Death.
Autophagy revealed as a targetable vulnerability in senescent cells by cell painting phenotypic profiling: a mechanistic study of MCOPPB and related compounds.
Tissue tension fosters macrophage-driven lipid peroxidation-induced DNA damage.
The circadian gene Dec2 promotes pancreatic cancer progression and dormancy through immune evasion.
Modulation of Oncogenic KRAS Signaling by Branched Actin-driven Cell Membrane Protrusions.
Lysosomal Profiling with LysoTracker for Quantitative Assessment of Cellular Senescence in Human Fibroblasts.
Navigating the Lipid Universe with LipidLibrarian: A Cross-Linked Database for Lipidomics Data Integration.
Dynamic heterogeneity and hidden fluidity in dense epithelial tissues.
Saturated cardiolipins are potent disruptors of inner mitochondrial membrane structure and function.
Unbiased niche labeling maps immune-excluded niche in bone metastasis.
Daraxonrasib Continues Victory Lap.
EMT and cell cycle control invadopodia and metastasis in breast cancer via Filip1L.
Characterization of a pancreatic cancer GWAS signal suggests PDX1 buffers stress in the exocrine pancreas.
Quality control of protein import into mammalian mitochondria.
Discovery tools: How powerful new scientific methods and instruments emerge and catalyze innovation.
Evolutionary characterization of lung cancer metastasis.
Safety and efficacy of intratumoural anti-CTLA4 with intravenous anti-PD1.
GLP-1R-GIPR-PPARα/γ/δ quintuple agonism corrects obesity and diabetes in mice.
Enforced ZFP281 expression delays breast cancer initiation and can provide lifelong protection against breast cancer metastasis.
Fra-2 controls the response to the KRAS inhibitor MRTX-1133 in pancreatic ductal adenocarcinoma.
A conserved re-epithelialization program underlies malignancy in pancreatic ductal adenocarcinoma.
Lipids Regulate Export of Lysosomal Enzymes from the Endoplasmic Reticulum.
Selective access to individual cells after assembling for advanced cell-cell interaction studies.
Systematic assessment of different wash solvents for the analysis of small molecule metabolites using mass spectrometry imaging.
A Sensitive Fluorescent Probe for Tracking Viscosity Changes in the Mitochondria Under Physiological and Pathological Conditions.

Updates Surg. 2026 Apr 29.

Heterogeneity in the management of patients with locally advanced pancreatic cancer: current surgeons' perspective and lessons for the future.

Ilaria Pergolini, Marc Martignoni, Alexander Novotny, Mert Erkan, Güralp O Ceyhan, Helmut Friess, Ugo Boggi, Ihsan Ekin Demir.



Keywords:  Arterial resection; Pancreatic cancer; Pancreatic surgery

DOI:  https://doi.org/10.1007/s13304-026-02651-5
Cancer Discov. 2026 Apr 29.

Diet-induced phospholipid remodeling dictates ferroptosis sensitivity and tumorigenesis in the pancreas.

Christian Felipe Ruiz, Xiangyu Ge, Rylee McDonnell, Sherry S Agabiti, Daniel C McQuaid, Andy Tang, Meera Kharwa, Jennifer Goodell, Rocio Del M Saavedra-Pena, Allison Wing, Guangtao Li, Natasha Pinto Medici, Marie E Robert, Rohan R Varshney, Michael C Rudolph, Fred S Gorelick, John Wysolmerski, Daniel Canals, John D Haley, Matthew S Rodeheffer, Mandar Deepak Muzumdar.

High-fat diet (HFD) intake has been linked to an increased risk of pancreatic ductal adenocarcinoma (PDAC), a lethal and therapy-resistant cancer. However, whether and how specific dietary fats drive cancer development remains unresolved. Leveraging an oncogenic Kras-driven mouse model that closely mimics human PDAC progression, we screened a dozen isocaloric HFDs differing solely in fat source and representing the diversity of human fat consumption. Unexpectedly, diets rich in oleic acid - a monounsaturated fatty acid (MUFA) typically associated with good health - markedly enhanced tumorigenesis. Conversely, diets high in polyunsaturated fatty acids (PUFAs) suppressed tumor progression. Relative dietary fatty acid saturation levels (PUFA/MUFA) governed pancreatic membrane phospholipid composition, lipid peroxidation, and ferroptosis sensitivity in mice, concordant with circulating PUFA/MUFA levels being linked to altered PDAC risk in humans. These findings directly implicate dietary unsaturated fatty acids in controlling ferroptosis susceptibility and tumorigenesis, supporting potential "precision nutrition" strategies for PDAC prevention.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0734
Cell Rep. 2026 Apr 27. pii: S2211-1247(26)00392-X. [Epub ahead of print]45(5): 117314

GLIS3 marks a neural-like progenitor cell state that drives metastasis in pancreatic ductal adenocarcinoma.

Dennis Gong, Jimmy A Guo, Jennifer Su, Sueda Cetinkaya, Connor Hennessey, Patrick Yu, Ananya Jambhale, Peter L Wang, Nicholas J Caldwell, Ashley Lam, Junning Wang, Carina Shiau, Kevin S Kapner, Julien Dilly, Laleh Abbassi, Seema Chugh, Shatavisha Dasgupta, Jonathan Nowak, Brian M Wolpin, M Lisa Zhang, Mari Mino-Kenudson, Tyler Jacks, Andrew J Aguirre, William L Hwang.

  Pancreatic ductal adenocarcinoma (PDAC) frequently recurs and metastasizes despite intensive therapy. The neural-like progenitor (NRP) transcriptional program is enriched in residual disease after neoadjuvant chemotherapy and radiotherapy, but its basis has remained unclear. We hypothesized that NRP represents a regeneration program co-opted by tumors recovering from cytotoxic injury. NRP signatures were strongly enriched in normal pancreatic injury and regeneration, and NRP cancer cells co-expressed transcription factors involved in pancreatic development. Our data support cell-intrinsic contributions and implicate IL-1β-associated inflammatory signaling as a plausible microenvironmental driver of elevated NRP expression. To enable direct phenotypic comparison with other cancer cell states, we established isogenic mouse organoid overexpression models for transcription factors linked to NRP, classical, and basal-like states. Glis3 emerged as a key NRP-associated factor, promoting clonogenicity, tumor growth, and metastasis. These findings identify a clinically relevant developmental regeneration program that emerges in PDAC after treatment.

Keywords:  CP: cancer; Glis3; cell states; chemoresistance; neural-like progenitor; pancreatic cancer; residual disease

DOI:  https://doi.org/10.1016/j.celrep.2026.117314
Proc Natl Acad Sci U S A. 2026 May 05. 123(18): e2508391123

ATG9A-mediated plasma membrane repair is linked to Vps13A and regulated by glycosylation.

Natali H Muskat, Inbar Nevo-Yassaf, Madhuri Chaurasia, Shani Reiss, Inna Goliand, Meital Kupervaser, Yoseph Addadi, Yishai Levin, Milana Fraiberg, Zvulun Elazar.

  Biological membranes provide a resilient framework for cellular structure and stability. Disrupting its integrity may result in irreparable damage, altering cellular homeostasis and ultimately leading to cell death. ATG9A, a transmembrane protein, has recently been implicated in plasma membrane repair. However, its role in the process and the mechanism by which it is targeted to the plasma membrane upon damage are unclear. We show here that glycosylation of ATG9A is essential for its membrane repair activity. This has been corroborated by using different mutant cells that are defective in their ability to process proteoglycan in the Golgi complex. Specifically, sialylation of the sugar moiety appears vital for plasma membrane repair activity. Additionally, we provide evidence indicating that ATG9A is targeted to the plasma membrane through interaction with the endosomal sorting complex required for transport complex. Finally, we found that ATG9A lipid scramblase activity and the lipid transfer protein VPS13A are needed for efficient membrane repair.

Keywords:  ATG9A; ESCRT-comples; Plasma membrane repair; VPS13A; glycosylation

DOI:  https://doi.org/10.1073/pnas.2508391123
Methods Cell Biol. 2026 ;pii: S0091-679X(26)00084-1. [Epub ahead of print]206 1-21

Techniques for monitoring and isolating lipid droplets in cell death.

Fangquan Chen, Rui Kang, Jiao Liu, Daolin Tang.

  Lipid droplets (LDs) are dynamic organelles that not only store energy and regulate metabolism but also serve as key modulators of cell death signaling and disease progression. LDs influence cell fate by buffering lipid peroxidation or releasing fatty acids during ferroptosis, modulating apoptotic protein expression, and facilitating autophagic degradation. Their multifunctional roles are context-dependent and span multiple cell death pathways. In disease, aberrant LD accumulation is closely linked to metabolic disorders, neurodegeneration, cancer therapy resistance, and pathogen infection. Alterations in LD morphology and abundance have emerged as diagnostic indicators. Thus, precise detection and efficient isolation of LDs are critical for elucidating disease mechanisms, advancing targeted therapies, and translating LD biology into clinical applications. This chapter outlines key methodologies-including lipid staining, fluorescent probes, high-content microscopy, density gradient centrifugation, and immunoaffinity purification-for evaluating lipid droplet function and achieving their isolation in the context of cell death.

