bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2025–07–06
33 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Phospholipase PAFAH2 Mediates Ferroptosis Surveillance and Lipid Remodeling to Promote Resistance in KEAP1 Mutant Cancers.
  2. Publisher Correction: Metabolic adaptations direct cell fate during tissue regeneration.
  3. Pancreatic cancer cells survive in the neural niche during neoadjuvant therapy.
  4. Signal peptide-independent secretion of keratin-19 by pancreatic cancer cells.
  5. PPAR-δ Orchestrates a Pro-metastatic Metabolic Response to Microenvironmental Cues in Pancreatic Cancer.
  6. The TWEAK/Fn14 signaling mediates skeletal muscle wasting during cancer cachexia.
  7. Self-organizing glycolytic waves tune cellular metabolic states and fuel cancer progression.
  8. Analysis of an engineered organoid model of pancreatic cancer identifies hypoxia as a contributing factor in determining transcriptional subtypes.
  9. Sense, plug and seal: Proteins as both rapid responders and constitutive barriers supporting organelle compartmentalization.
  10. A TFEB-TGFβ axis systemically regulates diapause, stem cell resilience and protects against a senescence-like state.
  11. Histidine decarboxylase inhibition attenuates cancer-associated muscle wasting.
  12. SPNS1 variants cause multi-organ disease and implicate lysophospholipid transport as critical for mTOR-regulated lipid homeostasis.
  13. Mapping and engineering RNA-driven architecture of the multiphase nucleolus.
  14. TP53 missense-specific transcriptional plasticity drives resistance against cell cycle inhibitors in pancreatic cancer.
  15. Chemotherapy awakens dormant cancer cells in lung by inducing neutrophil extracellular traps.
  16. Whole genome and transcriptome profiling in advanced pancreatic cancer patients on the COMPASS trial.
  17. Allosteric coupling between a lipid bilayer and a membrane protein.
  18. TRAF3IP2-AS1 Deficiency Induces Necroptosis to Promote Pancreatic Cancer Liver Metastasis.
  19. Self-amplifying NRF2-EZH2 epigenetic loop converts KRAS-initiated progenitors to invasive pancreatic cancer.
  20. Live-cell magnetic manipulation of recycling endosomes reveals their direct effect on actin protrusions to promote invasive migration.
  21. Progress on multifunctional transmembrane protein ATG9A.
  22. Imaging cancer metabolism using magnetic resonance.
  23. Lipid asymmetry and membrane trafficking: transbilayer distribution of structural phospholipids as regulators of exocytosis and endocytosis.
  24. Non-invasive characterization of melanoma depth at single-cell resolution.
  25. Genetic and oncogenic features of RASGRF fusions.
  26. Triglycerides are an important fuel reserve for synapse function in the brain.
  27. WSTF nuclear autophagy regulates chronic but not acute inflammation.
  28. Optogenetic engineering of lipid droplet spatial organization for tumor suppression.
  29. A primer on current status and future opportunities of clinical optoacoustic imaging.
  30. Applying physical principles to cancer research.
  31. Elevated KRAS protein level is associated with better survival in pancreatic cancer.
  32. Label-Free Multimodal Imaging Microscope for Damaged Cell Membrane Detection and Single-Cell Characterization.
  33. Clustered macrophages cooperate to eliminate tumors via coordinated intrudopodia.
  1. ACS Chem Biol. 2025 Jul 02.
    Phospholipase PAFAH2 Mediates Ferroptosis Surveillance and Lipid Remodeling to Promote Resistance in KEAP1 Mutant Cancers.
    Stephen B Ruiz, Daniel E Tylawsky, Janki Shah, Michelle Saoi, Brandon Cuevas, Shanay Desai, Boglarka Racz, Ana Marie Perea, Arianna R Izawa-Ishiguro, Justin Cross, Daniel A Heller.
      Although ferroptosis resistance is prevalent among many cancer cell types, precisely how ferroptosis surveillance mechanisms are induced remains elusive due to the heterogeneity of the cellular mutational status and metabolic states. Here, we find that phospholipase PAFAH2 regulates ferroptosis through its unique ability to specifically detoxify membrane-bound oxidized phospholipids in KEAP1 mutant and NRF2-active cancer cells. We show that the genetic or chemical perturbation of PAFAH2 is sufficient to sensitize KEAP1 mutant lung adenocarcinoma cells to ferroptosis. Lipidomic analyses reveal that PAFAH2 inhibition shifts the cellular lipidome to a distinctly ferroptosis state characterized by the enrichment of key phospholipids previously identified to be important in ferroptosis, like ether-linked phosphatidylethanolamines. Finally, we comparatively assessed the antitumor efficacy of PAFAH2 inhibitor monotherapy versus cotreatment with a nanoparticle-stabilized GPX4 inhibitor formulation. Our findings support that the broad applicability of PAFAH2 inhibition can be used in ferroptosis induction and abrogation of ferroptosis resistance across cancer types.
    DOI:  https://doi.org/10.1021/acschembio.5c00273
  2. Nature. 2025 Jul 01.
    Publisher Correction: Metabolic adaptations direct cell fate during tissue regeneration.
    Almudena Chaves-Perez, Scott E Millman, Sudha Janaki-Raman, Yu-Jui Ho, Clemens Hinterleitner, Valentin J A Barthet, John P Morris, Francisco M Barriga, Jose Reyes, Aye Kyaw, H Amalia Pasolli, Dana Pe'er, Craig B Thompson, Lydia W S Finley, Justin R Cross, Scott W Lowe.
      
    DOI:  https://doi.org/10.1038/s41586-025-09294-3
  3. Cancer Lett. 2025 Jun 26. pii: S0304-3835(25)00462-8. [Epub ahead of print]630 217894
    Pancreatic cancer cells survive in the neural niche during neoadjuvant therapy.
    Kaan Çifcibaşı, Ruediger Goess, Enkhtsetseg Munkhbaatar, Ilaria Pergolini, Carsten Jäger, Alexander Muckenhuber, Helmut Friess, Güralp Onur Ceyhan, Rouzanna Istvanffy, Ihsan Ekin Demir, Carmen Mota Reyes.
      
    Keywords:  Neoadjuvant therapy; Nerves; Neural invasion; Pancreatic cancer; Therapy resistance
    DOI:  https://doi.org/10.1016/j.canlet.2025.217894
  4. Proc Natl Acad Sci U S A. 2025 Jul 08. 122(27): e2426218122
    Signal peptide-independent secretion of keratin-19 by pancreatic cancer cells.
    Philip Moresco, Jonathan P Kastan, Jung-In Yang, Rishvanth Prabakar, Z Larkin Kelley, Francesca Minicozzi, Dexter W Adams, Paolo Cifani, David A Tuveson, Douglas T Fearon.
