bims-cagime 2026-01-25 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2026–01–25
thirty papers selected by
Kıvanç Görgülü, Technical University of Munich

Genomic evolution of pancreatic cancer at single-cell resolution.
Acetyl-CoA as a metabolic switch for selective mitophagy.
CRISPR knockout screens reveal JUN as the master mediator of resistance to MAPK inhibition in KRAS-mutant pancreatic cancer.
Dordaviprone/ONC201 Activation of the ClpP Mitochondrial Protease Inhibits the Growth of KRAS-Mutant Pancreatic Cancer and Overcomes RAS Inhibitor Resistance.
Multimodal profiling of pancreatic cancer reveals a TIMP-1-dominated secretory profile determining pro-tumor immunoinstruction in human cancers.
Critical role for a high-plasticity cell state in lung cancer.
Reduced lipid metabolite abundance in human pancreatic cancer and matched serum samples following neoadjuvant FOLFIRINOX treatment.
Membrane curvature enhances lipid peroxidation in a composition-dependent manner.
KRASG12R-Mutant Pancreatic Cancer Features Limited ERK/MAPK Transcriptional Activity and a Distinctive Tumor Microenvironment.
Peripheral lysosome levels dictate mTORC1 inactivation even when catabolically impaired.
Cell viscosity influences haematogenous dissemination and metastatic extravasation of tumour cells.
The molecular mechanism of lipid uptake by membrane-anchored bridge-like lipid transfer proteins.
Selective targeting of NRF2-high pancreatic ductal adenocarcinoma with an NQO1-activatable prodrug.
Longitudinal analysis of matched patient biospecimens reveals Neural Reprogramming of Cancer-Associated Fibroblasts Following Chemotherapy in Pancreatic Ductal Adenocarcinoma.
Distinct Metabolomic Alterations Are Associated With Physical Function, Weight Loss, and Muscle Mass in Men With Cancer.
ER membrane receptors engage core autophagy machinery to initiate ER-phagy.
Guardian ubiquitin E3 ligases target cancer-associated APOBEC3 deaminases for degradation to promote human genome integrity.
GDF15 in the tumor microenvironment: A central mediator of cancer immunometabolism and therapeutic resistance.
Ferroptosis in cancer toward molecular insights and clinical translation in pancreatic cancer.
Dual-Color Expansion Microscopy of Membrane Proteins Using Bioorthogonal Labeling.
Mechanometabolism of cell adhesion: Vinculin regulates bioenergetics via RhoA-ROCK.
Aberrant methylation limits antitumoral inflammation in lung adenocarcinoma by restricting RIPK3 expression.
TGFβ signaling regulates the response of the skeleton to phosphate.
The vulnerabilities of chemotherapy resistant pancreatic cancer revealed by organoids of pre- and post- neoadjuvant therapy.
Preclinical Characterization and Clinical Activity of RNK08954, a Highly Selective and Orally Bioavailable KRAS G12D Inhibitor.
Lactate sensing by Carotid Bodies: Is it necessary for ventilatory responses to exercise?
Disruption of iron homeostasis sensitizes pancreatic cancer to irreversible electroporation.
Targeting thymine DNA glycosylase induces synthetic lethality in p53-deficient cancers.
CLN3 mediates chloride efflux from lysosomes.
Infrared nanoscopy for subcellular chemical imaging.

Nat Genet. 2026 Jan 22.

Genomic evolution of pancreatic cancer at single-cell resolution.

Haochen Zhang, Palash Sashittal, Elias-Ramzey Karnoub, Akhil Jakatdar, Shigeaki Umeda, Jungeui Hong, Anne Marie Noronha, Agustin Cardenas, Amanda Erakky, Caitlin A McIntyre, Akimasa Hayashi, Nicolas Lecomte, Marc Hilmi, Wungki Park, Nan Pang, Eileen M O'Reilly, Alice C Wei, Benjamin J Raphael, Christine A Iacobuzio-Donahue.