Keywords:  Cell death; Lipid droplets; Methods

DOI:  https://doi.org/10.1016/bs.mcb.2026.02.016
bioRxiv. 2026 Apr 17. pii: 2026.04.14.718544. [Epub ahead of print]

Metabolic Salvage and Acyl-chain Remodeling Support Glycosphingolipid Synthesis with the PDAC Tumor Microenvironment.

Anna S Trimble, Casie S Kubota, Elaine Zhao, Maureen L Ruchhoeft, Jonathan R Weitz, Woncheol Jung, Kristina L Peck, Satoshi Ogawa, Ethan L Ashley, Herve Tiriac, Tae Gyu Oh, Andrew M Lowy, Dannielle D Engle, Christian M Metallo.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy where metabolic homeostasis is maintained by tumor and stromal cells within the tumor microenvironment (TME). To better assess pathways supporting macromolecule biosynthesis in PDAC tumors, we apply 13 C metabolic flux analysis (MFA) to slice cultures of treatment-naïve human tumors and mouse models that retain the native TME. Glycans, lipid headgroups, and very long-chain fatty acids are the most dynamic metabolic pools, while long chain fatty acids, purines, and pyrimidines are predominantly salvaged locally in situ . We use targeted pharmacological modulators to highlight the importance of recycling pathways and metabolic redundancies which mitigate changes in lipid abundances. Finally, we leverage targeted lipid fluxomics and the distinct ganglioside and globoside profiles of tumor and stromal cells, respectively, to demonstrate the role of the lipid kinase PIKfyve in supporting ganglioside homeostasis via sialic acid and ceramide salvage. These data establish application of MFA to slice cultures of PDAC tumors as an effective approach for assessing metabolic mechanisms and therapeutic responses within an intact TME.

DOI: https://doi.org/10.64898/2026.04.14.718544
Methods Cell Biol. 2026 ;pii: S0091-679X(26)00081-6. [Epub ahead of print]206 81-93

Evaluation of lipid peroxidation as a marker of ferroptosis in colon cancer cells.

María Pilar Corral-Sancho, Berta Buey, Elena Layunta, Eva Latorre.

  Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation, with emerging relevance in cancer biology, particularly in therapy-resistant tumors such as colorectal cancer. Accurate and reproducible methods to monitor ferroptosis are essential for understanding its mechanisms and therapeutic potential. In this methodological paper, we present an optimized protocol for the evaluation of lipid peroxidation as a surrogate marker of ferroptosis in colon cancer cell models. Specifically, we describe an approach for quantifying malonylaldehyde and hydroxyalkenals (MDA+ 4-HDA), as key byproducts of lipid oxidation, using a colorimetric assay adapted for cell culture. This methodological framework provides a reliable basis for dissecting ferroptotic responses and for evaluating the activity of ferroptosis-inducing compounds in colorectal cancer research.

Keywords:  4-HAs; Intestine; Lipids; MDA; Oxidation; Redox

DOI:  https://doi.org/10.1016/bs.mcb.2026.02.013
Cancer Cell. 2026 Apr 30. pii: S1535-6108(26)00177-7. [Epub ahead of print]

Activated T cell extracellular vesicle DNA transfer enhances antigen presentation and anti-tumor immunity.

Mengying Hu, Di-Ao Liu, Inbal Wortzel, Paul Collier, Theodore M Nelson, Jonathan Foox, Guojie Zhong, Gabriel Tobias, Tetsuhiko Asao, Linda Bojmar, Candia M Kenific, Gang Wang, Simone Caielli, Zurong Wan, Sarah Qureshy, Max Reed, Richard Piszczatowski, Purnima Ravisankar, Julia A Brown, Sihan Xiong, Huajuan Wang, Pernille Lauritzen, Yael Aylon, Henrik Molina, William R Jarnagin, Moshe Oren, Ben Z Stanger, Jack Bui, Gabriele Bergers, Agnès Noël, Paul M Grandgenett, Michael A Hollingsworth, David Tuveson, Nancy Boudreau, Jacqueline Bromberg, David Kelsen, David R Jones, Laura Santambrogio, Melody Y Zeng, Virginia Pascual, Han Sang Kim, Christopher E Mason, Haiying Zhang, Irina R Matei, David Lyden.

  Antigen processing and presentation (APP) is essential for adaptive immunosurveillance. We uncover a mechanism whereby activated T cell-derived extracellular vesicles (ATEVs) drive a positive feedback loop that enhances antigen presentation and immune responses in normal physiology and cancer. ATEV-induced immunogenicity relies on extracellular vesicular double-stranded DNA (EVDNA), which is notably abundant and primarily composed of genomic DNA enriched in immune-related genes, including those encoding APP machinery. Mechanistically, granzyme B (Gzmb) packaged by ATEVs disrupts the nuclear envelope of recipient cells, facilitating intranuclear transfer and subsequent transient expression of EVDNA encoding APP genes. DNase treatment removes most AT-EVDNA, abrogating APP upregulation and thus T cell activation and recruitment to tumors. Notably, ATEVs hold promise as an acellular immunotherapy, restoring APP and synergizing with checkpoint blockade in immunotherapy-refractory tumors. Collectively, our findings uncover a mechanism of transient, non-viral gene delivery by ATEVs that boosts APP and anti-tumor immunity while limiting autoimmunity.

Keywords:  EV(DNA); acellular immunotherapy; activated T cell-derived EVs; antigen presentation; gene transfer

DOI:  https://doi.org/10.1016/j.ccell.2026.03.023
Cancer Res. 2026 Apr 29.

KRAS Signaling Inhibition Induces a Targetable Metabolic Dependency on Lipophagy-Dependent Fatty Acid Oxidation in Pancreatic Cancer.

Ravi Thakur, Dezhen Wang, Tuo Hu, Chunbo He, Junzhang Zhao, Voddu Suresh, Girish H Rajacharya, Anjan K Pradhan, Vira Chumak, Carlos A Valenzuela, Asha D Kushwaha, Drew A Labreck, Tae Gyu Oh, Kar-Ming Fung, Daniel Zhao, Naoko Takebe, Susanna V Ulahannan, Surendra K Shukla, Kirsten L Bryant, Channing J Der, Kamiya Mehla, Pankaj K Singh.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by frequent KRAS mutations, which activate the MAPK pathway to promote PDAC progression. Here, we explored metabolic vulnerabilities of PDAC by assessing initial metabolic reprogramming upon ERK inhibition using metabolomics, lipidomics, and isotope-tracing experiments. ERK inhibition enhanced lipid turnover and fatty acid oxidation while inhibiting glycolysis, glucose oxidation, and glutamine metabolism in PDAC cells. Moreover, lipophagy, but not cytosolic lipolysis, was responsible for the increased lipid turnover and fatty acid oxidation upon ERK inhibition. Lipophagy and lipophagy-fueled fatty acid oxidation were induced by increased nuclear translocation and activity of the transcription factor TFEB. Pharmacological inhibition of fatty acid oxidation in combination with KRASG12D/MEK/ERK inhibitors synergistically decreased the growth of PDAC cell lines and organoids. The combination decreased tumor burden and improved survival in orthotopic cell line and patient-derived xenograft PDAC models. Overall, this study provides mechanistic insights into the development of metabolic resistance to KRAS signaling inhibition and demonstrates that fatty acid oxidation is a metabolic vulnerability following KRAS signaling inhibition that can be utilized as an effective therapeutic target to treat PDAC.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-1984
Clin Cancer Res. 2026 Apr 27.

Fingerprinting the Metabolic and Lipidomic Landscapes of Pancreatic Ductal Adenocarcinoma with MALDI Imaging.

Saleem Yousf, Kristine Glunde, Dalton R Brown, Caitlin Tressler, Meiyappan Solaiyappan, Balaji Krishnamachary, Yelena Mironchik, Mohamad Dbouk, Michael G Goggins, Zaver M Bhujwalla.