      The exclusion of T cells causes immune escape of pancreatic ductal adenocarcinoma (PDA). T cell exclusion is mediated by the interaction between CXCR4 on T cells and its ligand, CXCL12, which is complexed to keratin-19 (KRT19) on the surface of PDA cells. KRT19 secretion by PDA cells is essential to this process but is unusual because KRT19 lacks an endoplasmic reticulum (ER)-directing signal peptide (SP). By using biotinylation by an ER-restricted TurboID system and a split-GFP assay in PDA cells, we demonstrate that KRT19 enters the ER via its "head" domain. Additionally, KRT19 is shown to interact with the signal recognition particle and its secretion is sensitive to canonical protein secretion inhibitors. In vivo, mouse tumors formed with ER-TurboID-expressing PDA cells contain biotinylated KRT19. In contrast, keratin-8 (KRT8), which colocalizes with KRT19 on the surface of PDA cells, does not enter the ER. Rather, KRT8 is externalized via secretory autophagy possibly in a complex with KRT19. Thus, despite lacking a classical SP, PDA cells secrete KRT19 to capture CXCL12 and protect against immune attack.
    Keywords:  endoplasmic reticulum; pancreatic cancer; tumor immunology; unconventional protein secretion
    DOI:  https://doi.org/10.1073/pnas.2426218122
  5. Cancer Res. 2025 Jul 03.
    PPAR-δ Orchestrates a Pro-metastatic Metabolic Response to Microenvironmental Cues in Pancreatic Cancer.
    Beatriz Parejo-Alonso, David Barneda, Sara Maria David Trabulo, Sarah Courtois, Sara Compte-Sancerni, Jelena Zurkovic, Laura Ruiz-Cañas, Quan Zheng, Jiajia Tang, Matthias M Gaida, Ulf Schmitz, Pilar Irun, Laure Penin-Peyta, Shanthini Mary Crusz, Petra Jagušt, Pilar Espiau-Romera, Alba Royo-García, Andrés Gordo-Ortiz, Mariia Yuneva, Meng-Lay Lin, Shenghui Huang, Ming-Hsin Yang, Angel Lanas, Bruno Sainz, Christoph Thiele, Christopher Heeschen, Patricia Sancho.
      The pronounced desmoplastic response in pancreatic ductal adenocarcinoma (PDAC) contributes to the development of a microenvironment depleted of oxygen and nutrients. To survive in this hostile environment, PDAC cells employ various adaptive mechanisms that may represent therapeutic targets. Here, we showed that nutrient starvation and microenvironmental signals commonly present in PDAC tumors activate PPAR-δ to rewire cellular metabolism and promote invasive and metastatic properties both in vitro and in vivo. Mild mitochondrial inhibition induced by low-dose etomoxir or signals from tumor-associated macrophages altered the lipidome and triggered the downstream transcriptional program of PPAR-δ. Specifically, PPAR-δ reduced mitochondrial oxygen consumption and boosted the glycolytic capacity by altering the ratio of MYC and PGC1A expression, two key regulators of pancreatic cancer metabolism. Notably, genetic or pharmacological inhibition of PPAR-δ prevented this metabolic rewiring and suppressed both invasiveness in vitro and metastasis in vivo. These findings establish PPAR-δ as a central driver of metabolic reprogramming in response to starvation and tumor microenvironmental cues that promotes a pro-metastatic phenotype in PDAC, suggesting that PPAR-δ inhibition could serve as a therapeutic strategy to combat PDAC progression.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3475
  6. iScience. 2025 Jul 18. 28(7): 112714
    The TWEAK/Fn14 signaling mediates skeletal muscle wasting during cancer cachexia.
    Meiricris Tomaz da Silva, Anirban Roy, Anh Tuan Vuong, Aniket S Joshi, Cristeena Josphien, Meghana V Trivedi, Sajedah M Hindi, Vihang A Narkar, Ashok Kumar.
      Cancer cachexia is a multifactorial syndrome characterized by progressive skeletal muscle wasting. The TWEAK-Fn14 system regulates muscle mass in diverse conditions. However, its role in the regulation of muscle mass during cancer cachexia remains less understood. Here, we demonstrate that the levels of Fn14 are induced in skeletal muscle of multiple mouse models of cancer cachexia. Muscle-specific deletion of Fn14 reduces myofiber atrophy in mouse models of pancreatic and lung cancer cachexia. Silencing of Fn14 in KPC pancreatic cancer cells prior to their implantation in mice attenuates tumor growth without affecting myofiber size. Muscle-specific deletion of Fn14 reduces the gene expression of various components of the PERK and IRE1α arms of the unfolded protein response during KPC tumor growth. The inhibition of PERK improves protein synthesis and average myotube diameter in TWEAK-treated cultures. Altogether, our study suggests that the inhibition of TWEAK/Fn14 signaling can attenuate tumor growth and muscle wasting during cancer cachexia.
    Keywords:  Cancer; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2025.112714
  7. Nat Commun. 2025 Jul 01. 16(1): 5563
    Self-organizing glycolytic waves tune cellular metabolic states and fuel cancer progression.
    Huiwang Zhan, Dhiman Sankar Pal, Jane Borleis, Yu Deng, Yu Long, Chris Janetopoulos, Chuan-Hsiang Huang, Peter N Devreotes.
      Although glycolysis is traditionally considered a cytosolic reaction, here we show that glycolytic enzymes propagate as self-organized waves on the membrane/cortex of human cells. Altering these waves led to corresponding changes in glycolytic activity, ATP production, and dynamic cell behaviors, impacting energy-intensive processes such as macropinocytosis and protein synthesis. Mitochondria were absent from the waves, and inhibiting oxidative phosphorylation (OXPHOS) had minimal effect on ATP levels or cellular dynamics. Synthetic membrane recruitment of individual glycolytic enzymes increased cell motility and co-recruited additional enzymes, suggesting assembly of glycolytic multi-enzyme complexes in the waves. Remarkably, wave activity and glycolytic ATP levels increased in parallel across human mammary epithelial and other cancer cell lines with higher metastatic potential. Cells with stronger wave activity relied more on glycolysis than on OXPHOS for ATP. These results reveal a distinct subcellular compartment for enriched local glycolysis at the cell periphery and suggest a mechanism that coordinates energy production with cellular state, potentially explaining the Warburg effect.
    DOI:  https://doi.org/10.1038/s41467-025-60596-6
  8. Sci Rep. 2025 Jul 02. 15(1): 23610
    Analysis of an engineered organoid model of pancreatic cancer identifies hypoxia as a contributing factor in determining transcriptional subtypes.
    Natalie Landon-Brace, Simon Latour, Brendan T Innes, Michelle Nurse, Jose L Cadavid, Ileana L Co, Cassidy M Tan, Ferris Nowlan, Sibil Drissler, Faiyaz Notta, Hartland Warren Jackson, Gary D Bader, Alison P McGuigan.