Most evolutionary studies on pancreatic cancer rely on bulk sequencing, yet clonal evolution happens at the single-cell level. We used single-nucleus DNA sequencing to study 137,491 single nuclei from 24 pancreatic neoplasms reflecting various clinical scenarios. We found higher frequencies of somatic alterations to driver genes that bulk studies indicate; many manifest as copy number alterations and account for the majority of spatial heterogeneity. In pancreatic cancers with canonical KRAS oncogenic mutations, we found likely varied dependence on the genotype that may signify differential response to KRAS inhibition. In pancreatic cancers with germline heterozygous BRCA2 mutations, we discovered varied mechanisms and timing of inactivation of the wild-type allele that sculpted differential evolutionary trajectories. Inactivation of tumor-intrinsic response to transforming growth factor-β happens through various mechanisms, takes place after oncogenesis and coincides with invasion and metastasis, reflecting increasing selective pressure for the phenotype later in pancreatic ductal adenocarcinoma development.

DOI: https://doi.org/10.1038/s41588-025-02468-9
Autophagy. 2026 Feb;22(2): 235-237

Acetyl-CoA as a metabolic switch for selective mitophagy.

Daolin Tang, Rui Kang, Daniel J Klionsky.

  A recent study published in Nature by Zhang et al. reported that cytosolic acetyl-CoA functions as a signaling metabolite that regulates NLRX1-dependent mitophagy during nutrient stress. This discovery reveals a metabolic checkpoint for mitochondrial quality control and provides new insights into KRAS inhibitor resistance.

Keywords:  Acetyl-CoA; KRAS inhibitor; NLRX1; metabolic signaling; mitophagy

DOI:  https://doi.org/10.1080/15548627.2025.2593032
J Exp Clin Cancer Res. 2026 Jan 22.

CRISPR knockout screens reveal JUN as the master mediator of resistance to MAPK inhibition in KRAS-mutant pancreatic cancer.

Antonio Mulero-Sánchez, Astrid Bosma, Bonifiya Visuvasam, Niki Pouliopoulou, Marieke van de Ven, Natalie Proost, Manon Boeije, Cor Lieftink, Roderick Beijersbergen, Rene Bernards, Sara Mainardi.

   BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is often driven by KRAS mutations, but inhibitors targeting the most frequent KRAS substitutions in PDAC are not yet approved in the clinic. We previously discovered that KRAS-mutant PDAC is sensitive to the combination of SHP2 and ERK inhibitors, recently investigated in the Phase I/Ib clinical trial NCT04916236. Lately, RAS(ON) multi-selective inhibitors have entered clinical development, representing a promise for mono or combination therapies in PDAC. However, resistance may arise even for combination therapies. Here, we aimed at anticipating mechanisms of resistance to SHP2 plus ERK or RAS(ON) multi-selective inhibitors.
METHODS: We performed a genome-wide CRISPR-KO screening, followed by four follow-up focused screenings, leading to the identification of resistance mediators, which were further validated through functional genetic and pharmacological experiments, both in vitro and in vivo.
RESULTS: Through unbiased CRISPR-based screenings, we identified mTOR and JUN hyperactivation as interconnected mechanisms that overcome MAPK suppression. Further investigation pointed at JUN as the most downstream resistance mediator, and indirect therapeutic target, using MAP2K4 inhibitors.
CONCLUSIONS: Alterations in the PI3K/AKT/mTOR and JUN pathways can induce resistance to multiple combinations of MAPK pathway inhibitors, and may serve as biomarkers for sensitivity/resistance in clinical trials exploring such combinations in KRAS-mutant PDAC.

Keywords:  ERK; JUN; K-RAS; Pancreatic cancer; RAS inhibitors; Resistance; SHP2; Targeted therapy

DOI:  https://doi.org/10.1186/s13046-025-03616-z
bioRxiv. 2025 Dec 03. pii: 2025.12.01.691471. [Epub ahead of print]

Dordaviprone/ONC201 Activation of the ClpP Mitochondrial Protease Inhibits the Growth of KRAS-Mutant Pancreatic Cancer and Overcomes RAS Inhibitor Resistance.