PURPOSE: Metabolic reprogramming plays an integral role in progression, immune evasion, and response to treatment in many cancers, including pancreatic ductal adenocarcinoma (PDAC). This study aimed to spatially characterize the metabolic and lipidomic alterations in PDAC and its precursor lesion, intraductal papillary mucinous neoplasm (IPMN), compared to normal/non-neoplastic pancreatic tissue. Experimental details: Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was employed to perform spatial metabolic and lipidomic profiling of human PDAC, IPMN, and normal/non-neoplastic pancreatic tissues. MALDI-MSI provided multiplexed metabolic images of tissue samples at 200 um resolution, allowing spatial characterization of the tumor metabolic landscape.
RESULTS: Our data identified metabolic signatures characteristic of PDAC, with several of these altered in IPMN compared to normal/non-neoplastic tissue. The metabolic fingerprint of PDAC was characterized by increased levels of taurine, ascorbic acid, and a variety of lipid species, including most of the phosphatidylcholines and sphingomyelins compared to normal/non-neoplastic pancreas tissue, alongside elevated acetylcarnitine, butyrylcarnitine, and phosphatidylcholine (PC 34:3) relative to IPMN; significant reductions were observed in creatine, malate, lysophosphatidylcholine (LPC 16:0). In contrast, IPMN tissues demonstrated a significant reduction of xanthine, arginine, and tryptophan compared to normal/non-neoplastic pancreas tissue. These metabolic signatures were spatially heterogeneous.
CONCLUSION: Our findings provide novel insights into the metabolic and lipidomic underpinnings of PDAC. Metabolic alterations in PDAC were associated with proliferation, immune evasion, and treatment resistance.

DOI: https://doi.org/10.1158/1078-0432.CCR-25-1115
Cancer Cell. 2026 Apr 30. pii: S1535-6108(26)00178-9. [Epub ahead of print]

When tissue tension creates a mutagenic niche.

Nicole Cruz-Reyes, Derek C Radisky.

In this issue of Cancer Cell, Hayward et al. show that fibrotic tissue tension creates a mechanically organized mutagenic niche. A stiff stroma activates epithelial STAT3, recruits macrophages, and drives NOX-dependent lipid peroxidation, generating diffusible aldehydes that damage epithelial DNA in fibrotic tumors and mammographically dense breast tissue.

DOI: https://doi.org/10.1016/j.ccell.2026.04.001
Autophagy. 2026 Apr 25.

Overexpression of autophagy genes activates lipophagy in Arabidopsis.

Jilian Fan, Saroj Kumar Sah, Dongling Xie, Changcheng Xu.

  Cells possess an intrinsic recycling system called macroautophagy/autophagy, which delivers obsolete or damaged cytoplasmic components into the vacuole for degradation and reuse. Autophagy-mediated breakdown of organellar membrane lipids supplies fatty acids for the synthesis of triacylglycerols (TAGs), which are then packaged into subcellular organelles called lipid droplets (LDs). Conversely, autophagy contributes to TAG turnover by delivering LDs into vacuoles for breakdown by resident acid lipases. Additionally, LDs can undergo degradation through cytosolic lipolysis mediated by SDP1 (Sugar-Dependent1) lipase in Arabidopsis. Autophagy-mediated LD, a process referred to as lipophagy, has been described in plants. Nevertheless, the precise mechanisms of lipophagy and the specific types of vacuoles involved remain unclear. Here, we show that overexpression of autophagy genes ATG5 or ATG8 promotes autophagic activity and significantly reduces LD accumulation. We demonstrate that the decreased LD abundance is not due to increased LD degradation mediated by SDP1 but is dependent on autophagy. The abundance of vacuoles specifically labeled by δ-TIP3 (delta-tonoplast intrinsic protein 3) was markedly decreased in ATG5-overexpressing lines. In addition, disruption of autophagic genes prevented the formation of both δ-TIP3-positive vacuoles and the mysterious vacuolar lumen structures previously termed bulbs, indicating their autophagic origin. Furthermore, confocal imaging analysis revealed close associations between LDs and δ-TIP3-labeled vacuoles, as well as the presence of LDs within vacuoles delimited by δ-TIP3. Together, our findings indicate that overexpression of autophagy genes triggers lipophagy and identify a distinct type of vacuole involved in this process.

Keywords:  ATG5; ATG8; Arabidopsis thaliana; autophagic vacuole; lipid droplet; lipophagy

DOI:  https://doi.org/10.1080/15548627.2026.2664350
Mediators Inflamm. 2026 ;2026(1): e2632235

The Vitamin D3 Analog Calcipotriol Attenuates Pancreatic Cancer Malignancy via Downregulating Thrombospondin 1 in Pancreatic Stellate Cells.

Yang Wu, Chun Zhang, Matthias Ilmer, Maximilian Weniger, Quan Li, Jing Wang, Rainer C Miksch, Jens Werner, Jan G D'Haese, Bernhard Renz.

  Pancreatic ductal adenocarcinoma (PDAC) exhibits pronounced desmoplasia, primarily attributed to the activation of pancreatic stellate cells (PSCs) from a quiescent state (quiescent PSCs [qPSCs]) to an activated form (activated PSCs [aPSCs]), which facilitates tumor progression and therapeutic resistance. This study investigates the potential of the vitamin D3 (VD) analog calcipotriol (Cal) to modulate this activation process and its impact on PDAC cell malignancy, with a particular focus on the thrombospondin 1/cluster of differentiation 47 (THBS1/CD47) signaling axis. Through analyzing VDR mRNA expression in aPSCs versus PDAC cells, we found that aPSCs are more responsive to VD signaling. Treatment with Cal significantly reduced aPSC activation, as evidenced by decreased α-SMA expression and THBS1 secretion, thereby diminishing stromal support for PDAC cell proliferation, migration, and invasion. These changes were mediated by the inhibition of the THBS1/CD47 axis, highlighting a novel mechanism by which Cal disrupts the supportive tumor microenvironment. Our findings highlight the therapeutic potential of targeting aPSCs with VD analogs in PDAC, suggesting a new direction for treatments that aim to interrupt the desmoplastic reaction and thereby inhibit PDAC progression.

Keywords:  CD47; PSCs; THBS1; calcipotriol; pancreatic cancer; vitamin D receptor (VDR)

DOI:  https://doi.org/10.1155/mi/2632235
EMBO Rep. 2026 Apr 29.

Ras promotes macropinocytic nutrient uptake by suppressing the albumin recycling receptor FcRn.

Rafael Paschoal de Campos, Xuxia Wu, Aslihan Inal, Zhao Liu, Craig B Thompson, Wilhelm Palm.

Macropinocytosis and lysosomal degradation of extracellular protein constitute a nutrient acquisition pathway in Ras-driven cancers. By catabolizing albumin, the most abundant plasma protein, Ras-transformed cells sustain growth in environments where free amino acids are scarce. Under physiological conditions, however, albumin is normally protected from lysosomal degradation by the neonatal Fc receptor (FcRn), which recycles albumin back to the extracellular space. Here, by investigating how cancer cells overcome FcRn-mediated albumin recycling, we identify the Ras-Erk MAPK signaling pathway as a critical regulator of FcRn. Expression of constitutively active Ras variants or stimulation with growth factors represses FcRn transcription through activation of the MAPK pathway, leading to decreased FcRn protein abundance. Conversely, pharmacological inhibition of Ras-MAPK signaling de-represses FcRn expression. Restoring FcRn levels in Ras-transformed cells limits lysosomal albumin degradation and impairs the proliferation of cells that depend on albumin as an essential amino acid source. Thus, oncogenic Ras signaling promotes the nutritional utilization of albumin by suppressing FcRn, thereby supporting cancer cell adaptation to nutrient-poor environments.

DOI: https://doi.org/10.1038/s44319-026-00787-4
Environ Toxicol. 2026 Apr 26.

In Silico Transcriptomic Analysis Suggests That Nickel Exposure Upregulates NINJ1 Expression: Implications for Lytic Cell Death.

Sukran Yagmur Avcioglu, Busra Nur Ozdemir, Caglar Berkel.

  Nickel (Ni) has been shown to induce cell death in multiple studies, by the involvement of different programmed cell death mechanisms such as apoptosis and pyroptosis. NINJ1 (Ninjurin 1) is a recently identified transmembrane protein, mediating plasma membrane rupture and the loss of plasma membrane integrity during lytic cell death or following mechanical strain. The involvement of NINJ1-mediated plasma membrane rupture in nickel-induced cell death has not been previously studied. Here, by performing in silico transcriptomics analysis of publicly available datasets in the R programming environment, we observed that nickel exposure/treatment increases the expression of NINJ1 at the transcription (mRNA) level in various cell types such as human PBMCs and endothelial cells, and rat liver cells (fold changes of 1.1, 2.61, and 1.02, respectively). Besides, we observed that in skin biopsies of individuals who were exposed to nickel, those with nickel allergy have higher NINJ1 mRNA expression compared to those without nickel allergy (nonallergic controls) (fold change of around 1.05), pointing to the potential involvement of NINJ1 in nickel allergy in skin. Combined, based on computational data analyses, we here hypothesized that nickel-induced increases in NINJ1 mRNA expression might possibly lead to higher levels of NINJ1-mediated plasma membrane rupture and lytic cell death in these nickel-exposed cells, likely resulting in increased inflammation. However, since this bioinformatics study is solely based on computational reanalysis, and functional NINJ1-mediated plasma membrane rupture following nickel exposure was not experimentally demonstrated, additional experimental data is required to support the findings. Further research is needed to identify cellular mechanisms by which nickel induces NINJ1 mRNA expression and possibly lytic cell death, contributing to the nickel-induced inflammation.