      Pancreatic ductal adenocarcinoma (PDAC) is a high-mortality cancer characterized by its aggressive, treatment-resistant phenotype and a complex tumour microenvironment (TME) featuring significant hypoxia. Bulk transcriptomic analysis has identified the "classical" and "basal-like" transcriptional subtypes which have prognostic value; however, it is not well-established how microenvironmental heterogeneity contributes to these transcriptional signatures. Here, we exploited the TRACER platform to perform single cell transcriptome analysis of organoids at specific spatial locations to explore the effect of oxygen and other cell-generated microenvironmental gradients on organoid heterogeneity. We found that the microenvironmental gradients present in TRACER significantly impact the distribution of organoid transcriptional phenotypes and the enrichment of gene sets linked to cancer progression and treatment resistance. More significantly, we found that microenvironmental gradients, predominantly oxygen, drive changes in the expression of classical and basal-like transcriptional subtype gene signatures. This work suggests that hypoxia contributes to determining transcriptional subtypes in PDAC tumour cells independent of additional cells in the TME and broadly highlights the importance of considering microenvironmental gradients such as oxygen in organoid-based studies.
    DOI:  https://doi.org/10.1038/s41598-025-98344-x
  9. Mol Biol Cell. 2025 Jul 02. mbcE23080307
    Sense, plug and seal: Proteins as both rapid responders and constitutive barriers supporting organelle compartmentalization.
    Megan C King, C Patrick Lusk, Nicholas R Ader.
      While organellar compartmentalization is primarily established by the delimiting phospholipid bilayer membranes, the contribution of proteins has been less appreciated. Recently, studies across many realms of cell biology have put new focus on the role of proteins in acting as diffusion barriers in contexts where there are constitutive, regulated, or pathological discontinuities in membranes. Here, we synthesize longstanding observations of proteins acting as both barriers to lateral diffusion on membranes and diffusion in three-dimensional space. In particular, we focus on an emerging, conserved two-step paradigm of protein diffusion barriers that rapidly assemble in response to membranous organelle damage: a first phase of coincident sensing and stopgap "plugging" by responding repair proteins followed by a second phase of membrane sealing. We highlight recent work exemplifying this sense, plug, and seal paradigm at the post-mitotic nuclear envelope and at ruptures of the interphase nuclear envelope, lysosomes, and the plasma membrane. Taken together, we highlight how cells employ a variety of constitutive and induced proteinaceous barriers that support the role of biological membranes in defining organelle compartmentalization. Determining the biophysical nature of these barriers, and their means of "sensing" membrane rupture, will be an exciting avenue of future investigations.
    DOI:  https://doi.org/10.1091/mbc.E23-08-0307
  10. Nat Aging. 2025 Jun 30.
    A TFEB-TGFβ axis systemically regulates diapause, stem cell resilience and protects against a senescence-like state.
    Tim J Nonninger, Jennifer Mak, Birgit Gerisch, Valentina Ramponi, Kazuto Kawamura, Roberto Ripa, Klara Schilling, Christian Latza, Jonathan Kölschbach, Manuel Serrano, Adam Antebi.
      Diapause is a long-lived state of resilience that allows organisms to outlast adversity. Caenorhabditis elegans can endure months in a fasting-induced adult reproductive diapause (ARD) and, upon refeeding, regenerate and reproduce. Here we find that mutants of ARD master regulator hlh-30/TFEB arrest in a senescence-like state during ARD and refeeding, in which germline stem cells are characterized by DNA damage, nucleolar expansion, cell cycle arrest and mitochondrial dysfunction, alongside dysregulated immune and growth metabolic signatures, elevated senescence-associated β-galactosidase and premature aging at the organismal level. Forward genetic screens reveal a TFEB-TGFβ signaling axis that systemically controls diapause, stem cell longevity and senescence, aligning nutrient supply to proper metabolism and growth signaling. Notably, TFEB's vital role is conserved in mouse embryonic and human cancer diapause. Thus, ARD offers a powerful model to study stem cell longevity and senescence in vivo, directly relevant to mammals.
    DOI:  https://doi.org/10.1038/s43587-025-00911-4
  11. J Exp Med. 2025 Sep 01. pii: e20242239. [Epub ahead of print]222(9):
    Histidine decarboxylase inhibition attenuates cancer-associated muscle wasting.
    Aneesha Dasgupta, Rebecca E Schmitt, Tatsuyoshi Kono, Chih-Chun Lee, Mark I Zoberi, Savannah A Epstein, Jessica Z Schneider, Alejandro Hernandez, Paul M Grandgenett, Thomas C Caffrey, Dominick J DiMaio, Michael A Hollingsworth, Jason D Doles.
      Cancer cachexia is a multifactorial syndrome involving muscle and fat wasting, inflammation, and metabolic dysfunction. Across cancer subtypes, pancreatic cancer has one of the highest cachexia incidence rates at ∼80%. Given the advanced age of most pancreatic cancer patients, we sought to query cancer-associated muscle wasting using an age-matched murine model. We found that histamine and histamine decarboxylase (HDC) activity were specifically elevated in the muscles of aged tumor-bearing mice. We further found that (1) wasting stimuli induced histamine production and enhanced HDC activity; (2) exogenous histamine was sufficient to induce atrophy-associated gene expression; (3) inhibition of HDC activity by α-fluoromethylhistidine (FMH) protected against atrophy; (4) treatment of tumor-bearing mice with FMH rescued muscle wasting; and (5) a calcineurin inhibitor was able to rescue histamine-associated increases in calcium/atrogene signaling. In summary, we present a novel metabolic pathway that has significant implications for the treatment of cachectic cancer patients.
    DOI:  https://doi.org/10.1084/jem.20242239
  12. J Clin Invest. 2025 Jul 03. pii: e193099. [Epub ahead of print]
    SPNS1 variants cause multi-organ disease and implicate lysophospholipid transport as critical for mTOR-regulated lipid homeostasis.
    Menglan He, Mei Ding, Michaela Chocholouskova, Cheen Fei Chin, Martin Engvall, Helena Malmgren, Matias Wagner, Marlen C Lauffer, Jacob Heisinger, May Christine V Malicdan, Valérie Allamand, Madeleine Durbeej, Angelica M Delgado-Vega, Thomas Sejersen, Ann Nordgren, Federico Torta, David L Silver.
      SPNS1 is a lysosomal transporter mediating the salvage of lysoglycerophospholipids, the degradative products of lysosomal phospholipid catabolism. However, a role of lysolipid transport and salvage in regulating cellular lipid homeostasis and in disease is lacking. Here, we identified two families with biallelic SPNS1 loss-of-function variants that presented primarily with progressive liver and striated muscle injury. Patient fibroblasts accumulated lysophospholipids including lysoplasmalogens and cholesterol in lysosomes with reduced cellular plasmalogens. Notably, SPNS1 deficiency resulted in reduced biogenesis of cytosolic lipid droplets containing triglycerides and cholesteryl esters. Mechanistically, we found that lysophospholipids transported by SPNS1 into the cytosol quantitatively contributed to triglyceride synthesis while lysosomal buildup of lyso-ether-phospholipid inhibited lysosomal cholesterol egress, effects that were enhanced with inhibition of mTOR. These findings support a gene-disease association and reveal connectivity between lysosomal transport of lysophospholipids and storage of reserve cellular energy as triglyceride and in the regulation of cholesterol homeostasis, processes that become important under nutrient limitation.