Kristina Drizyte-Miller, Seamus E Degan, Ryan D Mouery, Amber M Amparo, Brandon L Mouery, Wen-Hsuan Chang, Runying Yang, Sheila R Nicewarner Peña, Elisa Baldelli, Jeffrey A Klomp, Edwin J Iwanowicz, Lee M Graves, Emanuel F Petricoin, Adrienne D Cox, Clint A Stalnecker, Kirsten L Bryant, Channing J Der.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS-driven oncogenic signaling and tumor growth. Blockade of the KRAS ERK-MAPK pathway via small molecule direct RAS inhibitors has shown clinical promise, but intrinsic and acquired resistance limit the efficacy of these inhibitors as single agents. To identify potential combination strategies, we first assessed the ability of dordaviprone/ONC201, an FDA-approved agent, to inhibit PDAC cell and organoid growth. We observed that ONC201 reduced the growth of a broad panel of KRAS-mutant PDAC cell lines, and that the expression of mitochondrial protease ClpP was required for this efficacy. Mechanistically, we observed that treatment with ONC201 led to inhibition of mitochondrial respiration, causing a compensatory increase in glycolysis. Furthermore, ONC201 caused ClpP-dependent activation of PI3K-AKT-mTOR signaling and concurrent PI3K and mTOR inhibition further enhanced ONC201 growth suppression. ONC201 demonstrated an additive effect when combined with a RAS(ON) multi-selective inhibitor RMC-7977 in PDAC cells and organoids. Finally, PDAC cell lines with acquired resistance to RMC-7977 or KEAP1 loss-driven resistance retained sensitivity to ONC201. We propose that concurrent treatment with ONC201 may delay onset of resistance to RAS inhibitor therapy.
Statement of Significance: ClpP activation by dordaviprone/ONC201 suppressed PDAC cell growth and overcame resistance to the RAS(ON) multi-selective inhibitor RMC-7977, providing support for investigating this combination as a potential combination treatment for KRAS-mutant pancreatic cancer.

DOI: https://doi.org/10.64898/2025.12.01.691471
Cell Rep Med. 2026 Jan 20. pii: S2666-3791(25)00619-6. [Epub ahead of print]7(1): 102546

Multimodal profiling of pancreatic cancer reveals a TIMP-1-dominated secretory profile determining pro-tumor immunoinstruction in human cancers.

Julian Frädrich, Carmen Mota Reyes, Michel Hendel, Vanessa Brunner, Batu Toledo, Damjan Manevski, Alexander Sommer, Daniel Häußler, Dominik Beck, Daniele Lucarelli, Jaime Martínez de Villareal, Lennard Halle, Raphael Kfuri-Rubens, Kaan Çifcibaşı, Anna Hirschberger, Rupert Öllinger, Percy A Knolle, Katja Steiger, Roland Rad, Fabian J Theis, Francisco X Real, Stefanie Bärthel, Jan P Böttcher, Dieter Saur, Ihsan Ekin Demir, Achim Krüger.

  The immunosuppressive tumor microenvironment (TME) fosters cancer progression, yet overarching determinants of cancer-borne immunoinstruction remain ill-defined. By multimodal integration of single-nucleus and bulk transcriptomics, proteomics, functional approaches, and clinical parameters, we discover a cancer-immunoinstructive secretory signature (CISS) across multiple human cancers-a set of inflammatory proteins correlated with poor prognosis and pro-tumorigenic TMEs. In pancreatic cancer (PC), CISS arises in pre-malignant epithelium, intensifies along transformation toward most malignant basal-like PC, and particularly correlates with suppressed natural killer (NK) cell activity. The CISS is quantitatively dominated by tissue inhibitor of metalloproteinases (TIMP)-1, most prevalent in TIMP-1hi/CISShi basal-like PC, and causal for PC-cell-mediated NK cell suppression, reflected by impaired cytotoxicity, interleukin-2 (IL-2) responses, and mammalian target of rapamycin (mTOR) signaling. In pre-clinical PC, TIMP-1/CISS proves targetable through combined inhibition of upstream kinases with clinically approved drugs trametinib and nintedanib. Collectively, CISS represents a ubiquitous signature of pro-tumor immunoinstruction with actionable diagnostic and therapeutic potential across human cancers.

