bims-cagime 2025-10-26 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2025–10–26
25 papers selected by
Kıvanç Görgülü, Technical University of Munich

A plastic EMP1⁺ to LGR5⁺ cell state conversion as a bypass to KRAS-G12D pharmacological inhibition in metastatic colorectal cancer.
p53 drives lung cancer regression through a TSC2/TFEB-dependent senescence program.
A paradoxical role of autophagy: promoting protein aggregates and hindering rejuvenation in a Caenorhabditis elegans L1 arrest model.
Metamorphoses in pancreatic cancer precursors: the role of simple mucinous cysts†.
PTEN Oxidation Promotes Constitutive PI3K Signaling and Inducible Macropinocytosis in Pancreatic Cancer.
Organellar pH as an emerging vulnerability to exploit in cancer.
ATG9 assists lipid replenishment for lysosome membrane repair.
Functional pseudo-synapses: A new nexus in extracranial cancer.
Mutant and Wild-type RAS Crosstalk and Stoichiometric Deficiencies are Determinants of Sensitivity to Targeted Therapies in KRASG12R Pancreatic Ductal Adenocarcinoma.
P21-positive senescent stromal cells promote prostate cancer immune suppression and progression that can be reversed by senolytic therapy.
Mechanistic Insights into How Juxtamembrane Residue Modulation Leads To LAMP2A Inactivation in Chaperone-Mediated Autophagy.
Sex impacts inflammatory signaling, body composition, and physical function in tumor-bearing mice receiving chemotherapy.
Intracellular Peptide N-Myristoylation for Cancer Cell Ferroptosis without Acquired Resistance.
Identifying Key Questions and Challenges in Microchimerism Biology.
Microphysiological systems for metastasis research: a stepwise approach.
A Structurally Robust Phospholipid Microtube Constructed by Membrane Phase Separation as a Scaffold for On-Tube Characterization of Membrane-Bound Proteins.
Unsaturated fat alters clock phosphorylation to align rhythms to the season in mice.
Physics-based evolution of transmembrane helices reveals mechanisms of cholesterol attraction.
TfR in focus: Orchestrating autophagosome biogenesis.
Incorporating nivolumab with preceded gemcitabine and S-1 chemotherapy for patients of metastatic pancreatic cancer: a pilot study.
Navigating the landscape of protein folding and proteostasis: from molecular chaperones to therapeutic innovations.
A multimodal cross-species comparison of pancreas development.
The genetically encoded biosensor FEOX is a molecular gauge for cellular iron environment dynamics at single cell resolution.
YAP/TEAD inhibitor VT3989 in solid tumors: a phase 1/2 trial.
Live, spatially-resolved imaging of absolute intracellular water content using holotomography.

Cancer Discov. 2025 Oct 21.

A plastic EMP1⁺ to LGR5⁺ cell state conversion as a bypass to KRAS-G12D pharmacological inhibition in metastatic colorectal cancer.

Alessia Centonze, Adrià-Jaume Roura, Meritxell Novillo-Font, Cristina Giordano, Xavier Hernando-Momblona, Montserrat Llanses, Paula Prats, Marta Sevillano, Débora Cabot, Mireia Novell, Gabriel Pabst, Florian Andersch, Adrià Cañellas-Socias, Chong Zhang, Nikolaos-Nikiforos Giakoumakis, Hugh Sparks, Chris Dunsby, Julien Colombelli, Asunción Fernández-Barral, Elena Sancho, Camille Stephan-Otto Attolini, Alberto Muñoz, Antonio Barbachano, Héctor G Palmer, Jordi Martínez-Quintanilla, Johannes Zuber, Cristina Blaj, Elsa Quintana, Carme Cortina, Marc A Marti-Renom, Eduard Batlle.

Inhibitors of the oncogene KRAS hold promise for treating metastatic CRC (mCRC). Here we show that a selective, covalent small molecule inhibitor of the active (ON) conformation of RAS-G12D, RMC-9945, exerts durable disease control in preclinical CRC models of early liver metastasis, but its therapeutic activity was diminished in the advanced metastatic disease. RMC-9945-treated metastases underwent a transition from a poor-prognosis-associated Emp1⁺ transcriptional state to a WNT-driven Lgr5⁺ stem cell-like state that withstands the absence of RAS-G12D activity. This cell state change occurred within hours of RAS(ON) inhibitor treatment through a shift in transcription factor usage that involved limited chromatin remodeling. Forced conversion of metastatic cells to the Lgr5⁺ state through RAS-G12D inhibition, followed by genetic ablation of this population, reduced metastatic burden and prolonged survival in a mouse mCRC model. Overall, these preclinical findings demonstrate a central role for oncogenic KRAS in governing cellular plasticity in mCRC.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0679
Cancer Discov. 2025 Oct 21.

p53 drives lung cancer regression through a TSC2/TFEB-dependent senescence program.

Mengxiong Wang, Kathryn T Bieging-Rolett, Alyssa M Kaiser, Colleen A Brady, John H Lockhart, Sofia Ferreira, Kha T Nguyen, Arati Rajeevan, Simone A Evans, Tianyu Zhao, Nitin Raj, Arielle Elkrief, Sam E Tischfield, Marc Ladanyi, Michael G Ozawa, Nam Q Bui, Christopher T Chen, Elsa R Flores, Laura D Attardi.