    Keywords:  Cell biology; Cholesterol; Lipidomics; Lysosomes; Metabolism
    DOI:  https://doi.org/10.1172/JCI193099
  13. Nature. 2025 Jul 02.
    Mapping and engineering RNA-driven architecture of the multiphase nucleolus.
    Sofia A Quinodoz, Lifei Jiang, Aya A Abu-Alfa, Troy J Comi, Hongbo Zhao, Qiwei Yu, Lennard W Wiesner, Jordy F Botello, Anita Donlic, Elizabeth Soehalim, Prashant Bhat, Christiane Zorbas, Ludivine Wacheul, Andrej Košmrlj, Denis L J Lafontaine, Sebastian Klinge, Clifford P Brangwynne.
      Biomolecular condensates are key features of intracellular compartmentalization1,2. As the most prominent nuclear condensate in eukaryotes, the nucleolus is a multiphase liquid-like structure in which ribosomal RNAs (rRNAs) are transcribed and processed, undergoing multiple maturation steps to form the small (SSU) and large (LSU) ribosomal subunits3-5. However, how rRNA processing is coupled to the layered organization of the nucleolus is poorly understood owing to a lack of tools to precisely monitor and perturb nucleolar rRNA processing dynamics. Here we developed two complementary approaches to spatiotemporally map rRNA processing and engineer de novo nucleoli. Using sequencing in parallel with imaging, we found that rRNA processing steps are spatially segregated, with sequential maturation of rRNA required for its outward movement through nucleolar phases. By generating synthetic nucleoli in cells using an engineered rDNA plasmid system, we show that defects in SSU processing can alter the ordering of nucleolar phases, resulting in inside-out nucleoli and preventing rRNA outflux, while LSU precursors are necessary to build the outermost layer of the nucleolus. These findings demonstrate how rRNA is both a scaffold and substrate for the nucleolus, with rRNA acting as a programmable blueprint for the multiphase architecture that facilitates assembly of an essential molecular machine.
    DOI:  https://doi.org/10.1038/s41586-025-09207-4
  14. Sci Adv. 2025 Jul 04. 11(27): eadu2339
    TP53 missense-specific transcriptional plasticity drives resistance against cell cycle inhibitors in pancreatic cancer.
    Laura Urbach, Lena Wieland, Frederike Penz, Rebecca Diya Samuel, Stefan Küffer, Lukas Klein, Christof Lenz, Ulrich Sax, Michael Ghadimi, Ramona Schulz-Heddergott, Elisabeth Hessmann, Volker Ellenrieder, Nelson Dusetti, Shiv K Singh.
      In ~70% of patients with pancreatic ductal adenocarcinoma, the TP53 gene acquires gain-of-function (GOF) mutations leading to rapid disease progression. Specifically, missense p53 (misp53) GOF mutations associate with therapy resistance and worse clinical outcomes. However, the molecular functions of distinct misp53 mutants in plasticity and therapy response remain unclear. Integrating multicenter patient data and multi-omics, we report that the misp53R273H/C mutant is associated with cell cycle progression and a basal-like state compared to the misp53R248W/Q mutant. Loss of misp53R273H/C decreased tumor growth and liver metastasis while prolonging survival in preclinical models. We found that misp53R273H/C specifically regulated the Rb/DREAM axis involved in cell cycle regulation. Notably, a clinical CDK4/6 inhibitor reduced misp53R273H/C mutant expression. However, it triggered MAPK/ERK-mediated resistance mechanisms, enhancing cell survival and resistance to CDK4/6 inhibitors. Combining MAPK/ERK and CDK4/6 inhibitors reduced misp53R273H/C-associated oncogenic functions. Thus, distinct misp53 mutants show unique cell-intrinsic plasticity, therapeutic vulnerabilities, and resistance mechanisms.
    DOI:  https://doi.org/10.1126/sciadv.adu2339
  15. Cancer Cell. 2025 Jun 24. pii: S1535-6108(25)00257-0. [Epub ahead of print]
    Chemotherapy awakens dormant cancer cells in lung by inducing neutrophil extracellular traps.
    Dasa He, Qiuyao Wu, Pu Tian, Yin Liu, Zhenchang Jia, Zhenwei Li, Yuan Wang, Yuchen Jin, Wenqian Luo, Ling Li, Peiyuan Zhang, Qianlu Jin, Wenjing Zhao, Weiguo Hu, Yajun Liang, Bin Zhou, Qifeng Yang, Yi-Zhou Jiang, Zhi-Ming Shao, Guohong Hu.
      Disseminated tumor cells (DTCs) can remain in a non-proliferative, dormant state for years in distant organs, but the exogenous causes triggering their reactivation and metastatic colonization are unclear. Here, we demonstrate that chemotherapeutic drugs, including doxorubicin and cisplatin, enhance proliferation and lung metastasis of dormant breast cancer cells. Using a recombinase-based dormancy tracing system, DormTracer, we confirm chemotherapy-induced reactivation of dormant DTCs leading to metastatic relapse. Mechanistically, chemotherapy induces fibroblast senescence, which promotes formation of neutrophil extracellular traps (NETs) through secreted proteins. NETs promote dormant DTC proliferation through extracellular matrix remodeling. Importantly, combining senolytic drugs, dasatinib and quercetin, with doxorubicin inhibits post-therapy DTC reactivation and suppresses metastatic relapse. This study provides direct evidence of dormancy awakening and reveals a mechanism underlying detrimental effect of chemotherapy on metastasis, highlighting potential strategies to improve cancer treatment.
    Keywords:  chemotherapy; dormancy awakening; metastatic dormancy; neutrophil extracellular trap
    DOI:  https://doi.org/10.1016/j.ccell.2025.06.007
  16. Nat Commun. 2025 Jul 01. 16(1): 5919
    Whole genome and transcriptome profiling in advanced pancreatic cancer patients on the COMPASS trial.
    Jennifer J Knox, Gun Ho Jang, Robert C Grant, Amy Zhang, Lucy Ma, Elena Elimova, Raymond Jang, Malcolm Moore, James Biagi, Mustapha Tehfe, Ravi Ramjeesingh, Erica S Tsang, Spring Holter, Stephanie Ramotar, Shawn Hutchinson, Sheng-Ben Liang, Ilinca M Lungu, Shari Moura, Yifan Wang, Sheron Perera, Michelle Chan-Seng-Yue, Maryam Monajemzadeh, Kyaw Aung, Rebecca Prince, Joan Miguel Romero, Jesus Fuentes-Antras, Galileo A Gonzalez Conchas, Sarah Picardo, Ricardo Gonzalez, Sangeet Ghai, Korosh Khalili, Tae Kyoung Kim, Karen Ng, John Bartlett, Trevor J Pugh, Sangeetha N Kalimuthu, Sandra E Fischer, Julie M Wilson, Anna Dodd, George Zogopoulos, Barbara T Grünwald, Faiyaz Notta, Steven Gallinger, Grainne M O'Kane.