Keywords:  TIMP-1; cancer heterogeneity; cancer immunosuppression; epithelial heterogeneity; natural killer cells; pan-cancer; pancreatic cancer

DOI:  https://doi.org/10.1016/j.xcrm.2025.102546
Nature. 2026 Jan 21.

Critical role for a high-plasticity cell state in lung cancer.

Jason E Chan, Chun-Hao Pan, Jonathan Rub, Gary Guzman, Klavdija Krause, Emma Brown, Zeda Zhang, Hannah Styers, Griffin Hartmann, Zhuxuan Li, Xueqian Zhuang, Scott W Lowe, Doron Betel, Yan Yan, Tuomas Tammela.

Plasticity-the ability of cells to undergo phenotypic transitions-drives cancer progression and therapy resistance1-3. Recent studies have suggested that plasticity in solid tumours is concentrated in a minority subset of cancer cells4-6, yet functional studies examining this high-plasticity cell state (HPCS) in situ are lacking. Here we develop mouse models enabling the detection, longitudinal lineage tracing and ablation of the HPCS in autochthonous lung tumours in vivo. Lineage tracing reveals that the HPCS cells possess a high capacity for cell state transitions, giving rise to both early neoplastic (differentiated) and progressed lung cancer cell states in situ. Longitudinal lineage tracing using secreted luciferases reveals that HPCS-derived cells have a high capacity for growth compared with bulk cancer cells or another cancer cell state with features of differentiated lung epithelium. Ablation of HPCS cells in early neoplasias abrogates benign-to-malignant transition, whereas ablation in established tumours by suicide gene or chimeric antigen receptor (CAR) T cells robustly reduces tumour burden. We further demonstrate that the HPCS gives rise to therapy-resistant cell states, whereas HPCS ablation suppresses resistance to chemotherapy and oncoprotein-targeted therapy. Notably, an HPCS-like state is ubiquitous in regenerating epithelia and in carcinomas of multiple other tissues, revealing a convergence of plasticity programs. Our work establishes the HPCS as a critical hub enabling reciprocal transitions between cancer cell states. Targeting the HPCS in lung cancer and in other carcinomas may suppress cancer progression and eradicate treatment resistance.

DOI: https://doi.org/10.1038/s41586-025-09985-x
Metabolomics. 2026 Jan 19. 22(1): 18

Reduced lipid metabolite abundance in human pancreatic cancer and matched serum samples following neoadjuvant FOLFIRINOX treatment.

Manoj Amrutkar, Sander Johannes Thorbjørnsen Guttorm, Knut Jørgen Labori, Helge Rootwelt, Katja Benedikte Prestø Elgstøen, Ivar P Gladhaug, Caroline S Verbeke.