Keywords:  NINJ1; cell death; cell lysis; inflammation; nickel; plasma membrane rupture; pyroptosis

DOI:  https://doi.org/10.1002/tox.70113
Geroscience. 2026 Apr 30.

Autophagy revealed as a targetable vulnerability in senescent cells by cell painting phenotypic profiling: a mechanistic study of MCOPPB and related compounds.

Matthew Lacey, Lucie Beresova, Alzbeta Srovnalova, Pavlo Polishchuk, Michal Sala, Zdenek Skrott, Marian Hajduch, Petr Dzubak, Jiri Bartek, Anna Siskova, Martin Loffelmann, Radim Nencka, Martin Mistrik.

  Senescent cells accumulate with age and contribute to tissue dysfunction and chronic inflammation. Senolytic agents that selectively eliminate senescent cells hold therapeutic promise; however, few mechanistic classes have been established. Using Cell Painting-based morphological profiling, we identified a distinct cluster of senolytic compounds comprised of both known and novel autophagy inhibitors, including AZ191, bafilomycin A1, chloroquine, daurisoline, dauricine, MCOPPB, and its derivative MS1108. These compounds selectively eliminated senescent cells by disrupting autophagic flux. Our findings reveal senescent cell dependence on autophagy as an essential survival mechanism, define the existence of a mechanistically distinct class of senolytics acting through autophagy inhibition, and demonstrate the predictive value of Cell Painting in aging-related drug discovery. Our results provide new insights into senescent cell vulnerability and expand the therapeutic landscape for aging-related pathologies by highlighting autophagy as a targetable dependency.

Keywords:  Autophagy; Cell Painting; Proteotoxic stress; SASP; Senescence; Senolytics

DOI:  https://doi.org/10.1007/s11357-026-02258-z
Cancer Cell. 2026 Apr 30. pii: S1535-6108(26)00176-5. [Epub ahead of print]

Tissue tension fosters macrophage-driven lipid peroxidation-induced DNA damage.

Mary-Kate Hayward, Jason J Northey, Valentina Opazo-Mellado, Connor Stashko, Ori Maller, Alastair J Ironside, Xuchu Que, Jonathon N Lakins, E Shelley Hwang, Joseph L Witztum, Hugo Gonzalez, Valerie M Weaver.

  Inflammation can induce mutagenic DNA damage to enhance cancer risk and progression. Inflammation also increases fibrosis and stromal stiffening that promotes malignancy, and tissues with higher cancer risk are often stiffer. Despite this connection, how stromal stiffness contributes to inflammatory-mediated DNA damage in tumorigenesis remains unclear. Here, we show that tissue tension engages macrophages to generate lipid peroxidation-induced DNA damage, contributing to mutational burden that may promote malignant progression. We identify that fibrotic breast tumors display higher mutational burdens. Mechanistically, tissue tension increases epithelial STAT3 to drive chemokine-mediated macrophage recruitment. Stiffness promotes reactive oxygen species-induced lipid peroxidation in recruited macrophages, generating aldehydes that damage DNA and enhance progression. Notably, high mammographically dense breast tissues-associated with increased cancer risk-are stiffer and inflamed and display elevated lipid aldehydes and DNA damage. This work links fibrosis and inflammation to tension-mediated cancer initiation and progression.

Keywords:  DNA damage; breast cancer; extracellular matrix; inflammation; lipid peroxidation; macrophages; stromal stiffness; tissue fibrosis; tumor microenvironment

DOI:  https://doi.org/10.1016/j.ccell.2026.03.022
Dev Cell. 2026 Apr 28. pii: S1534-5807(26)00124-3. [Epub ahead of print]

The circadian gene Dec2 promotes pancreatic cancer progression and dormancy through immune evasion.

Lan Wang, Chris R Harris, Crissy Dudgeon, Orjola Prela, Juliana Cazares de Menezes, Ching-Hua Shih, Christina Davidson, Anthony Casabianca, Subhajyoti De, Wade Narrow, Jennifer Becker, Paul M Grandgenett, Michael A Hollingsworth, Jean L Grem, Minsoo Kim, Yeonsun Hong, Scott Gerber, Paula M Vertino, Chongfeng Gao, Zachary Klamer, Anna Repesh, Yansheng Hao, Allison T Ryan, Mitchell Breitenbach, Anna Bianchi, Jashodeep Datta, Brian J Altman, Brian Haab, Darren R Carpizo.

  The mechanisms that regulate immune evasion by pancreatic ductal adenocarcinomas (PDACs) remain poorly understood. Using a mouse model of resectable PDAC, we identified an unknown role of the circadian rhythm gene Differentially Expressed in Chondrocytes 2 (Dec2) in regulating tumor progression and dormancy. Deletion of Dec2 from tumor cells substantially increased mouse survival after resection due to an immune-mediated mechanism, as the survival benefit was abrogated under immunodeficient conditions. Dec2 promotes immune evasion by repressing major histocompatibility complex class I (MHC-I)-dependent antigen presentation and by repolarizing the tumor microenvironment from immunologically cold (low T cell infiltration) to hot (elevated T cell infiltration). Dec2 is also a regulator of circadian rhythms, and we found that genes involved in MHC-I antigen presentation and MHC-I surface localization oscillated in a circadian manner, which was lost upon deletion of Dec2 in vitro. We conclude that Dec2 promotes primary PDAC progression and likely metastatic dormancy through immune evasion.

Keywords:  Dec2; antigen presentation; cancer dormancy; circadian rhythm; immune evasion; mouse model resectable PDAC; pancreatic ductal adenocarcinoma; sTRA

DOI:  https://doi.org/10.1016/j.devcel.2026.04.001
bioRxiv. 2026 Apr 13. pii: 2026.04.09.717047. [Epub ahead of print]

Modulation of Oncogenic KRAS Signaling by Branched Actin-driven Cell Membrane Protrusions.

Gabriel Muhire Gihana, Kushal Bhatt, Bo-Jui Chang, Vasanth Murali, Felix Zhou, Jungsik Noh, Roshan Ravishankar, Hazel Borges, Jinlong Lin, Jessica Oceguera, Pedro Augusto Nogueira, Lizbeth Perez Castro, Niranjan Venkateswaran, Bingying Chen, Reto Fiolka, Maralice Conacci-Sorrell, Kevin Dean, Gaudenz Danuser.

For over three decades, we have known that oncogenic RAS alters the actin cytoskeleton organization and cell surface morphology 1,2 . RAS activates the GTPase RAC1, which triggers the growth of branched actin networks to promote cell membrane protrusions 3,4 . In melanoma, the hyperactive RAC1 mutant, Rac1 P29S , was recently shown to drive extended lamellipodia, which then empower cell proliferation through sequestration and localized inhibition of the merlin tumor suppressor 5 . This discovery illustrates cell morphological programs not only as outputs but also as regulators of human oncogenic signals. Hence, we wondered whether the pronounced branched actin-driven membrane protrusions (BAMPs) downstream of oncogenic RAS are not mere outputs of RAS signaling but rather an active component in mediating the oncogenic penetrance of RAS mutants. We used volumetric light sheet microscopy and biochemical approaches to investigate the role of BAMPs in regulating the molecular signaling of oncogenic KRAS in pancreatic and lung cancer models. We found that elevated BAMP formation regulated the interaction of oncogenic KRAS with downstream effectors, specifically with the RAC1 GEF TIAM1. This implies that BAMPs amplify their own upstream regulators in a positive feedback. This meritorious cycle upregulates cyclin D1 expression by inactivating the merlin tumor suppressor, independently of the mitogen activated protein kinase pathway (MAPK). In the absence of BAMPs, cells carrying oncogenic KRAS mutations are unable to attain their full penetrance in proliferation. Overall, this work unveils the long-overlooked role of branched actin-driven cell morphology in the functionalization of KRAS mutants as potent oncogenes.

DOI: https://doi.org/10.64898/2026.04.09.717047
bioRxiv. 2026 Apr 17. pii: 2026.04.16.719007. [Epub ahead of print]

Lysosomal Profiling with LysoTracker for Quantitative Assessment of Cellular Senescence in Human Fibroblasts.

Javier Estrada, Scott Tenenbaum, Melinda Larsen, Thomas J Begley, J A Melendez.