Pharmacological restoration of p53 tumor suppressor function is a conceptually appealing therapeutic strategy for the many deadly cancers with compromised p53 activity, including lung adenocarcinoma (LUAD). However, the p53 pathway has remained undruggable, partly because of insufficient understanding of how to drive effective therapeutic responses without toxicity. Here, we use mouse and human models to deconstruct the transcriptional programs and sequelae underlying robust therapeutic responses in LUAD. We show that p53 drives potent tumor regression by direct Tsc2 transactivation, leading to mTORC1 inhibition and TFEB nuclear accumulation, which in turn triggers lysosomal gene expression programs, autophagy, and cellular senescence. Senescent LUAD cells secrete factors to recruit macrophages, precipitating cancer cell phagocytosis and tumor regression. Collectively, our analyses reveal a surprisingly complex cascade of events underlying a p53 therapeutic response in LUAD and illuminate targetable nodes for p53 combination therapies, thus establishing a critical framework for optimizing p53-based therapeutics.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0525
Autophagy. 2025 Nov;21(11): 2311-2312

A paradoxical role of autophagy: promoting protein aggregates and hindering rejuvenation in a Caenorhabditis elegans L1 arrest model.

Yuxiang Huang, Daniel J Klionsky.

  Macroautophagy (hereafter referred to as autophagy) is widely recognized as a central pathway for the clearance of protein aggregates and the maintenance of proteostasis. However, a recent study by Murley et al. challenges this conventional view. Using a Caenorhabditis elegans L1 arrest aging model, the authors found that autophagy activation impedes rejuvenation by promoting the accumulation of intra- 10 lysosomal protein aggregates and inducing lysosomal membrane damage. This unexpected finding reveals that autophagy may play dual, context-dependent roles in proteostasis, acting not only as a protective mechanism but also, under certain conditions, as a contributor to cellular stress.

Keywords:  Aging; autophagy; protein aggregates; proteostasis; rejuvenation; stress

DOI:  https://doi.org/10.1080/15548627.2025.2541430
J Pathol. 2025 Oct 22.

Metamorphoses in pancreatic cancer precursors: the role of simple mucinous cysts†.

Paolo Riccardo Camisa, Daniele Campa, Irene Esposito, Stefano Crippa.

  Pancreatic cystic lesions present a unique opportunity to identify and potentially prevent pancreatic ductal adenocarcinoma (PDAC), one of the deadliest solid tumors. Until now, research has primarily focused on intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs), whose potential for malignant transformation is well established. In recent years, however, a new pathological entity has emerged: the simple mucinous cyst (SMC). SMCs are distinct from other cystic lesions, as they lack both communication with the pancreatic ductal system (a hallmark of IPMNs), and the ovarian-like stroma, characteristic of MCNs. The recent work by Pea et al, published in The Journal of Pathology, suggests that these lesions can progress to PDAC, underscoring the need for further characterization. In this commentary, we review the key findings of this study and discuss the potential next steps required to translate these discoveries into actionable clinical practice. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords:  IPMN; MCN; PanIN; cancer; mucinous cystic neoplasm; pancreas; pancreatic cancer; precursor; simple mucinous cysts

DOI:  https://doi.org/10.1002/path.6493
Cancer Res. 2025 Oct 24. OF1-OF14

PTEN Oxidation Promotes Constitutive PI3K Signaling and Inducible Macropinocytosis in Pancreatic Cancer.

Rachel A Burge, Lucas Bialousow, Amanda J Linke, Hannah S Coalson, Sara J Adair, Kamala Sundararaj, Merissa Smith, Cameron Bumbleburg, Todd W Bauer, David F Kashatus, G Aaron Hobbs.

Pancreatic ductal adenocarcinoma (PDAC) is defined by the near universal occurrence of KRAS mutations. The KRASG12R mutation is detected in approximately 15% to 20% of patients with PDAC and rare in other KRAS-mutant cancers. KRASG12R is unable to activate the lipid kinase PIK3CA, suggesting that alternative mechanisms might be employed to activate KRASG12R-independent PI3K signaling in PDAC. In this study, we detected elevated expression of all four PI3K isoforms in PDAC cell lines, with the PIK3CG isoform showing higher overall expression in KRASG12R-mutant PDAC. All four PI3K isoforms contributed to global PI3K signaling, and inhibition of any single isoform was insufficient to limit PDAC proliferation. The combined inhibition of all PI3K isoforms was required to limit proliferation, providing a potential explanation for the limited efficacy of PI3K inhibitors in the clinic. Additionally, PTEN, a negative regulator of PI3K signaling, was inactivated in PDAC by the formation of an intramolecular disulfide, which elevated overall PI3K signaling and reduced the dependency of PI3K signaling on KRAS. Oxidation of PTEN was independent of KRAS mutation status. Finally, nutrient-limiting conditions mimicking the PDAC tumor microenvironment further elevated PTEN oxidation and significantly increased macropinocytosis. Thus, this study uncovered a mechanism that supports elevated PI3K signaling in PDAC, thereby reducing the need for KRAS to directly activate the PI3K pathway.
SIGNIFICANCE: PTEN inactivation by intramolecular disulfide bond formation and elevated expression of PI3K isoforms in pancreatic cancer leads to unchecked KRAS-independent PI3K signaling, highlighting the need for therapeutic approaches targeting constitutive PI3K signaling.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4501
Trends Cancer. 2025 Oct 23. pii: S2405-8033(25)00234-1. [Epub ahead of print]

Organellar pH as an emerging vulnerability to exploit in cancer.