      Integrated whole genome and transcriptome sequencing can unveil distinct molecular subgroups in pancreatic cancer (PDAC). The COMPASS trial (NCT02750657) enrolled 268 patients with advanced PDAC; patients were given either modified (m) FOLFIRINOX or Gemcitabine-nab-paclitaxel (GnP) as per physicians choice. Median follow-up is 52 months and median overall survival in those receiving mFOLFIRINOX is 10.6 months and 8.4 months for GnP. KRAS specific mutants and allelic states alone are not prognostic; however basal-like PDAC are more likely to harbour major imbalances in mutant KRAS (KRASmaj). In the presence of KRASmaj, pre-existing type II DM is more common. Distinct prognostic cohorts include homologous-recombination deficient PDAC, predictive of mFOLFIRINOX response. Basal-like PDAC and patients exhibiting evidence of systemic inflammation as annotated using the Gustave Roussy Immune Score are unique poor prognostic cohorts. The latter associates with low CD8 T cell infiltration while basal-like PDAC documents an inflamed tumour microenvironment.
    DOI:  https://doi.org/10.1038/s41467-025-60808-z
  17. Biophys J. 2025 Jun 27. pii: S0006-3495(25)00410-2. [Epub ahead of print]
    Allosteric coupling between a lipid bilayer and a membrane protein.
    Clarisse Fourel, Yanna Gautier, Alexandre Pozza, François Giraud, Elodie Point, Christel Le Bon, Karine Moncoq, Guillaume Stirnemann, Jérôme Hénin, Ewen Lescop, Laurent J Catoire.
      Biological membranes are complex environments whose functions are closely tied to the dynamic interactions between lipids and proteins. Here, we utilize high-pressure NMR of lipid nanodiscs paired with molecular dynamics simulations to elucidate at the atomic scale the allosteric dialog between the lipid bilayer and a model membrane protein, OmpX. We discover that OmpX delays the gelation process by liquefying the annular shell of lipids through hydrophobic and roughness matching processes at the protein surface. Furthermore, modification of the mechanical properties of the lipid bilayer directly impacts the energy landscape of amino acid side chains at the lipid/protein interface but also unexpectedly at the protein core. Our work highlights a thermodynamically coupled but kinetically uncoupled allosteric pathway linking lipid dynamics with the interior of membrane proteins, directly impacting our understanding of membrane function.
    DOI:  https://doi.org/10.1016/j.bpj.2025.06.033
  18. Cancer Res. 2025 Jun 30.
    TRAF3IP2-AS1 Deficiency Induces Necroptosis to Promote Pancreatic Cancer Liver Metastasis.
    Yong-Ding Wu, Xiao-Xiao Huang, Hao-Xiang Zhang, Yu Pan, Cheng-Ke Xie, Ge Li, Cai-Feng Lin, Xin-Quan Lin, Zhi-Yuan Li, Yin-Hao Chen, Jian-Fei Hu, Hong-Yi Lin, Shun-Cang Zhu, Zu-Wei Wang, Yi-Feng Tian, Qiao-Wei Li, Cheng-Yu Liao, Shi Chen.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies. PDAC is characterized by prominent necrotic foci within the tumor and a high propensity for distant liver metastasis, leading to poor prognosis. Here, using patient-derived organoid models, single-cell RNA sequencing and multiplex immunofluorescence staining of PDAC patient samples, in vivo TGFβ1 conditional knockout mouse models, and 3D in vitro models, we discovered that the formation of intratumoral necrotic foci in pancreatic cancer is closely associated with liver metastatic events. This process was triggered by deficiency of the lncRNA TRAF3IP2-AS1 that induced necroptosis, which was accompanied by an immunosuppressive microenvironment. Mechanistically, TRAF3IP2-AS1 blocked necroptosis by reducing the mRNA stability of MLKL through competitively binding to IGF2BP2. Loss of TRAF3IP2-AS1 also promoted necroptosis by promoting RIPK3 phosphorylation via interference with the ubiquitination of the phosphatase PPM1B that dephosphorylates RIPK3. Additionally, TRAF3IP2-AS1 deficiency promoted the release of TGFβ1 from tumor cells, which induced an M2-like immunosuppressive phenotype and the release of more TGFβ1. The elevated production of TGFβ1 created a feedback loop that promoted the transcription of TRAF3IP2-AS1 in tumor cells to balance necroptosis. Overall, these findings identify TRAF3IP2-AS1 as a key regulator of necroptosis and the formation of an immunosuppressive microenvironment in PDAC, providing potential therapeutic targets for treating liver metastasis in patients with pancreatic cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-4784
  19. Nat Cancer. 2025 Jun 30.
    Self-amplifying NRF2-EZH2 epigenetic loop converts KRAS-initiated progenitors to invasive pancreatic cancer.
    Laura Antonucci, Na Li, Angeles Duran, Isidoro Cobo, Chiara Nicoletti, Kosuke Watari, Shuvro Prokash Nandi, Feng Zhu, Yongmei Zhao, Irene Riahi, Motoyuki Tsuda, Vidhi M Shah, Terry Morgan, Trent Waugh, Luca Caputo, Yuan Liu, Alexandra Rundberg Nilsson, Hongxu Xian, Jelena Todoric, Li Gu, Elsa Sanchez-Lopez, Guido Eibl, Emily A Vucic, Michal Krawczyk, Qianlan Xu, Andrew M Lowy, Georgia Hatzivassiliou, Merone Roose-Girma, Dorota Skowronska-Krawczyk, David A Scott, Dafna Bar-Sagi, Pablo Tamayo, Ying Wu, Rosalie C Sears, Christopher K Glass, Ludmil B Alexandrov, Pier Lorenzo Puri, David W Dawson, Yinling Hu, Maria T Diaz-Meco, Jorge Moscat, Michael Karin.
      Pancreatic ductal adenocarcinoma (PDAC) emerges from mutant KRAS-harboring but dormant low-grade pancreatic intraepithelial neoplasia (PanIN). To examine the role of oxidative stress, a putative PDAC risk factor, we established an organoid-based transformation system. Although the prototypic oxidant H2O2 induced organoid transformation, its effect was nonmutational and was mediated by the oxidant-responsive transcription factor NRF2, which induced the histone methyltransferase EZH2. Congruently, nonoxidizing NRF2 activators triggered organoid malignant conversion through NRF2 and EZH2, establishing a hitherto unknown epigenetic mechanism underlying PanIN-to-PDAC progression. While NRF2 induced EZH2 gene transcription in mouse and human PDAC, EZH2, a general repressor, coactivated transcription of NRF2-encoding NFE2L2 and interacted with other transcription factors to induce genes that sustain PDAC metabolic demands. The self-amplifying NRF2-EZH2 epigenetic loop also accounted for inflammation-driven PanIN-to-PDAC progression in vivo and was upregulated in established human PDAC, whose malignancy was maintained by NRF2 binding to the EZH2 promoter.