Cellular senescence is a stable cell-cycle arrest state associated with characteristic phenotypes, including enlarged cell morphology, altered secretory signaling, and pronounced lysosomal remodeling. Senescent cells commonly accumulate increased numbers of enlarged lysosomes with changes in acidity and degradative capacity, creating an opportunity for simple live-cell readouts of senescence-linked organelle remodeling. Here, I describe a live-cell lysosomal profiling protocol that uses LysoTracker Deep Red, an acidotropic fluorescent dye, to label and quantify acidic organelles in individual living cells as an indicator of senescence-associated lysosomal expansion. The method is demonstrated in IMR-90 human lung fibroblasts undergoing replicative senescence across serial passaging. The protocol details cell culture and passage tracking, LysoTracker staining, fluorescence imaging, and straightforward image-based quantification of lysosomal signal intensity and lysosome-enriched area per cell. As an optional validation step, senescence-associated β-galactosidase staining is performed on parallel cultures to confirm senescent cell identity. Representative outcomes show increased LysoTracker signal and expanded lysosome-enriched regions in late-passage cultures compared to early-passage controls, consistent with lysosomal remodeling during senescence. This protocol is designed to be simple to adopt and can be adapted to other cell types or senescence-inducing stresses, providing a practical, quantitative complement to conventional endpoint assays.
SUMMARY: This article presents a live-cell imaging protocol using LysoTracker Deep Red to quantify lysosomal remodeling as a marker of cellular senescence in IMR-90 human fibroblasts. We demonstrate quantitative lysosomal readouts derived from fluorescence imaging, including lysosome-enriched area and intensity measurements that can be summarized per cell and, when desired, as stitched-field, per-nucleus normalized metrics. Senescence status can be validated against senescence-associated β-galactosidase (SA-β-Gal) staining performed on parallel cultures. The method can be adapted to other cell types or senescence-inducing stresses and enables quantitative analysis of lysosomal remodeling during senescence.

DOI: https://doi.org/10.64898/2026.04.16.719007
J Lipid Res. 2026 Apr 27. pii: S0022-2275(26)00075-1. [Epub ahead of print] 101049

Navigating the Lipid Universe with LipidLibrarian: A Cross-Linked Database for Lipidomics Data Integration.

Felix Niedermaier, Konstantinos Mechteridis, Konstantin Pelz, Vivian Würf, Nikolai Köhler, Josch K Pauling.

  There are numerous public resources and guidelines available for lipidomics research, including standard nomenclatures, classification systems, and lipid databases. However, these resources are not always aligned with one another, making it difficult to find and compare information on the same lipid across different databases. To tackle these challenges we present LipidLibrarian, a lipid search engine that enables a combined search of all major lipid databases by aggregating the available information and presenting it in a unified manner. The three main sources of information that build the foundation of LipidLibrarian as a comprehensive search-engine are SwissLipids, LIPID MAPS and ALEX123. Furthermore, various secondary resources such as LION/web, LINEX, LipidLynxX, and Goslin were incorporated to enhance the results and conduct name and hierarchy conversions. LipidLibrarian is accessible via a user-friendly website, allowing the user to query lipids using their trivial names, shorthand notations, database identifiers, or their masses. Alternatively, LipidLibrarian can be accessed as a Python package for integration into high-throughput lipidomics pipelines. The output of a LipidLibrarian query is split into multiple categories, such as nomenclature, database identifiers, masses, adducts, fragments, ontology terms, and reactions. For each of these categories, LipidLibrarian aggregates the results from all databases and provides the source from which each value originates. This enables the user to quickly assess if the databases contain differing or conflicting information. In summary, LipidLibrarian provides an effortless, comprehensive and automated search for lipid information, thereby accelerating the research workflow and making it a meaningful tool for the scientific community; lipidlibrarian.ciobio.io.

Keywords:  Biochemistry; Bioinformatics; Database; Integration; Lipid; Lipidomics; Mass Spectrometry; Metabolism; Multi-omics; Visualization

DOI:  https://doi.org/10.1016/j.jlr.2026.101049
Sci Adv. 2026 May;12(18): eaec3773

Dynamic heterogeneity and hidden fluidity in dense epithelial tissues.

Yuan Shen, Wang Xi, René-Marc Mège, Walter Kob, Benoit Ladoux.

Epithelial tissues maintain organ integrity while continuously remodeling during morphogenesis, repair, and disease. At high cell densities, these tissues often appear mechanically arrested in a disordered, solid-like state, raising the question of how they retain the ability to reorganize. Here, we show that, unlike thermal glasses, dense epithelial tissues do not exhibit caging behavior but instead behave as a complex fluid. Cells display subdiffusive creep together with Fickian yet non-Gaussian dynamics and compressed exponential relaxation, hallmarks of stress-driven fluidity. This fluidity arises from the tissue's structural and mechanical organization rather than from cell division or extrusion, which only transiently enhance local dynamics. Fast-moving cells organize into collective, anisotropic clusters whose spatial heterogeneity correlates with local structural entropy and soft vibrational modes. Together, these findings reveal a hidden fluidity in densely packed epithelia that supports mechanical stability while preserving the capacity for remodeling during development, wound healing, and early tumor invasion.

DOI: https://doi.org/10.1126/sciadv.aec3773
bioRxiv. 2026 Apr 17. pii: 2026.04.14.718012. [Epub ahead of print]

Saturated cardiolipins are potent disruptors of inner mitochondrial membrane structure and function.

Kailash Venkatraman, Daniel Milshteyn, Carolina Sarto, Elida Kocharian, Cailyn M Sakurai, Aaron M Armando, Adrian M Wong, Edward A Dennis, Xi Fang, Christopher T Lee, Itay Budin.

Cardiolipin (CL) is a four-chained, mitochondrial-specific phospholipid crucial for maintenance of inner mitochondrial membrane (IMM) structure and function. In healthy tissues, CL acyl chains are highly unsaturated and maintained by a conserved remodeling pathway. However, dysregulation of CL acyl chain composition can arise from mutations in the CL transacylase, Tafazzin (TAZ), resulting in Barth syndrome (BTHS), where patients exhibit heightened mitochondrial dysfunction. Cells lacking TAZ accumulate three-chained monolysocardiolipin (MLCL) as well as CL species with saturated acyl chains (CLsat). While the presence of MLCL destabilizes electron transport chain (ETC) complexes and IMM-shaping proteins, the contributions of CLsat to mitochondrial dysfunction have not been elucidated. Here, we find that treatment of TAZ knockout cells with exogenous saturated fatty acids causes accumulation of CLsat and loss of mitochondrial inner membrane structure despite only minimal changes in MLCL composition. Imaging of cells with elevated CLsat showed reduced fluidity of the inner membrane. Biophysical measurements and molecular dynamics analyses showed that di-saturated (C16:0 18:1)2 CL species order and rigidify membranes, while also losing the intrinsic lipid curvature characteristic of tetra-unsaturated CL. These results implicate CLsat as a potential driver of mitochondrial dysfunction and an additional therapeutic target in mitigating BTHS pathology.

DOI: https://doi.org/10.64898/2026.04.14.718012
Cell. 2026 Apr 28. pii: S0092-8674(26)00398-3. [Epub ahead of print]

Unbiased niche labeling maps immune-excluded niche in bone metastasis.

Zhan Xu, Fengshuo Liu, Yunfeng Ding, Tianhong Pan, Yi-Hsuan Wu, Yujiao Han, Jun Liu, Igor L Bado, Weijie Zhang, Ling Wu, Yang Gao, Xiaoxin Hao, Liqun Yu, Xuan Li, David G Edwards, Hilda L Chan, Sergio Aguirre, Michael Warren Dieffenbach, Elina Chen, Siyue Wang, Yichao Shen, Dane Hoffman, Luis Becerra Dominguez, Charlotte Helena Rivas, Xiang Chen, Hai Wang, Yibin Kang, Zbigniew Gugala, Robert L Satcher, Xiang H-F Zhang.

  Metastatic cancer cell fate is shaped by the local microenvironment niches. To unbiasedly define the cellular and molecular features of metastatic niches, we developed sortase A-based microenvironment niche tagging (SAMENT), which selectively labels cells encountered by cancer cells during metastasis. Applying SAMENT across multiple cancer models and target organs revealed shared niche features, including macrophage enrichment and T cell depletion, alongside marked organ-specific phenotype heterogeneity in niche macrophages. In bone, metastatic niches are enriched for macrophages expressing estrogen receptor alpha (ERα) with active ERα signaling. Conditional deletion of Esr1 in macrophages significantly impaired bone colonization by enabling T cell infiltration. ERα⁺ macrophages were also identified in human bone metastases across multiple cancer types. Together, these findings define a distinct ERα⁺ macrophage niche and establish macrophage ERα signaling as a key driver of T cell exclusion during metastatic colonization.

Keywords:  bone metastasis; estrogen receptor; estrogen signaling; fatty acid; immune exclusion; macrophage; metastatic niche; niche labeling; sortase A; tumor microenvironment

DOI:  https://doi.org/10.1016/j.cell.2026.04.009
Cancer Discov. 2026 Apr 28. OF1

Daraxonrasib Continues Victory Lap.