   INTRODUCTION: Exploiting the full potential of neoadjuvant treatment (NAT) in pancreatic ductal adenocarcinoma (PDAC) is hampered by the lack of biomarkers for treatment response. Dysregulated lipid metabolism has been suggested to promote PDAC growth and resistance to therapy.
OBJECTIVES: To investigate lipid metabolic changes in PDAC following NAT.
METHODS: Cross-sectional study of mass spectrometry-based global lipidomic profiling of tumour tissue (n = 35) and paired serum samples (n = 35) from treatment-naïve (TN; n = 18) and neoadjuvant FOLFIRINOX-treated (NAT; n = 17) PDAC patients was conducted. Pre- and post-treatment CA 19-9 levels were available from 15 NAT patients. Differentially abundant lipids (DALs) in NAT versus TN were assessed for correlation with various clinical parameters and the performance of all serum DALs to distinguish NAT from TN samples was explored using receiver operating characteristic analysis.
RESULTS: A total of 40 tissue and 35 serum DALs were identified, which mainly belonged to glycerophospholipids and sphingolipids in tissue and glycerolipids, glycerophospholipids, and fatty acyls in serum. All 19 serum glycerolipids were less abundant in NAT and 18 of these were triacylglycerols. The abundance of 26 tissue and 11 serum DALs correlated moderately with % reduction in serum CA 19-9 following NAT. The top five of 23 serum DALs with moderate discriminatory potential (AUC = 0.66-0.87) ‒ PI(18:0_20:3), AcCa(13:0), PC(O-42:6), TG(49:6), TG(66:14), performed better together (AUC = 0.93 and 95% CI = 0.79‒1) and combined with CA 19-9 (AUC = 0.99 and 95% CI = 0.81‒1).
CONCLUSIONS: Both tumour tissue and serum samples from PDAC patients showed lower abundance of lipid metabolites following neoadjuvant FOLFIRINOX treatment. Moreover, a biomarker panel of CA 19-9 together with five serum DALs could potentially be used to assess NAT response in PDAC but requires further validation.

Keywords:  FOLFIRINOX; Global lipidomics; LC–MS; Neoadjuvant chemotherapy; Pancreatic cancer

DOI:  https://doi.org/10.1007/s11306-025-02388-z
bioRxiv. 2025 Dec 07. pii: 2025.12.03.692219. [Epub ahead of print]

Membrane curvature enhances lipid peroxidation in a composition-dependent manner.

Juhee Kim, Stephanie N Bartholomew, Wade F Zeno.

Excessive production of reactive oxygen species (ROS) in cells results in oxidative stress, which can promote lipid peroxidation in cellular membranes. This oxidation of membrane lipids accompanies various diseases and can even result in cell death through processes such as ferroptosis. The complex compositions and diverse morphologies of cellular membranes make understanding the mechanisms of lipid peroxidation challenging, especially when attempting to investigate membrane composition and curvature simultaneously. Here, we utilize reconstituted lipid membranes and the fluorescent oxidation probe C11-BODIPY to quantify lipid oxidation as functions of both lipid composition and membrane curvature. By tethering synthetic lipid vesicles to glass substrates, we were able to monitor lipid oxidation on a per vesicle basis using fluorescence microscopy. Our results demonstrate that highly curved membranes markedly increase both the rate and extent of lipid peroxidation across diverse membrane compositions. This effect arises from greater exposure of lipid tails to the aqueous environment, which allows more efficient transport of ROS into the hydrophobic core of the bilayer. Compositional effects on lipid peroxidation are most pronounced in membranes with low curvature (i.e., greater than 100 nm diameter) and become progressively weaker as curvature increases. We found that low to moderate cholesterol levels (i.e., 10-25 mol%) suppress curvature-dependent oxidation by tightening lipid packing, whereas high cholesterol content (i.e., 50 mol%) restores curvature sensitivity by influencing lateral lipid mobility. Together, these findings establish membrane curvature and lipid composition as interdependent determinants of oxidative susceptibility, offering new insight into how cells regulate or resist oxidative stress.
Statement of significance: Oxidative stress drives lipid peroxidation in cellular membranes, but the combined influence of membrane curvature and composition remains poorly defined. Using reconstituted lipid vesicles and a fluorescent oxidation probe, we show that lipid peroxidation is enhanced in smaller vesicles (i.e., highly curved membranes). The oxidation rate increases with unsaturated lipids, while cholesterol suppresses this effect. Measurements of membrane packing and diffusivity support these findings, demonstrating how curvature and composition together govern membrane susceptibility to oxidative damage. These results provide new insight into the physicochemical basis of membrane stability under oxidative stress and have broad implications for understanding the vulnerability of curved cellular membranes.

DOI: https://doi.org/10.64898/2025.12.03.692219
Cancer Res. 2026 Jan 20.

KRASG12R-Mutant Pancreatic Cancer Features Limited ERK/MAPK Transcriptional Activity and a Distinctive Tumor Microenvironment.