Cheska Marie Galapate, Cosimo Commisso.

  Cancer cells undergo metabolic reprogramming to sustain their energy demands, and favor glycolysis despite the presence of functional mitochondria. This metabolic shift leads to the rapid production of lactate and protons. If not managed, this accumulation of acidic byproducts would lower the intracellular pH (pHi). To counteract this, cancer cells employ diverse mechanisms to extrude excess protons through membrane transporters, and also sequester them within acidic organelles. Consequently, an alkaline pHi provides cancer cells with a survival advantage by promoting their proliferation, migration, and resistance to cell death. Given the role of organellar acidification in sustaining this altered pH balance, targeting this process represents a potential therapeutic vulnerability in cancer. We explore the mechanisms by which cancer cells maintain pH homeostasis, with a particular focus on organellar pH and its impact on tumor progression. In addition, we assess inhibitors of the key transporters involved in organellar acidification and discuss their therapeutic potential in cancer.

Keywords:  cancer metabolism; organelle acidification; pH homeostasis

DOI:  https://doi.org/10.1016/j.trecan.2025.09.006
Dev Cell. 2025 Oct 20. pii: S1534-5807(25)00570-2. [Epub ahead of print]60(20): 2701-2702

ATG9 assists lipid replenishment for lysosome membrane repair.

Hemmo Meyer, Bojana Kravic.

Lysosomal membranes can be permeabilized under various conditions with detrimental consequences for the cell. In this issue, de Tito et al. report that the lipid scramblase ATG9, best known for its role in autophagosome formation, helps distribute lipids from the ER to reseal the limiting membrane and restore lysosomal function.

DOI: https://doi.org/10.1016/j.devcel.2025.09.010
Cancer Cell. 2025 Oct 23. pii: S1535-6108(25)00407-6. [Epub ahead of print]

Functional pseudo-synapses: A new nexus in extracranial cancer.

Xiaofei Zhi, Puran Zhang, Timothy C Wang.

Functional cancer-to-neuron synapse-like connections are recognized as essential structures and hallmarks of both intracranial and extracranial tumors. In this issue of Cancer Cell, Ren et al. present high-resolution EM structures of pseudo-synaptic connections between sensory nerves and pancreatic ductal adenocarcinoma (PDAC).

DOI: https://doi.org/10.1016/j.ccell.2025.10.001
Cancer Res. 2025 Oct 24.

Mutant and Wild-type RAS Crosstalk and Stoichiometric Deficiencies are Determinants of Sensitivity to Targeted Therapies in KRASG12R Pancreatic Ductal Adenocarcinoma.

Mandana Kamgar, G Aaron Hobbs, Raven Davidson, Daniel Dorbin, Juliannie Herrera, John F Langenheim, Rachel A Burge, Mohammed Aldakkak, Ryan D Conrardy, Aniko Szabo, Sam Z Thalji, Bradley Mayer, Justin J Grahl, Brian Y Chung, Alexandria Phan, James P Thomas, Y David Seo, Douglas B Evans, Kathleen K Christians, Beth Erickson, William Hall, Ben George, Susan Tsai, Nikki K Lytle, Channing J Der, Razelle Kurzrock, Thomas McFall.

Therapies targeting the RAF-MEK-ERK pathway are generally considered to have limited efficacy in KRAS mutant cancers. However, specific KRAS mutants exhibit distinct behaviors. Notably, KRASG12R pancreatic ductal adenocarcinoma (PDAC) tumors have shown sensitivity to MEK inhibitors (MEKi) in combination with autophagy inhibitors, but a better understanding of the underlying mechanisms is needed to optimize this treatment strategy. Using a systems-level approach, we uncovered a mechanistic explanation for this phenomenon. Due to distinct biophysical properties, KRASG12R had an impaired ability to activate wild-type HRAS and NRAS (WT-RAS) compared to other KRAS mutants, such as KRASG12D. This reduced activation stemmed from the weaker interaction between KRASG12R and guanine exchange factors (SOS), as well as the tumor suppressor neurofibromin (NF1), crucial in regulating WT-RAS activity. The impaired ability to activate WT-RAS led to weaker holistic MAPK signaling in KRASG12R driven tumors, which conferred increased sensitivity to MEKi. To substantiate the preclinical findings, the utility of MEKi in combination with the autophagy inhibitor hydroxychloroquine was analyzed in patients with KRASG12R mutated metastatic PDAC. Five of the eight patients (62.5%) treated in first- or second-line settings had a progression-free survival exceeding six months. Three patients had impressive disease control: two had stable disease of 11 and 22.7 months, and one achieved a partial response with an 83% decrease in tumor size that lasted for 8.9 months. Overall, this work highlights how systems-based approaches in precision medicine can uncover mechanistic insights to guide the identification of PDAC patients most likely to benefit from tailored therapeutic strategies.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0018
Cancer Discov. 2025 Oct 27.

P21-positive senescent stromal cells promote prostate cancer immune suppression and progression that can be reversed by senolytic therapy.

Lin Zhou, Kelly D DeMarco, Katherine C Murphy, Zhenpeng Wu, Jinping Li, Calvin Johnson, Bin Liu, Hadiya K Giwa, Boyang Ma, Nikita Bhalerao, Junhui Li, Zhong Jiang, Shi Bai, Chaitanya N Parikh, Tianyi Ye, Karl Simin, Lihua J Zhu, Jason R Pitarresi, Hong Wu, Marcus Ruscetti.