Results from two separate phase I/II studies investigating the pan-RAS inhibitor daraxonrasib suggest it is safe and effective for patients with pancreatic ductal adenocarcinoma, building on recently announced data showcasing the drug's superior performance in a phase III study. Together, these new data are an exciting sign that daraxonrasib could become the first targeted pancreatic cancer therapy to spur sustained responses.

DOI: https://doi.org/10.1158/2159-8290.CD-NW2026-0046
Res Sq. 2026 Apr 19. pii: rs.3.rs-9349300. [Epub ahead of print]

EMT and cell cycle control invadopodia and metastasis in breast cancer via Filip1L.

Bojana Gligorijevic, Elizaveta Belova, Afrooz Jarrah, Gleb Abalakov, Adam Karami.

Invadopodia are actin- and protease-rich membrane structures that enable cancer cells to degrade extracellular matrix (ECM). Invadopodia activity is cell cycle-dependent, but how their regulation across the cell cycle is influenced by epithelial-to-mesenchymal transition (EMT) remains unclear. We show that as the EMT progresses, cell engagement in invadopodia-mediated ECM degradation shits from G2 phase in Early E/M cells to G1 phase in Late E/M or M cells. Using bulk mRNA sequencing of Early- versus Late- E/M cells sorted by cell cycle phase, we identified FILIP1L as an EMT- and cell cycle-regulated candidate whose expression peaks in the invasive phase of each cell state: G2 in Early E/M cells and G1 in Late E/M cells. We next demonstrated that FILIP1L is a novel invadopodia component, whose loss increases ECM degradation while impairing migration and 3D invasion. In mouse models, FILIP1L KD tumors develop fewer metastatic colonies, suggesting that FILIP1L supports productive invasion by coordinating between invadopodia and migratory cell states. FILIP1L expression increases with EMT progression and correlates with poor outcomes in breast cancer patients. Together, these findings identify a previously unrecognized link between EMT, cell cycle and invadopodia and establish FILIP1L as the key regulator of this process.

DOI: https://doi.org/10.21203/rs.3.rs-9349300/v1
medRxiv. 2026 Apr 15. pii: 2026.04.13.26350790. [Epub ahead of print]

Characterization of a pancreatic cancer GWAS signal suggests PDX1 buffers stress in the exocrine pancreas.

Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium (PanScan/PanC4)

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest human cancers. The current largest published PDAC Genome-Wide Association Study (GWAS) identified 23 genetic risk signals, but most lack sufficient characterization. This study aimed to functionally characterize the chr13q12.2 ( PLUT / PDX1 ) PDAC GWAS risk locus. Fine-mapping, luciferase reporter assays, and electrophoretic mobility shift assays implicated rs9581943, a PDX1 promoter SNP, as a functional variant underlying this GWAS signal. GTEx expression QTL analyses identified rs9581943 as a significant PDX1 eQTL in pancreas, and CRISPR/Cas9 editing in PDAC-derived cell lines confirmed a functional relationship. PDX1 is a transcription factor involved in early pancreas development and β-cell homeostasis, but its role in exocrine pancreatic cells is unclear. Single-nucleus RNA-seq analyses of pancreatic acinar and ductal cells from neonatal, adult, and chronic pancreatitis donors suggested PDX1 activity alleviates high secretory load and ER-stress in acinar and biases ducts toward homeostatic phenotypes. Similarly, scRNA-seq analyses of pancreatic tumors suggested PDX1 activity reduces biosynthetic and inflammatory stress and promotes epithelial differentiation. Our study therefore implicates rs9581943 as a causal variant for the chr13q12.2 PDAC GWAS signal wherein the risk allele reduces PDX1 expression, eroding PDX1's capacity to buffer stress and stabilize epithelial cell fate in the exocrine compartment.

DOI: https://doi.org/10.64898/2026.04.13.26350790
Protein Sci. 2026 May;35(5): e70585

Quality control of protein import into mammalian mitochondria.

Madeleine Goldstein, Laurie Lee-Glover, Hilla Weidberg.

  Mitochondrial function depends on the continuous import of hundreds of nuclear-encoded proteins. Targeting and translocation of mitochondrial proteins is a multistep process that is inherently vulnerable to defects in cytosolic quality control systems as well as perturbations in mitochondrial protein import machinery and organelle function. Failure of mitochondrial protein import has dual consequences: it compromises mitochondrial biogenesis and activity, and it poses a cytosolic proteotoxic threat due to the accumulation of unimported precursor proteins. Accordingly, mitochondrial protein import defects are detrimental to cellular homeostasis and are associated with a wide range of disorders, including metabolic and neurodegenerative diseases. Cells therefore rely on layered quality control systems that monitor mitochondrial protein biogenesis and mitigate stress arising from mislocalized mitochondrial proteins. In this review, we summarize recent progress in understanding pathways that modulate mitochondrial protein import and the fate of unimported proteins in mammals. We highlight cytosolic and mitochondrial protein quality control mechanisms and discuss how import defects are translated into cellular stress responses and mitochondrial protective programs to restore cellular and mitochondrial homeostasis.

Keywords:  Proteostasis; mitochondrial dysfunction; mitochondrial protein import; quality control mechanisms; stress responses

DOI:  https://doi.org/10.1002/pro.70585
PNAS Nexus. 2026 Apr;5(4): pgag107

Discovery tools: How powerful new scientific methods and instruments emerge and catalyze innovation.

Alexander Krauss.

  Powerful new methods and tools drive scientific progress-but how do we actually make such innovations? No theory yet explains how we invent major tools across fields. To address this gap, we examine all nobel-prize-winning method discoveries-that enabled breakthrough findings not possible without them-and we trace science's most influential toolmakers across fields, from Ernst Ruska's electron microscope and Kary Mullis's PCR method to Ernest Lawrence's particle accelerator. Here, we lay out the critical pathways taken to create these groundbreaking tools. We introduce a taxonomy of science's methods and tools: a scientific table of discovery methods that is a map of underexplored and unexplored method opportunities. By mapping the method landscape, we reveal gaps and possibilities that help guide where methods can be adapted, recombined, or strategically developed to catalyze discovery. It can help identify and predict untapped combinations of tools-and where the next breakthroughs can come from. What if we no longer wait for new discovery tools to emerge by chance but begin deliberately prioritizing their development? How many big breakthroughs are we missing because we have not yet strategically focused on designing the needed tools? We also outline the need for establishing methods labs and hubs-as incubators of innovation-that catalyze tool creation.

Keywords:  method innovation; methods labs; scientific methods; scientific tools; tool-driven discovery

DOI:  https://doi.org/10.1093/pnasnexus/pgag107
Nature. 2026 Apr 29.

Evolutionary characterization of lung cancer metastasis.

TRACERx Consortium

Limited understanding of the biological processes that govern metastatic dissemination hinders its prevention and treatment1. Here, using 501 longitudinally collected primary and metastatic tumour samples from 24 patients with non-small cell lung cancer (NSCLC) enrolled in the TRACERx lung study and PEACE autopsy programme, we infer tumour evolution from diagnosis to death. With DNA-sequencing data encompassing 70% of the metastases that were radiologically detected before death and paired multi-region sampled primary tumours, we show that the genomes of metastases diverge markedly from those of their ancestral primary tumour, with additional driver alterations and genome doubling events occurring after metastatic dissemination. In 62.5% of patients, multiple primary tumour subclones disseminated, each founding a distinct metastasis. These metastases served as sources of onward spread: more than half of the metastases sampled were seeded by other metastases. The duration that metastases existed in situ influenced their likelihood of seeding further metastases. Most metastatic migrations started and ended in the same anatomical cavity. The few subclones that exited the thorax to seed metastases disseminated widely and were enriched for somatic copy-number alterations, suggesting that chromosomal instability may facilitate extrathoracic spread. This spatial and temporal evolutionary analysis sheds light on the extent of metastatic diversity and seeding in advanced NSCLC-which tends to be underestimated in single metastasis biopsies-and identifies genomic and clinical mediators of metastatic progression.

DOI: https://doi.org/10.1038/s41586-026-10428-4
Nature. 2026 Apr 29.

Safety and efficacy of intratumoural anti-CTLA4 with intravenous anti-PD1.

Lambros Tselikas, Sandrine Susini, Matthieu Texier, Andrey Yurchenko, Emilie Routier, Mona Amini-Adle, Edi Tihic, Séverine Mouraud, François-Xavier Danlos, Samy Ammari, Thibault Raoult, Séverine Roy, Delphine Bredel, Siham Farhane, Lydie Cassard, Irma Molinaro, Alexander Eggermont, Jean-Charles Soria, Laurence Zitvogel, Christophe Massard, Angelo Paci, Thierry de Baere, Jean-Yves Scoazec, Nathalie Chaput, Sergey Nikolaev, Nicolas Meyer, Céleste Lebbé, Stéphane Dalle, Caroline Robert, Aurélien Marabelle.