    DOI:  https://doi.org/10.1038/s43018-025-01003-3
  20. Sci Adv. 2025 Jul 04. 11(27): eadu6361
    Live-cell magnetic manipulation of recycling endosomes reveals their direct effect on actin protrusions to promote invasive migration.
    Jakub Gemperle, Domenik Liße, Marie Kappen, Emilie Secret, Mathieu Coppey, Martin Gregor, Christine Menager, Jacob Piehler, Patrick Caswell.
      Endocytic recycling pathways play key roles in a broad range of cellular processes, and many vesicle trafficking regulators are implicated in progression of disease such as cancer. The Rab11 family (Rab11a, Rab11b, and Rab25) controls the return of internalized cargos to the plasma membrane, and Rab25 has been implicated in the aggressiveness of cancer by promoting invasive migration. However, while Rab25 vesicles distribute to the leading edge of moving cells, how directly they contribute to cell protrusion is not clear. Here, we adopt a magnetogenetic approach that allows direct manipulation of Rab25 positioning to show that localization to the cell periphery drives the formation of F-actin protrusions. We demonstrate that endogenous Rab25 vesicles coordinate the positioning of key cargos, including the actin regulator FMNL1 and integrin β1, with the activation of Rho guanosine triphosphatases at the plasma membrane to generate and maintain F-actin-rich filopodium-like protrusions and promote cancer cell invasive migration in the three-dimensional matrix.
    DOI:  https://doi.org/10.1126/sciadv.adu6361
  21. Cell Commun Signal. 2025 Jul 01. 23(1): 314
    Progress on multifunctional transmembrane protein ATG9A.
    Xi Lin, Lin Liang, Shan Liao, Yanling Li, Yanhong Zhou.
      ATG9A is the only transmembrane protein among the components required for autophagosome formation and participates in multiple cellular biological processes. ATG9A undergoes intracellular transport via microtubules and actin. As a lipid scramblase, ATG9A facilitates the random movement of lipid molecules between the inner and outer leaflets of lipid bilayers. Additionally, it can influence the homeostasis of the plasma membrane and membranous organelles. In autophagy, ATG9A is recruited to autophagic initiation sites to initiate cellular autophagy and subsequently participates in the process by promoting lipid transfer. Moreover, ATG9A also plays roles in maintaining neuronal homeostasis and is involved in embryonic development, infection, and immune responses. In this review, we comprehensively and systematically summarize the roles and mechanisms of ATG9A, aiming to provide a new perspective for understanding its functions.
    Keywords:  ATG9A; Autophagosome formation; Autophagy; Disease progression; Regulatory factors
    DOI:  https://doi.org/10.1186/s12964-025-02317-6
  22. Npj imaging... 2024 Jan 11. 2(1): 1
    Imaging cancer metabolism using magnetic resonance.
    Kevin M Brindle.
      The challenge in clinical oncology is to select the most appropriate treatment for an individual patient. Transcriptome and metabolite profiling have revealed that tumours can display metabolic subtypes with different therapeutic vulnerabilities1-4. Metabolic imaging has the potential to distinguish these subtypes and therefore those treatment(s) that should be most effective. Moreover, since changes in tumour metabolism can occur early during treatment, metabolic imaging can also be used subsequently to detect early evidence of treatment response. In this Perspective I briefly review and discuss the relative advantages and disadvantages of magnetic resonance imaging of tumour metabolism using hyperpolarized 13C- and 2H-labelled substrates.
    DOI:  https://doi.org/10.1038/s44303-023-00004-0
  23. J Biol Chem. 2025 Jul 01. pii: S0021-9258(25)02291-4. [Epub ahead of print] 110441
    Lipid asymmetry and membrane trafficking: transbilayer distribution of structural phospholipids as regulators of exocytosis and endocytosis.
    Margherita Caputo, Olga Gubar, Petra Tóth, Nicolas Vitale, Stéphane Gasman, Stéphane Ory.
      The plasma membrane of eukaryotic cells is highly dynamic and asymmetrically organized. Its continuous remodeling plays a crucial role in diverse cellular processes, including apoptosis, blood coagulation, and vesicular trafficking. The distribution and rearrangement of phospholipids (PLs) within the bilayer are tightly regulated, influencing membrane curvature, tension, and organization. This review examines the role of PL asymmetry in vesicle fusion, the final step of exocytosis, and in vesicular membrane retrieval by compensatory endocytosis in neurosecretory cells, with a particular emphasis on structural PLs such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS). We discuss the molecular mechanisms that maintain and disrupt PLs asymmetry and explore how lipid rearrangements affect vesicle dynamics. Additionally, we highlight recent findings on lipid scramblases, particularly phospholipid scramblase-1 (PLSCR1), and their role in regulated exocytosis and compensatory endocytosis.
    Keywords:  PLSCR1; cholesterol; endocytosis; exocytosis; flippase; floppase; membrane asymmetry; phospholipids; scramblase
    DOI:  https://doi.org/10.1016/j.jbc.2025.110441
  24. J Eur Acad Dermatol Venereol. 2025 Jul 03.
    Non-invasive characterization of melanoma depth at single-cell resolution.
    Juan Aguirre, Christine Gasteiger, Benedikt Hindelang, Markus Seeger, Andrei Bereznhoi, Ina Weidenfeld, Ulf Darsow, Andre C Stiel, Susanne Annette Steimle-Grauer, Christian Posch, Tilo Biedermann, Vasilis Ntziachristos.
       BACKGROUND: Efficient staging and management of cutaneous melanoma, one of today's deadliest skin cancers, requires non-invasive determination of tumour depth (Breslow depth). However, current imaging technologies lack the necessary contrast or penetration to measure Breslow depth.
    OBJECTIVES: To determine if raster-scanning optoacoustic mesoscopy (RSOM) can fill this gap in dermatology.
    METHODS: We used phantoms to optimize RSOM for melanoma imaging and demonstrated its capability to image melanocytes at single-cell resolution in deep tissue. We then compared RSOM's ability to measure Breslow depth against the clinical standard in a pilot study. For the phantoms studies, we compared the ability of an optimized RSOM system to measure the concentration and diameter of single melanoma cells against gold-standard microscopy methods. For the pilot clinical study, we used linear regression to compare RSOM's Breslow depth against the clinical standard, obtaining the goodness of fit (R2) and the p-value. For the pilot clinical study, we imaged nine lesions: 7 superficially spreading melanomas, 1 benign dysplastic nevus and 1 blue nevus. The average age of the patients was 56.2 ± 12.5 years. We also imaged 10 non-lesional skin areas from healthy volunteers.
    RESULTS: By utilizing ultra-wideband frequency detection and optimized illumination wavelength, we show that RSOM achieves non-invasive imaging of melanoma at the resolution of single melanocytes, penetrating more than 3 mm into the skin. The agreement between RSOM and the standard-of-care histological assessment was R2 = 0.886 (p = 0.0002) for Breslow depth determination.
    CONCLUSIONS: RSOM provides non-invasive imaging performance that correlates with the Breslow depth determination. Further work is needed to confirm these findings and to test RSOM against other non-invasive methods.