Cellular senescence is a well-established tumor-suppressive cell cycle arrest program. However, chronic inflammation through the senescence-associated secretory phenotype (SASP) can alternatively drive immune suppression and cancer progression. Using prostate cancer patient samples and murine models, we find p16+ and p21+ senescent cells accumulate throughout malignant progression and associate with immune suppression. Single cell sequencing revealed p16 and p21 mark distinct epithelial and stromal senescent populations, with p21+ non-tumor cells expressing the highest SASP. p21+ stromal cell removal blocked the SASP to reverse immune suppression and slow tumor growth. Senolytic BCL-xL inhibitor treatment could clear p21+ stromal senescent cells, reactivating anti-tumor CD8+ T cell immunity and inhibiting prostate tumor progression in mice. Suppression of BCL-xL or p21 also potentiated anti-PD-1 ICB in preclinical prostate cancer models. Our findings demonstrate that targeting p21+ senescent stromal populations can yield therapeutic benefits in advanced prostate cancer through activating anti-tumor immunity and enhancing immunotherapy outcomes.

DOI: https://doi.org/10.1158/2159-8290.CD-25-1212
J Phys Chem B. 2025 Oct 19.

Mechanistic Insights into How Juxtamembrane Residue Modulation Leads To LAMP2A Inactivation in Chaperone-Mediated Autophagy.

Ishwar Patel, Nidhi Malhotra.

The lysosome-associated membrane protein type 2A (LAMP2A) is a critical mediator of chaperone-mediated autophagy (CMA), a selective degradation pathway essential for cellular homeostasis. The trimeric assembly of LAMP2A serves as an intermediate in forming higher-order oligomers that are responsible for substrate translocation and degradation. However, the molecular determinants of the trimeric stability remain poorly understood. We performed 30 μs of all-atom molecular dynamics simulations in a realistic lysosomal membrane environment to investigate how different protonation states of juxtamembrane histidine residues influence the structural dynamics of wild-type (WT) LAMP2A and compare these with an experimentally characterized inactive mutant, in which four charged residues were replaced by alanines. Comparative analyses reveal that in the WT protein, this region is stabilized through charged lipid nanoclusters and contributes to maintaining proper tilt angles and membrane anchoring of the monomeric and trimeric assemblies, while the mutant buries these residues within the lipid bilayer due to hydrophobic mismatch, leading to altered tilting, reduced dynamicity, disrupted oligomeric stability, altered lipid distribution, and membrane properties. We identified key interacting residues stabilizing the WT oligomeric state and demonstrated how their loss compromises trimeric assembly in the mutant. Our results offer mechanistic insights into how the disruption of juxtamembrane residues impairs CMA activity, with potential implications for CMA regulation.

DOI: https://doi.org/10.1021/acs.jpcb.5c06192
Am J Physiol Cell Physiol. 2025 Oct 24.

Sex impacts inflammatory signaling, body composition, and physical function in tumor-bearing mice receiving chemotherapy.

Jessica L Halle, Quan Zhang, Dryden R Baumfalk, Melissa J Puppa, Junaith S Mohamed, Evan S Glazer, Ashley J Smuder, Stephen E Alway, James A Carson.

  Cancer-induced inflammation has been widely investigated as a driver of cachexia, and sex can affect the inflammatory response to cancer. We have an incomplete understanding of how anti-cancer treatments and sex impact the relationship between inflammatory responses and changes to body composition and physical function during cancer treatment. We investigated the effect of FOLFOX chemotherapy (5-fluorouracil, leucovorin, oxaliplatin) on circulating inflammatory cytokines, body composition, and physical function in CT26 tumor-bearing male and female mice. BALB/c mice were injected with CT26 tumor cells, and after the tumor was palpable, underwent three cycles of FOLFOX. FOLFOX reduced tumor mass in both sexes. CT26 induced plasma IL-6, LIF, and TNF-α in males and females. FOLFOX attenuated the CT26-induced IL-6 and LIF levels in males, but in females FOLFOX alone induced IL-6 and TNF-α, and did not attenuate their CT26 induction. In CT26 males, but not females, total lean and hindlimb mass were negatively associated with IL-6, and FOLFOX disrupted this association. The CT26-induced muscle p-STAT3 was inversely associated with muscle mass in males only and disrupted by FOLFOX. Circulating inflammatory cytokines were associated with body composition changes and functional deficits in CT26 males, but FOLFOX and female sex altered this relationship. Our results provide evidence that the female response to circulating inflammatory cytokines in the CT26 tumor environment, following FOLFOX chemotherapy, differs from that of males, and the physiological ramifications of this regulation warrant further investigation.

Keywords:  FOLFOX; Interleukin-6 (IL-6); colorectal cancer; leukemia inhibitory factor (LIF); signal transducer and activator of transcription 3 (STAT3)

DOI:  https://doi.org/10.1152/ajpcell.00643.2025
J Am Chem Soc. 2025 Oct 21.

Intracellular Peptide N-Myristoylation for Cancer Cell Ferroptosis without Acquired Resistance.

Qiuxin Zhang, Weiyi Tan, Isabela Ashton-Rickardt, William Lau, Linrui Zou, Bing Xu.