Intravenous administration of anti-CTLA4 with anti-PD1 provides durable tumour responses but causes severe treatment-related adverse events in patients with cancer1. Intratumoural administration at lower doses but high local concentrations could enhance antitumour efficacy while minimizing systemic exposure and toxicity. Here we report the randomized multicentre phase 1b NIVIPIT trial (ClinicalTrials.gov: NCT02857569 ), which enrolled 61 patients with untreated metastatic melanoma, randomly assigned 2:1 to receive intravenous nivolumab (anti-PD1; 1 mg kg-1) combined with either intratumoural ipilimumab (anti-CTLA4; 0.3 mg kg-1) or intravenous ipilimumab (3 mg kg-1). The primary end-point was met with significantly lower incidence of grade 3 or 4 treatment-related adverse events at 6 months in the intratumoural versus intravenous arm (22.6% versus 57.1%), equivalent to anti-PD1 monotherapy. RECIST (response evaluation criteria in solid tumours) best objective response rate reached 65.7% for anti-CTLA4 injected lesions and 50% for uninjected lesions, confirming the relationship between intratumoural exposure to anti-CTLA4 and efficacy. Baseline tumour immune profiling revealed that protumoural activated regulatory T (Treg) cells and M2 macrophages predict durable clinical benefit, regardless of the anti-CTLA4 administration route. A decrease in activated intratumoural Treg cells occurred only in patients who showed durable clinical benefit, who also presented high intratumoural Fcγ receptor (FcγR) expression. Our results provide a rationale for intratumoural anti-CTLA4 strategies in oligometastatic and early-stage cancers and indicate that high intratumoural activated Treg cell and FcγR+ M2 macrophage numbers are prerequisites for efficacy of combined anti-CTLA4 and anti-PD1.

DOI: https://doi.org/10.1038/s41586-026-10341-w
Nature. 2026 Apr 29.

GLP-1R-GIPR-PPARα/γ/δ quintuple agonism corrects obesity and diabetes in mice.

Daniela Liskiewicz, Aaron Novikoff, Ahmed Khalil, Seun Akindehin, Jonathan E Campbell, Pietra Candela, Russell L Castelino, Callum Coupland, Maxime Culot, W Scott Dodson, Jonathan D Douros, Hannes Embring, Annette Feuchtinger, Brian Finan, Cristina Garcia-Caceres, Xiao-Bing Gao, Fabien Gosselet, Gerald Grandl, Robert M Gutgesell, Daniel T Haas, Martin Jastroch, Ezgi Karaoglu, Pamela Kakimoto, Anna Cristina Kaltenbach, Michaela Keuper, Christine M Kusminski, Danielle C Leander, Arkadiusz Liskiewicz, Xue Liu, Gandhari Maity-Kumar, Sara Martinez Martinez, Stephanie A Mowery, Ruben Nogueiras, Marshall Paisley, Diego Perez-Tilve, Patricia S S Petersen, Paul T Pfluger, Sneha Prakash, Sabine Steffens, Alberto Cebrian-Serrano, Monica Tost, Jordan Wean, Christian Weber, Junichi Yoshida, Zachary Gerhart-Hines, Tamas L Horvath, Philipp E Scherer, Randy J Seeley, Richard D DiMarchi, Matthias H Tschöp, Natalie Krahmer, Patrick J Knerr, Timo D Müller.

There are increasing numbers of effective drugs to improve obesity-linked metabolic dysfunction; GLP-1R-GIPR co-agonism is effective in the management of obesity and type 2 diabetes1,2, and lanifibranor-a nuclear-acting small-molecule triple agonist of PPARα, PPARγ and PPARδ-is in clinical phase 3 trials for the treatment of metabolic dysfunction-associated steatohepatitis3. Here, seeking to further improve the metabolic efficacy of GLP-1R-GIPR co-agonism, we report the development of a unimolecular quintuple agonist that combines the body weight-reducing and blood glucose-lowering effects of GLP-1R-GIPR co-agonism with the insulin-sensitizing and anti-inflammatory effects of lanifibranor via its targeted delivery into GLP-1R- and GIPR-expressing cells. In vitro, GLP-1-GIP-lanifibranor is indistinguishable from GLP-1-GIP in relation to incretin receptor signalling and shows equal stimulation of insulin secretion in isolated mouse islets. In vivo, however, GLP-1-GIP-lanifibranor outperforms GLP-1R-GIPR co-agonism and semaglutide, further decreasing body weight, food intake and hyperglycaemia in obese and insulin-resistant mice through synergistic incretin and PPAR action. The metabolic action of GLP-1-GIP-lanifibranor is blunted in mice with genetic or pharmacological inhibition of GLP-1R, GIPR or PPARδ and is absent in DIO double incretin receptor-knockout mice, collectively suggesting that GLP-1-GIP-lanifibranor has substantial therapeutic value in the treatment of obesity and diabetes.

DOI: https://doi.org/10.1038/s41586-026-10427-5
bioRxiv. 2026 Apr 15. pii: 2026.04.13.718280. [Epub ahead of print]

Enforced ZFP281 expression delays breast cancer initiation and can provide lifelong protection against breast cancer metastasis.

Deepak K Singh, Hongwei Zhou, Nyima Sherpa, Xiang Yu Zheng, Artem Lomakin, Pedram Razghandi, Xin Hunag, Rama Kadamb, Suryansh Shukla, Luis E Valencia Salazar, David Entenberg, Deyou Zheng, Christina Curtis, Jianlong Wang, Julio A Aguirre-Ghiso.

Breast cancer metastatic reactivation and its links to mammary development are largely unknown. Here, using conditional knockout and overexpression in normal and HER2+ mammary glands, we show that the dormancy regulator ZFP281 promotes branching and dissemination while suppressing growth, and its overexpression can even override HER2-driven cancer initiation. Notably, while ZFP281 does not limit HER2-driven early dissemination, it constrains DCC plasticity, confining cells to a dormant mesenchymal/hybrid-like state and effectively suppressing metastasis throughout the mouse lifespan. ZFP281 is induced by estrogen, progesterone, and glucocorticoid signaling, and RNA sequencing of early lesions revealed that it regulates glutathione metabolism and ferroptosis, potentially supporting fitness during dormancy, while repressing angiogenesis, Th17-like inflammation, innate immune genes, and pro-inflammatory programs that might otherwise trigger awakening. Integrating these findings with human data, we show that DCIS and IBC (invasive breast cancer) lesions that later relapse are selectively enriched for ZFP281-regulated M-like and dormancy signatures and, after pregnancy, depleted for a ZFP281-induced stress-autophagy module, indicating that erosion or imbalance of these programs marks lesions that seed DCCs with higher reactivation potential. We propose that ZFP281 acts as a hormone-regulated dormancy gatekeeper that uncouples dissemination from growth, enforcing a metabolically fit, angiogenesis-low, immune-evasive dormant state in breast DCCs, thereby shaping the timing of metastatic relapse and potentially exploitable for durable prevention of metastasis.
STATEMENT OF SIGNIFICANCE: ZFP281, a hormone-regulated dormancy gatekeeper, uncouples dissemination from growth and constrains DCCs into long-term arrest, defining human gene signatures that distinguish dormancy-prone from awakening-prone lesions and predict breast cancer relapse dynamics.

DOI: https://doi.org/10.64898/2026.04.13.718280
Proc Natl Acad Sci U S A. 2026 May 05. 123(18): e2601788123

Fra-2 controls the response to the KRAS inhibitor MRTX-1133 in pancreatic ductal adenocarcinoma.

Erika Testa, Clara Dezi, Francesca Lovat, Geny Piro, Carmine Carbone, Marina Capece, Giovanni Nigita, Erisa Putro, Elisabetta Di Renzi, Alessandra Simeone, Luca Reggiani Bonetti, Roberto Cirombella, Paolo Magistri, Vincenzo Corbo, Davide Pasini, Barbara Belletti, Gustavo Baldassarre, Andrea Vecchione, Carlo M Croce, Gian Luca Rampioni Vinciguerra.

  KRAS mutations are a hallmark of pancreatic ductal adenocarcinoma (PDAC), driving tumor initiation and progression in the vast majority of cases, with KRASG12D being the most prevalent variant. Recent advances have led to the development of mutation-specific KRAS inhibitors (KRASi), yet their clinical impact is hindered by the rapid onset of drug resistance. In this study, we identify Fos-related antigen-2 (Fra-2), a stress-responsive transcription factor of the AP-1 family, as a key mediator of adaptive resistance to the KRASG12D selective inhibitor MRTX-1133. Using a combination of established PDAC cell lines, xenograft models, and patient-derived organoids, we demonstrate that Fra-2 expression is consistently upregulated following MRTX-1133 treatment. Functional assays reveal that Fra-2 overexpression promotes resistance by reprogramming the transcriptional landscape, directly enhancing mTOR expression and signaling. Consistently, FRA2 and MTOR levels strongly correlate in PDAC patient samples. Collectively, these findings uncover a mechanistic interplay between Fra-2 and the mTOR pathway in MRTX-1133-resistant PDAC, highlighting that targeting Fra-2 may represent a valuable approach to enhance the efficacy of KRASi.