    Keywords:  cells; imaging; melanoma; melanoma classification
    DOI:  https://doi.org/10.1111/jdv.20811
  25. NPJ Precis Oncol. 2025 Jul 05. 9(1): 224
    Genetic and oncogenic features of RASGRF fusions.
    Sreya Das, Daniel S Lenchner, Ellen Jaeger, Lisa Hunihan, Dana F DeSantis, Stamatina Fragkogianni, Karyn Ronski, Frederick H Wilson.
      The identification of recurrent oncogenic drivers has enabled targeted therapeutic strategies for subsets of non-small cell lung carcinoma (NSCLC) and other malignancies. Oncogenic fusions involving the RAS-activating guanine exchange factor (GEF) RASGRF1 are reported in multiple tumors, but their prevalence and genetic heterogeneity remain undefined. Here, we query RNA-seq data from a real-world database of diverse human malignancies and identify 40 tumors with rearrangements involving RASGRF1 or the related RASGRF2 predicted to generate chimeric proteins. Half of these fusions occur in NSCLC, pancreatic cancer, and melanoma and are enriched in tumors without other established driver alterations. A subset of RASGRF fusions contains transmembrane partners, and membrane localization enhances RAS activation and transforming activity. Loss of N-terminal PH1 and DH domains in RASGRF fusions also promotes transformation. Although some fusions lack the PH1 but not the DH domain, our functional assays indicate that loss of the PH1 domain alone is insufficient to drive cellular transformation. Our findings provide insights about the tissue distribution, structural diversity, and oncogenic mechanisms of RASGRF fusions. As cell models driven by these fusions are sensitive to MAPK pathway inhibition, oncogenic RASGRF fusions may represent a therapeutic target in rare molecular subsets of cancer.
    DOI:  https://doi.org/10.1038/s41698-025-01017-1
  26. Nat Metab. 2025 Jul 01.
    Triglycerides are an important fuel reserve for synapse function in the brain.
    Mukesh Kumar, Yumei Wu, Justin Knapp, Catherine L Pontius, Daehun Park, Rose E Witte, Rachel McAllister, Kallol Gupta, Kartik N Rajagopalan, Pietro De Camilli, Timothy A Ryan.
      Proper fuelling of the brain is critical to sustain cognitive function, but the role of fatty acid (FA) combustion in this process has been elusive. Here we show that acute block of a neuron-specific triglyceride lipase, DDHD2 (a genetic driver of complex hereditary spastic paraplegia), or of the mitochondrial lipid transporter CPT1 leads to rapid onset of torpor in adult male mice. These data indicate that in vivo neurons are probably constantly fluxing FAs derived from lipid droplets (LDs) through β-oxidation to support neuronal bioenergetics. We show that in dissociated neurons, electrical silencing or blocking of DDHD2 leads to accumulation of neuronal LDs, including at nerve terminals, and that FAs derived from axonal LDs enter mitochondria in an activity-dependent fashion to drive local mitochondrial ATP production. These data demonstrate that nerve terminals can make use of LDs during electrical activity to provide metabolic support and probably have a critical role in supporting neuron function in vivo.
    DOI:  https://doi.org/10.1038/s42255-025-01321-x
  27. Nature. 2025 Jul 02.
    WSTF nuclear autophagy regulates chronic but not acute inflammation.
    Yu Wang, Vinay V Eapen, Yaosi Liang, Athanasios Kournoutis, Marc Samuel Sherman, Yanxin Xu, Angelique Onorati, Xianting Li, Xiaoting Zhou, Kathleen E Corey, Kuo Du, Ana Maria Cabral Burkard, Chia-Kang Ho, Jing Xie, Hui Zhang, Raquel Maeso-Díaz, Xinyi Ma, Ulrike Rieprecht, Tara O'Brien, Murat Cetinbas, Lu Wang, Jihe Liu, Corey Bretz, Aaron P Havas, Zhuo Zhou, Shannan J Ho Sui, Srinivas Vinod Saladi, Ruslan I Sadreyev, Peter D Adams, Robert E Kingston, Anna Mae Diehl, Benjamin Alman, Wolfram Goessling, Zhenyu Yue, Xiao-Fan Wang, Terje Johansen, Zhixun Dou.
      Acute inflammation is an essential response that our bodies use to combat infections1. However, in the absence of infections, chronic inflammation can have a pivotal role in the onset and progression of chronic diseases, such as arthritis, cancer, autoimmune disorders, metabolic-dysfunction-associated steatohepatitis (MASH), and most ageing-associated pathologies2,3. The underlying mechanisms that distinguish chronic inflammation from its acute counterpart remain unclear, posing challenges to the development of targeted therapies for these major diseases. Here we identify a mechanism that separates the two responses: during chronic but not acute inflammation, chromatin remodelling is influenced by nuclear autophagy, in which the WSTF protein of the ISWI chromatin-remodelling complex interacts with the ATG8 autophagy protein family in the nucleus. This interaction leads to WSTF nuclear export and subsequent degradation by autophagosomes and lysosomes in the cytoplasm. Loss of WSTF leads to chromatin opening over inflammatory genes, amplifying inflammation. Cell-penetrating peptides that block the WSTF-ATG8 interaction do not affect acute inflammation but suppress chronic inflammation in senescence as well as in MASH and osteoarthritis in mouse models and patient samples. The ability to specifically target chronic inflammation without blunting acute inflammation offers an approach for treating common chronic inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41586-025-09234-1
  28. Trends Biotechnol. 2025 Jul 01. pii: S0167-7799(25)00217-3. [Epub ahead of print]
    Optogenetic engineering of lipid droplet spatial organization for tumor suppression.
    Qingjie Bai, Xintian Shao, Qinghua Xia, Shuo Yang, Yanan Gao, Kai Sun, Jian Li, Xiuxiu Wang, Zhiqi Tian, Xiaoyuan Chen, Jing Zhao, Jiajie Diao, Qixin Chen.
      In cancer cells, lipid droplets (LDs) establish extensive membrane contact sites (MCSs) with mitochondria to facilitate fatty acid transfer and sustain energy production, thus enabling cancer cell survival, in nutrient-deprived tumor microenvironments. However, effective strategies to disrupt these LD-mitochondria interactions remain unavailable. We engineered an optogenetic system to control LD intracellular organization through clustering. Upon blue light stimulation, the system induces LDs to undergo spatial reorganization and form clusters, thereby restricting LD accessibility by reducing the available surface area for mitochondrial interaction. Consequently, this clustering significantly diminishes the number of LD-mitochondria MCSs, suppresses fatty acid transport from LDs to mitochondria during starvation, and ultimately leads to cancer cell death in vitro and tumor growth inhibition in vivo. Collectively, our results demonstrate that optogenetically controlled LD clustering offers a novel approach to impede tumor progression by blocking nutrient flow from LDs to mitochondria.