N-Myristoylation, a well-known protein lipidation process, has yet to be explored for in situ peptide lipidation. Here, we report intracellular peptide N-myristoylation for potently inhibiting cancer cells. A self-assembling d-peptide, Gbb-NBD (1), comprising an N-terminal glycine, a d-dibiphenylalanine backbone, and a C-terminal nitrobenzofurazan, formed nanospheres in aqueous solution and exhibited strong cytotoxicity against cancer cells (GI50 = 500 nM) while sparing neuronal cells. Live-cell imaging showed that 1 traversed the plasma membrane to the ER, Golgi and mitochondria. NMT inhibition, LC-MS of cell lysates, and click chemistry confirmed the N-myristoylation of 1. Functional studies showed that blocking NMT activity or modifying the N-terminus suppressed cytotoxicity, establishing N-myristoylation as essential for activity. Mechanistically, immunoblotting, lipidomic profiling, and rescue assays demonstrated that myristoylated 1 disrupted lipid metabolism and induced ferroptotic cell death, notably without the emergence of acquired resistance. In contrast, premyristoylated 1 displayed poor uptake and weak activity, underscoring the importance of in situ lipidation for cellular entry and function. Together, these findings reveal intracellular N-myristoylation of a short peptide as a new approach to drive ferroptosis and highlight its potential for developing membrane-targeting supramolecular therapeutics.

DOI: https://doi.org/10.1021/jacs.5c15621
Adv Sci (Weinh). 2025 Oct 24. e14969

Identifying Key Questions and Challenges in Microchimerism Biology.

Kristine J Chua, Rachel C Quilang, Katja Sallinger, Christina Athena Aktipis, Petra Arck, Diana W Bianchi, Hyun-Dong Chang, Henderson J Cleaves, Michael Eikmans, Heidi E S Fjeldstad, David Haig, Whitney E Harrington, William Horsnell, Daniel P Jacobsen, Mads Kamper-Jørgensen, Sami B Kanaan, Kiarash Khosrotehrani, Nathalie C Lambert, Jane Lee Nelson, Maria B Olsen, Tiffany D Pan, Jelmer R Prins, Frank A Schildberg, Anne Cathrine Staff, Anders Ståhlberg, Ina A Stelzer, Christopher Urbschat, Sing Sing Way, Melissa A Wilson, Jody Ye, Thomas Kroneis, Amy M Boddy.

  Microchimerism research has recently gained renewed attention despite known existence of these rare cells for decades. Fetal and maternal microchimeric-derived cells may have functional capabilities, and are increasingly associated with both beneficial and adverse health outcomes. Yet, establishing the role of microchimerism in health has been largely constrained methodologically and theoretically. The Microchimerism, Human Health, and Evolution Project address these challenges by calling on 29 leading microchimerism experts to put forth key research questions that can substantially advance the field. Seven major categories are identified: function and mechanism; microchimerism in interventions, treatment, and transplant; mapping "generational microchimerism"; evolution; microchimerism detection; appropriate experimental model systems; and definition of microchimerism. Identifying these questions - and continuing to find answers - will be crucial for advancing the knowledge of microchimerism in health and disease.

Keywords:  autoimmunity; detection methods; evolution; immune tolerance; maternal‐fetal interaction; microchimerism; pregnancy

DOI:  https://doi.org/10.1002/advs.202514969
Cell Oncol (Dordr). 2025 Oct 22.

Microphysiological systems for metastasis research: a stepwise approach.

Vira Sharko, Ignacio Ochoa, Estela Solanas.

  Metastasis, the leading cause of cancer-related mortality, is a complex process involving tumor cell detachment from the primary site, survival and dissemination through the circulation, and colonization of distant organs. At each stage, tumor cells face adaptive pressures from successive biological and biomechanical challenges in the local microenvironment, which collectively shape their progression. Traditional in vitro models often fail to replicate these dynamics, while animal models are limited by species differences and restricted real-time monitoring. Microphysiological systems (MPS) have emerged as powerful tools to address these limitations, delivering physiologically relevant cues and precise experimental control to recapitulate step-specific metastatic contexts. This review outlines recent advances in MPS designs for modeling critical hallmarks of metastasis, beginning with matrix interactions, stromal cells, and mechanical forces from the tumor microenvironment that drive epithelial-mesenchymal transition and invasion. The discussion then transitions to MPS that reproduce vascular physiology during intravasation, circulation, and extravasation, and concludes with organ-specific environments for studying colonization and organotropic behavior in the final stages of metastasis. Additionally, common MPS configurations, categorized into horizontal and vertical compartmental arrangements, and strategies for integrating vascularization are explored. Together, these advances highlight the potential of MPS in elucidating metastatic mechanisms and advancing targeted therapies.

Keywords:  Cancer; Metastasis; Microfluidics; Microphysiological systems; Tumor microenvironment

DOI:  https://doi.org/10.1007/s13402-025-01110-4
J Am Chem Soc. 2025 Oct 23.

A Structurally Robust Phospholipid Microtube Constructed by Membrane Phase Separation as a Scaffold for On-Tube Characterization of Membrane-Bound Proteins.

Noriyuki Uchida, Ryu Ishizaka, Anju Kawakita, Hiroshi Ueno, Hiroyuki Noji, Rinshi S Kasai, Takeshi Yokoyama, Saburo Kurihara, Tomoki Noguchi, Go Watanabe, Ayaka Iwasaki, Itsuki Ajioka, Kazuyoshi Muranishi, Ken Yoshizawa, Shingo Kanemura, Masaki Okumura, Takahiro Muraoka.