Keywords:  Fra-2; KRAS inhibitors; MRTX-1133; mTOR pathway; pancreatic cancer

DOI:  https://doi.org/10.1073/pnas.2601788123
Cancer Cell. 2026 Apr 30. pii: S1535-6108(26)00175-3. [Epub ahead of print]

A conserved re-epithelialization program underlies malignancy in pancreatic ductal adenocarcinoma.

Meilian Zhuo, Yong Li, Yifeng Zhang, Chenlu Yang, Di Zou, Wenhao Xu, Jing Han, Saisai Wang, Haohao Deng, Xu Pan, Ruikang Dun, Ruizhe He, Yihong Shi, Xianlin Han, Taiping Zhang, Weibin Wang, Menghua Dai, Qiang Xu, Lulu Liu, Wenze Wang, Yuanhao Liu, Mingyang Liu, Ziqing Deng, Yupei Zhao, Wenming Wu, Junya Peng, Mo Chen, Charles J David.

  Pancreatic intraepithelial neoplasia (PanIN) is common in healthy individuals, but can progress to invasive pancreatic ductal adenocarcinoma (PDAC). PanIN cells spread non-invasively throughout pancreatic ducts, while PDAC is defined by the ability to exit ducts and invade the parenchyma. Using high-resolution spatial transcriptomics, we identify a conserved epithelial program, MP10 that marks invasive cancer cells across human PDAC and is activated during PanIN-to-PDAC progression in mice. MP10 resembles the re-epithelialization program of wound-edge keratinocytes, including hemidesmosome components, integrins, and metabolic genes required for keratinocyte migration. Rare PanIN cells spontaneously activate MP10 while also triggering tumor suppressor genes (TSGs), which keep the incipient malignant cells in check. TSG loss unleashes these cells to invade the parenchyma, driven by the wound-induced transcription factor FOSL1. MP10-expressing cancer cells induce nearby CAFs into a wound-like CTHRC1high state, which in turn promote neoplastic MP10 through EGFR activation, forming a wound-like loop that underlies invasive PDAC.

Keywords:  CTHRC1-expressing myCAF; FOSL1; PDAC; PanIN; malignancy; pancreatic cancer; re-epithelialization; spatial transcriptomics; stereo-seq

DOI:  https://doi.org/10.1016/j.ccell.2026.03.021
bioRxiv. 2026 Apr 17. pii: 2026.04.16.719038. [Epub ahead of print]

Lipids Regulate Export of Lysosomal Enzymes from the Endoplasmic Reticulum.

Baolong Xia, Myeonghoon Han, Isaac Park, Norbert Perrimon.

Lysosomal enzymes are synthesized in the Endoplasmic Reticulum (ER) and transported to lysosomes to execute their functions. Deficiencies in lysosomal enzymes or components of the lysosomal transport machinery result in lysosomal storage disorders. While mannose-6-phosphate mediated lysosomal enzymes sorting in the Golgi has been extensively characterized, the mechanisms governing their export from the ER remain elusive. Here, we show that de novo lipogenesis, a metabolic pathway responsible for fatty acid synthesis, regulates lysosomal enzyme transport. Inhibition of de novo lipogenesis leads to the retention of lysosomal enzymes within the ER. Mechanistically, fatty acid derived from de novo lipogenesis is used for Arf1 myristoylation. Myristoylated Arf1 promotes retrograde vesicle trafficking from the Golgi to the ER, thereby maintaining the homeostatic bidirectional flux required for efficient ER export of lysosomal enzymes. Our findings uncover a critical functional link between lipid metabolism and lysosomal enzyme trafficking.

DOI: https://doi.org/10.64898/2026.04.16.719038
J Nanobiotechnology. 2026 Apr 29.

Selective access to individual cells after assembling for advanced cell-cell interaction studies.

Faruk Shaik, Bahram Ahmadian, Aurélie Guillemette, Sofia Titah, Hua Cao, Bruno Quesnel, Dominique Collard, Loïc Lemonnier, Yasmine Touil, Mehmet Cagatay Tarhan.

  Understanding the mechanisms underlying cell-cell interactions necessitates a versatile method to assemble cells in a precisely-controlled, cell-specific environment, enabling analysis with high spatiotemporal resolution. Here, we introduce a microfluidic technique using stacked flows to create "virtual" channels under constant or pulsatile flow conditions, supporting various assembly geometries, e.g., doublets and triplets of cells with similar or different sizes, while maintaining independent access to each cell. We demonstrate the method using cell lines and primary human cells within the physiological context of immune cell interactions. Selective access to individual cell types is demonstrated with different molecules: fluorescent dyes for staining the nucleus and plasma membrane and to follow cell activity, antibodies for specific molecular targeting, and calcium ionophores to stimulate cellular activity. As shown by real-time observation of early immune-cell activation following immunological synapse formation between T lymphocytes and leukemic cells, this platform provides a powerful tool for analyzing cell-cell interactions and holds strong potential for fundamental research and clinical applications in precision medicine, drug testing, and disease monitoring.

Keywords:  Cell access; Cell assemblies; Cell-cell interactions; Laminar flows; Microfluidics

DOI:  https://doi.org/10.1186/s12951-026-04337-x
Anal Bioanal Chem. 2026 May 01.

Systematic assessment of different wash solvents for the analysis of small molecule metabolites using mass spectrometry imaging.

Barbara Matić, Lieby Zborovsky, Min Qiu, Katrin Jana Frank, Kıvanç Görgülü, Nicole Strittmatter.

  Wash protocols are a simple, commonly used approach to enhance the detectability of low-abundant or poorly ionisable compounds in mass spectrometry imaging (MSI). The washing procedures aim to enhance analyte ionisation by removing interfering metabolites that affect the ionisation efficiency and detection of the target metabolites. However, despite the widespread use of wash protocols in MSI, their impact on small molecule metabolites (SMM) has not been systematically evaluated. In this study, 12 different aqueous and organic wash solvents were investigated to assess their impact on the signal intensities of SMMs in tumour tissue using desorption electrospray ionisation mass spectrometry imaging (DESI-MSI). The added wash steps proved to be a promising tool for increasing detection sensitivity for targeted metabolites, with >90% of analytes investigated here showing increased sensitivity following the optimum wash solvent step. While chloroform was found most efficient in removing lipids overall, the most versatile solvent to significantly enhance the detection of polar and semi-polar metabolites, including amino acids, nucleic acid compounds, sugars, and organic acids, was found to be ethyl acetate. In contrast, water-based washes enhanced fatty acids and lipids while removing hydrophilic metabolites. This study emphasises the importance of adjusting pretreatment protocols to the molecular class of interest and provides a targeted guide for increasing ion detection sensitivity across a broad range of metabolites.

Keywords:  Ionisation efficiency; MS imaging; Sample preparation; Spatial metabolomics; Tumour; Wash protocols

DOI:  https://doi.org/10.1007/s00216-026-06534-x
Luminescence. 2026 May;41(5): e70497

A Sensitive Fluorescent Probe for Tracking Viscosity Changes in the Mitochondria Under Physiological and Pathological Conditions.

Zhongren Zhu, Hanwen Chi, Jingyin Li, Yinsheng Huang, Weiying Lin.

  Mitochondrial viscosity is a key microenvironmental parameter regulating its function, and its dysregulation is associated with various diseases. However, achieving specific and dynamic monitoring of mitochondrial viscosity remains challenging. To address this, we developed a novel near-infrared fluorescent probe, FTZ-BTZ, based on a twisted intramolecular charge transfer mechanism. The probe demonstrates high sensitivity (R2 = 0.9906), excellent selectivity, good stability, and low cytotoxicity in viscosity detection. Colocalization imaging confirmed its precise mitochondrial targeting capability, with a Pearson's coefficient of 0.9052. Using this probe, we successfully achieved real-time, in situ visualization of dynamic changes in mitochondrial viscosity within living cells. These changes were induced by various pharmacological stimuli, including lipopolysaccharide, dexamethasone, nystatin, and monensin. Specifically, we established the concentration-dependent response of mitochondrial viscosity to monensin. Further in vivo experiments showed that FTZ-BTZ can effectively distinguish viscosity gradients induced by different drug stimulations in mouse models. The FTZ-BTZ probe developed in this work provides a high-performance molecular tool for real-time investigation of mitochondrial viscosity-related physiological and pathological processes at the subcellular level.

Keywords:  cell imaging; fluorescent probe; mitochondrial; viscosity

DOI:  https://doi.org/10.1002/bio.70497