    Keywords:  cancer therapy; lipid droplets; membrane contact sites; optogenetics; organelles
    DOI:  https://doi.org/10.1016/j.tibtech.2025.06.002
  29. Npj imaging... 2025 Jan 27. 3(1): 4
    A primer on current status and future opportunities of clinical optoacoustic imaging.
    Ferdinand Knieling, Serene Lee, Vasilis Ntziachristos.
      Despite its introduction in the 1970's, it is only recent technology advances that have propelled growth in clinical optoacoustic (photoacoustic) imaging over the past decade. We analytically present the broad landscape of clinical optoacoustic applications in the context of these key technology advances, the unique contrast achieved, and the tissue biomarkers resolved. We then discuss current challenges and future opportunities to address the unmet clinical needs.
    DOI:  https://doi.org/10.1038/s44303-024-00065-9
  30. APL Bioeng. 2025 Jun;9(2): 020402
    Applying physical principles to cancer research.
    Claudia Fischbach, Corey S O'Hern, Adam J Engler.
      
    DOI:  https://doi.org/10.1063/5.0282296
  31. BMC Cancer. 2025 Jul 01. 25(1): 1080
    Elevated KRAS protein level is associated with better survival in pancreatic cancer.
    S M Stålberg, L Silwal-Pandit, J Hamfjord, D J H Nebdal, J Lehtiö, O C Lingjærde, B S Skålhegg, E H Kure.
       BACKGROUND: Activating somatic KRAS mutations in hotspot loci occur almost universally (> 95%) in pancreatic ductal adenocarcinoma (PDAC). Both the presence of a KRAS mutation and high mRNA expression levels of KRAS in tumor tissue have been associated with worse outcome. Less is known about the expression of KRAS at the protein level and its association with clinical and molecular parameters. In the present study, we investigated the prognostic significance of the KRAS protein level and its relation to KRAS mutation status and the mRNA expression level.
    METHODS: A total of 41 PDAC tumors were screened for seven KRAS mutations (p.G12D, p.G12V, p.G12R, p.G12C, p.G12S, p.G13D, p.G12A) by the Wobble-enhanced ARMS method. Whole transcriptome and proteome profiles were obtained using mRNA microarrays (Agilent) and quantitative mass spectrometry-based proteomics (HiRIEF LC-MS/MS), respectively. The clinical outcome was overall survival (OS).
    RESULTS: KRAS mutations were identified in 88% of the tumors with p.G12D and p.G12V mutations being the most frequent. Tumors with p.G12V mutation had significantly higher KRAS mRNA expression than tumors with p.G12D, p.G12C, p.G12R or no mutation identified (P < 0.01). KRAS protein levels did not associate significantly to neither KRAS mRNA levels (Spearman's rho = 0.18, P = 0.28) nor type of KRAS mutation. High KRAS protein level and mutation p.G12V were found to be significantly associated with better (P < 0.01) and worse OS (P < 0.05), respectively.
    CONCLUSIONS: The KRAS protein level correlated poorly with KRAS mRNA expression level and was not significantly associated with the type of mutation present. Interestingly, we found that patients with high KRAS protein level in their tumors had a better clinical outcome.
    Keywords:   KRAS mRNA expression; KRAS mutation; KRAS protein level; PDAC; Pancreatic cancer
    DOI:  https://doi.org/10.1186/s12885-025-14461-w
  32. ACS Sens. 2025 Jul 03.
    Label-Free Multimodal Imaging Microscope for Damaged Cell Membrane Detection and Single-Cell Characterization.
    Huijun Wang, Lu Zhang, Chen Fan, Jie Huang, Yuxiang Huang, Weihao Zhao, Lifang Tian, Hong Zhao, Cuiping Yao.
      Multimodal characterization of single cells offers unprecedented resolution and depth for research in fundamental biology, pathology, and drug development. However, limited by labeling techniques or complex systems, developing a simple, label-free multimodal detection system remains challenging. In this work, a label-free multimodal imaging microscope (MMIM) is proposed for single-cell characterization. The MMIM system simultaneously performs forward scattering, degree of circular polarization, and phase measurements to quantify the volume and to image intracellular refractive index distribution and morphology. Four features, from external morphology (volume, roughness average (Ra), and root-mean-square) to intracellular substance (refractive index), are extracted for characterization. Moreover, the potential high classification accuracy of multimodal characterization is verified by a decision tree model. The MMIM system detected that surface roughness of damaged human kidney-2 (HK-2) cells induced by lipid peroxidation was 39.7% higher than normal HK-2 cells. Scanning electron microscopy images of the control group confirmed that MMIM can directly detect cell membrane damage, without the need for fluorescent staining or complex systems. Multimodal features improved accuracy by 21.5 and 22.4% for classifying different cancer cell types and normal versus damaged HK-2 cells compared to single features. Overall, the MMIM system provides a simple method of multimodal characterization and cell membrane damage detection for single cells, demonstrating great potential in biomedical research.
    Keywords:  damaged cell membrane detection; imaging microscope; label-free; multimodal; single-cell characterization
    DOI:  https://doi.org/10.1021/acssensors.5c00968
  33. Proc Natl Acad Sci U S A. 2025 Jul 08. 122(27): e2425452122
    Clustered macrophages cooperate to eliminate tumors via coordinated intrudopodia.
    Lawrence J Dooling, Alişya A Anlaş, Michael P Tobin, Nicholas M Ontko, Tristan Marchena, Maximilian Wang, Jason C Andrechak, Dennis E Discher.
      Macrophages often pervade solid tumors, and clusters of macrophages sometimes associate with longer survival of patients. However, clustering mechanisms and impacts on key functions such as phagocytosis remain obscure. Here, under conditions that maximize cancer cell phagocytosis within cohesive tumors, we uncover pathways that favor dynamic clusters and find a colocalization of tumor-intrusive pseudopodia which we term "intrudopodia." Cluster formation over hours on low-adhesion substrates occurs after macrophage induction to a state colloquially referred to as M1 after exposure to interferons and T cell-derived cytokines. Clusters prove fluid on timescales of minutes and also sort from interleukin-4-treated, so-called M2 macrophages that tend to disperse. M1 macrophages upregulate specific cell-cell adhesion receptors but suppress actomyosin contractility, with both pathways contributing to cluster formation. Decreased cortical tension was not only reflected in a low level of nuclear lamin-A that downregulates cytoskeletal targets of serum response factor and tends to soften the nucleus but was also predicted to unleash pseudopodia. Macrophage neighbors in tumor spheroids indeed coextend intrudopodia between cancer cell junctions-at least when phagocytosis conditions are maximized. Intrudopodia from neighbors help detach and individualize cancer cells for rapid engulfment. Juxtaposition of a macrophage cluster with tumor cell nests defines a broad interface that minimizes cancer cell nearest neighbor interactions and maximizes coordination of macrophage intrudopodia. Cooperative phagocytosis thus overcomes solid tumor cohesion-and might explain why the macrophage clustering factor ITGAL associates with patient survival.
    Keywords:  cell–cell adhesion; macrophage; phagocytosis
    DOI:  https://doi.org/10.1073/pnas.2425452122
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