Artificial phospholipid assemblies, such as liposomes, have become indispensable scaffolds for the characterization of membrane proteins. Phospholipid microtubes (PMTs) are universal biological architectures, as seen in the endoplasmic reticulum and neurites, that are constructed by curvature-sensing membrane-bound proteins such as Bin/Amphiphysin/Rvs (BAR) proteins. Inspired by the biological PMTs, artificial PMTs have been constructed by physically pulling the membranes using optical tweezers or kinesin motors. However, the inherent low stability of artificial PMTs, which collapse after the removal of the energy source, has critically limited their applications as scaffolds. Here, we report the construction of structurally robust PMTs as practically useful scaffolds for on-tube characterization of membrane-bound proteins. We focused on a membrane deformation driven by phase separation between saturated and unsaturated phospholipids. We developed a polycationic peptide lipid (PCaL) that dissociates the phase separation. Interestingly, complexation of PCaL with an anionic ligand prompted the spontaneous formation of phospholipid microtubes (PMTPCaL). Importantly, PMTPCaL exhibited high robustness against harsh physical stresses, including increased temperatures, increased salt concentrations, osmotic stress, physical pulling using optical tweezers, and molecular crowding. Taking advantage of the high structural stability, PMTPCaL was utilized as a scaffold for on-tube characterization of a curvature-sensing membrane-bound protein. We revealed that sorting nexin-1 enhances its binding property with a tubular membrane under highly crowded cell-mimicking conditions relative to noncrowding conditions.

DOI: https://doi.org/10.1021/jacs.5c13384
Science. 2025 Oct 23. 390(6771): eadp3065

Unsaturated fat alters clock phosphorylation to align rhythms to the season in mice.

Daniel C Levine, Rasmus H Reeh, Thomas McMahon, Thomas Mandrup-Poulsen, Ying-Hui Fu, Louis J Ptáček.

The circadian clock maintains synchrony between biological processes and light/dark cycles by integrating environmental cues. How the clock adapts to seasonal variations in the environment is incompletely understood. We found that a high-fat diet increased phosphorylation of the clock protein PERIOD2 (PER2) on serine 662 (S662), which was necessary and sufficient for regulating phase shifting of daily locomotor activity to entrain to seasonal light cycles. PER2-S662 phosphorylation correlated with genome-wide expression pathways that regulate polyunsaturated fatty acid (PUFA) conversion into oxylipins in the hypothalamus. Partial hydrogenation of dietary PUFAs increased hypothalamic PER2-S662 phosphorylation and entrainment to a summer photoperiod in control mice, but not in mice for which PER2-S662 could not be phosphorylated. PER2-S662 phosphorylation is influenced by, and alters the regulation of, unsaturated fat to control circadian phase shifting across the seasons.

DOI: https://doi.org/10.1126/science.adp3065
Nat Commun. 2025 Oct 20. 16(1): 9275

Physics-based evolution of transmembrane helices reveals mechanisms of cholesterol attraction.

Jeroen Methorst, Nino Verwei, Christian Hoffmann, Paweł Chodnicki, Roberto Sansevrino, Partha Pyne, Han Wang, Niek van Hilten, Dennis Aschmann, Alexander Kros, Loren Andreas, Jacek Czub, Dragomir Milovanovic, Herre Jelger Risselada.

The existence of linear cholesterol-recognition motifs in transmembrane domains has long been debated. Evolutionary molecular dynamics (Evo-MD) simulations-genetic algorithms guided by (coarse-grained) molecular force-fields-reveal that thermodynamic optimal cholesterol attraction in isolated alpha-helical transmembrane domains occurs when multiple consecutive lysine/arginine residues flank a short hydrophobic segment. These findings are supported by atomistic simulations and solid-state NMR experiments. Our analyses illustrate that linear motifs in transmembrane domains exhibit weak binding affinity for cholesterol, characterized by sub-microsecond residence times, challenging the predictive value of linear CRAC/CARC motifs for cholesterol binding. Membrane protein database analyses suggest even weaker affinity for native linear motifs, whereas live cell assays demonstrate that optimizing cholesterol binding restricts transmembrane domains to the endoplasmic reticulum post-translationally. In summary, these findings contribute to our understanding of cholesterol-protein interactions and offer insight into the mechanisms of protein-mediated cholesterol regulation within membranes.

DOI: https://doi.org/10.1038/s41467-025-63769-5
Dev Cell. 2025 Oct 20. pii: S1534-5807(25)00568-4. [Epub ahead of print]60(20): 2697-2699

TfR in focus: Orchestrating autophagosome biogenesis.

Yan G Zhao, Hong Zhang.

Transferrin receptors, responsible for iron importation into cells, exhibit additional iron-independent functions. In this issue, Puri et al. reveal that the transferrin receptor recruits the VPS34 complex I, stimulating PI(3)P synthesis. This PI(3)P production aids in autophagosome elongation and closure by facilitating recruitment of the LC3 conjugation system and ESCRT, respectively.

DOI: https://doi.org/10.1016/j.devcel.2025.09.008
Am J Cancer Res. 2025 ;15(9): 4108-4120

Incorporating nivolumab with preceded gemcitabine and S-1 chemotherapy for patients of metastatic pancreatic cancer: a pilot study.

Shih-Hung Yang, Bang-Bin Chen, Jen-Chieh Lee, Yu-Ting Kuo, Sun-Hsin Kuo, Ann-Lii Cheng, Kun-Huei Yeh.

  Pancreatic ductal adenocarcinoma (PDAC) rarely responds to immune checkpoint inhibitors. We conducted a pilot study to investigate chemotherapy followed by the addition of nivolumab in metastatic PDAC with limited tumor burden. A single cycle of gemcitabine (850 mg/m2 on days 1 and 8) and S-1 (60-100 mg/day on days 1-12) was administered. Patients who had achieved control of carbohydrate antigen 19-9 (CA 19-9) (a decreased level of CA 19-9 or <10% increased level of CA 19-9 comparing to baseline) were provided adding-on nivolumab (3 mg/kg on days 1, 15, and 29) with the same doses of gemcitabine (on days 1, 8, 22, and 29) and S-1 (on days 1-12 and 22-33). The primary endpoint was response rate (RR). After enrolling seven patients, the study was terminated owing to slow recruitment. Five of the seven patients who completed one cycle of gemcitabine plus S-1 (GS) fulfilled the criteria for CA 19-9 and proceeded to receive nivolumab in addition to GS. One patient demonstrated a partial response, and the other four patients had stable disease (SD). The RR and disease control rate (DCR) for gemcitabine and S-1 plus nivolumab (GSN) were 20% and 100%, respectively. The median progression-free survival (PFS) was 6.3 (95% confidence interval [CI], 0-16.4) months. The median overall survival (OS) was 20.8 (95% CI, 16.4-25.2) months. Two patients who did not receive nivolumab continued the GS regimen; one SD and one progressive disease (PD) were observed with a PFS of 3.5 and 3.0 months, respectively. The most common adverse events (AEs) during the GS phase (n = 7) were grade 1-2 neutropenia (n = 5), skin rashes (n = 4), and fever (n = 3). During the nivolumab adding-on phase (n = 5), one grade 3 and one grade 4 neutropenia were observed. Grade 1-2 mucositis (n = 3) was the most common nonhematological AE. In conclusion, adding nivolumab to chemotherapy in patients who had achieved control of CA 19-9 in metastatic PDAC was feasible. (Registration at ClinicalTrials.gov: NCT04377048).

Keywords:  Pancreatic cancer; S-1; adding-on nivolumab; disease control; gemcitabine

DOI:  https://doi.org/10.62347/NJOX8790
Signal Transduct Target Ther. 2025 Oct 23. 10(1): 358

Navigating the landscape of protein folding and proteostasis: from molecular chaperones to therapeutic innovations.

Omer Faruk Kuzu, Lars Jørgen Tvenge Granerud, Fahri Saatcioglu.

Protein folding is a fundamental process ensuring that polypeptide chains acquire the correct three-dimensional structures required for biological function. This complex journey from nascent polypeptides to mature proteins is tightly regulated by the cellular proteostasis network-an integrated system of molecular chaperones, folding enzymes, and degradation machineries. Disruptions in this network lead to dysproteostasis, a pathological state implicated in a growing list of human diseases, including neurodegenerative disorders, metabolic syndromes, and cancer. In this review, we provide a comprehensive and multidimensional analysis of protein folding biology, tracing its evolution from early theoretical foundations to cutting-edge biophysical and computational techniques that now permit near-atomic-resolution modeling of folding dynamics. We explore the historical progression of protein folding research, including landmark discoveries of secondary structure, chaperone biology, and energy landscape theory. We detail the roles of key molecular chaperones across cytosolic, mitochondrial, and endoplasmic reticulum compartments, emphasizing their collaborative actions in protein folding and quality control. We also discuss the multifactorial causes of protein misfolding-from genetic mutations to aging and oxidative stress-and examine the pathological consequences, paying special attention to diseases characterized by toxic protein aggregation and loss of proteome fidelity. We then examine therapeutic innovations targeting proteostasis, including chaperone modulators, proteostasis pathway inhibitors, and emerging strategies to increase proteome resilience. By consolidating insights at the molecular, cellular, and systems levels, this review underscores the central role of protein folding homeostasis in health and disease and highlights novel opportunities for therapeutic intervention through the modulation of the proteostasis network.

DOI: https://doi.org/10.1038/s41392-025-02439-w
Nat Commun. 2025 Oct 22. 16(1): 9355

A multimodal cross-species comparison of pancreas development.

Kaiyuan Yang, Hannah Spitzer, Michael Sterr, Karin Hrovatin, Sean de la O, Xinghao Zhang, Eunike Sawitning Ayu Setyono, Minhaz Ud-Dean, Thomas Walzthoeni, Krzysztof Flisikowski, Tatiana Flisikowska, Angelika Schnieke, Katharina Scheibner, James M Wells, Julie B Sneddon, Barbara Kessler, Eckhard Wolf, Elisabeth Kemter, Fabian J Theis, Heiko Lickert.

Human pancreas development remains incompletely characterized due to restricted sample access. We investigate whether pigs resemble humans in pancreas development, offering a complementary large-animal model. As pig pancreas organogenesis is unexplored, we first annotate developmental hallmarks throughout its 114-day gestation. Building on this, we construct a pig single-cell multiome pancreas atlas across all trimesters. Cross-species comparisons reveal pigs resemble humans more closely than mice in developmental tempo, epigenetic and transcriptional regulation, and gene regulatory networks. This further extends to progenitor dynamics and endocrine fate acquisition. Transcription factors regulated by NEUROG3, the endocrine master regulator, are over 50% conserved between pig and human, many being validated in human stem cell models. Notably, we uncover that during embryonic development, emerging beta-cell heterogeneity coincides with a species-conserved primed endocrine cell (PEC) population alongside NEUROG3-expressing cells. Overall, our work lays the foundation for comparative investigations and offers unprecedented insights into evolutionarily conserved pancreas organogenesis mechanisms across animal models.

DOI: https://doi.org/10.1038/s41467-025-64774-4
Sci Rep. 2025 Oct 21. 15(1): 36596

The genetically encoded biosensor FEOX is a molecular gauge for cellular iron environment dynamics at single cell resolution.

Carolyn Sangokoya.

Iron-sensing is evolutionarily conserved among life on Earth, and mammalian cells are known to sense cellular iron through mechanisms similar to bacteria and marine invertebrates. While iron regulatory proteins (IRPs) function as RNA-binding proteins during iron-limiting conditions and reflect cellular iron status, we lack genetically-encodeable tools to quantify bioavailable intracellular iron status over developmental time and at single-cell resolution. In order to better understand the cellular environment that supports or restricts IRP-active conditions, particularly during complex and dynamic changes leading to differentiated states, we present a ratiometric genetically-encoded biosensor called FEOX. FEOX is a ratiometric fluorescent biosensor of the cellular iron environment based on a mammalian hemerythrin-like domain, acting as an iron-dependent ligand-based regulatory switch. Compared to increased IRP activity in response to iron-limitation, FEOX dynamics demonstrate decreased ratiometric fluorescence representing decreased cellular iron during iron-limitation. Using FEOX we are able to quantify the dynamics of the bioavailable cellular iron environment during early stem cell differentiation by ratiometric measurements at single-cell resolution. Results from FEOX and from an IRP activity sensor during stem cell pluripotency transition and early differentiation provide orthogonal support for an increased iron demand state. Using these genetically-encodeable tools will allow greater insight into cellular iron homeostasis within mammalian systems. IRPs function as RNA-binding proteins during iron-limiting conditions, regulating the stability and translation of messenger RNAs that are essential for cellular iron homeostasis. However, to better understand and study the cell and molecular regulators of the iron-limiting conditions required for IRP RNA-binding activity, new tools are needed to monitor iron-responsive alterations in the intracellular environment at single-cell resolution and over developmental time. We devised a genetically-encoded biosensor called FEOX that depends on molecular iron interactions independent of IRP function and directly gauges bioavailable cellular iron.

DOI: https://doi.org/10.1038/s41598-025-20428-5
Nat Med. 2025 Oct 19.

YAP/TEAD inhibitor VT3989 in solid tumors: a phase 1/2 trial.

Timothy A Yap, David J Kwiatkowski, Ibiayi Dagogo-Jack, Michael Offin, Marjorie G Zauderer, Robert Kratzke, Jayesh Desai, Amy Body, Michael Millward, Anthony W Tolcher, Kanwal P S Raghav, Archie Thurston, Len Post, F Andrew Dorr, Tracy T Tang, Yufeng Li, Neelesh Sharma, Hedy L Kindler.

Constitutive YAP activation resulting from dysregulated Hippo signaling drives tumor progression in mesothelioma and other cancers. VT3989, a first-in-class potent oral TEAD palmitoylation inhibitor, disrupts YAP transcriptional activity. Here we report the first-in-human phase 1/2 trial findings evaluating VT3989 in refractory solid tumors with a focus on mesothelioma. This study is ongoing, and we report results from the dose escalation and non-prespecified interim efficacy results of the expansion cohorts for which recruitment is ongoing. Dose escalation (n = 85) and expansion (n = 87) cohorts included 172 patients (135 mesothelioma). VT3989 exhibited a favorable safety profile with mostly grade 1-2 toxicities, including increased urine albumin:creatinine ratio (UACR), proteinuria, peripheral edema and fatigue. Proteinuria was reversible with dose adjustment and did not result in renal impairment. The overall response rate (ORR) was 26% in 47 patients with mesothelioma treated at clinically optimized doses, whereas the ORR was 32% (disease control rate 86%; median progression-free survival 10 months) in 22 patients with mesothelioma when clinically optimized doses and UACR thresholds were incorporated. These data provide the first early clinical proof of concept for effectively drugging the Hippo-YAP-TEAD pathway. VT3989 was recently awarded orphan drug designation and fast-track designation for the treatment of mesothelioma by the US Food and Drug Administration (FDA). ClinicalTrials.gov Identifier: NCT04665206 .

DOI: https://doi.org/10.1038/s41591-025-04029-3
Biomed Opt Express. 2025 Oct 01. 16(10): 4104-4117

Live, spatially-resolved imaging of absolute intracellular water content using holotomography.

Sean P O'Connor, Anna V Sedelnikova, Zachary T Brawley, Stacey L Martens, Zachary A Steelman.

Water is the predominant component of living systems, and its regulation and movement in response to stimuli is a critical feature of homeostasis. While many techniques report relative changes in the water content of cells, measuring the absolute water content in live cells is difficult. In this work, we introduce methodologies for quantifying the absolute intracellular water content using holotomography, which can be applied to unlabeled live cells of arbitrary shape. Using the volumetric and mass-sensitive nature of holotomography, we treat the cell as a two-component mixture model of solid and aqueous materials and solve for the absolute water content. We apply these techniques to quantify absolute intracellular water content of cells undergoing mitosis and responding to external stressors, including osmotic shock and pulsed electric fields, which induce rapid osmotic change. These techniques will aid in elucidating biological, chemical, and physical mechanisms of water transport.

DOI: https://doi.org/10.1364/BOE.574974