Rachel A Burge, Ozgun Le Roux, Olesja Popow, Victoria K Spadafora, Christabelle Rajesh, Sara J Adair, Lucas Bialousow, Cailey Murphy, Samaneh Saberi, Silvia G Vaena, Margaret C Taquey, Sarah Allen, Lu Han, Kristi L Helke, Sudarshana Sharma, Michael C Ostrowski, Denis C Guttridge, Toros A Dincman, Todd W Bauer, David F Kashatus, Thomas McFall, Kevin M Haigis, Michael A Hollingsworth, Christopher M Counter, Channing J Der, G Aaron Hobbs.

Patients with pancreatic ductal adenocarcinoma (PDAC) harboring KRASG12R mutations have increased overall survival relative to patients with KRASG12D/V mutations. To investigate the mechanisms underlying this differential outcome, we developed a genetically engineered mouse model (GEMM) harboring KRASG12R and p53R172H mutations (KrasLSL-G12R/+;Trp53LSL-R172H/+;p48Cre-ERTM). Unlike KRASG12D models, KRASG12R-GEMMs exhibited limited tumorigenesis, with only 10% developing pancreatic tumors after one year. Additionally, mice harboring whole-body expression of KRASG12R remained healthy for over one year, whereas KRASG12D mice developed rapid multifocal disease. Comparison of KRAS mutant-selective transcription and signaling in murine and human PDAC cell lines, GEMMs, and patient-derived xenograft mouse models revealed that direct KRAS-mediated PI3K activation is necessary for robust tumor initiation in GEMMs. Unexpectedly, KRAS was not the primary driver of PI3K activity in human PDAC cell lines and patient-derived xenograft models regardless of KRAS mutation. KRASG12R and KRASG12D activated a similar pancreas-specific transcriptional network, but KRASG12R promoted these pathways less robustly due to limited ERK/MAPK nuclear translocation. Finally, KRASG12R human pancreatic tumors had an altered tumor microenvironment (TME) with reduced collagen deposition and metastatic liver invasion. Together, this study demonstrated that KRASG12R is capable of driving tumorigenesis despite the reduced ERK/MAPK nuclear translocation and transcriptional output. Although human KRASG12D and KRASG12R-mutant tumors display unexpected similarities in PI3K activity, the differential ERK/MAPK signaling activity and the extrinsic consequences on the TME provide support for using KRASG12R mutation status as a prognostic biomarker for therapeutic strategies.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-2630
Cell Commun Signal. 2026 Jan 20.

Peripheral lysosome levels dictate mTORC1 inactivation even when catabolically impaired.

Huy Quang Dang, Therése Forssén, Spyridon Pantelios, Aisegkioul Nteli Chatzioglou, Ewa Kurzejamska, C Theresa Vincent, Yasir Ibrahim, Anders P Mutvei.

  The mechanistic target of rapamycin complex 1 (mTORC1) is a central driver of cell growth that is frequently hyperactivated in cancer. While mTORC1 is activated at the lysosomal surface in response to growth factors and amino acids, the processes governing its inactivation are not fully understood. Here, we report that sustained mTORC1 suppression during leucine or arginine starvation requires the translocation of peripheral lysosomes to the perinuclear region. Our data suggest that a pool of mTOR remains active at peripheral lysosomes during starvation, and that increased spatial separation between lysosomes and the plasma membrane attenuates PI3K/Akt signaling-thereby reducing inputs that otherwise maintain mTORC1 activity. Consequently, preventing lysosome translocation and increasing peripheral lysosome levels sustains mTORC1 signaling during prolonged starvation in a PI3K/Akt-dependent manner independently of autophagy. Under these conditions, mTORC1 signaling persists even when lysosomal catabolism is perturbed by chloroquine or concanamycin A. Collectively, these data indicate that the peripheral lysosome pool, even when catabolically impaired, can sustain mTORC1 signaling under nutrient scarcity, by modulating PI3K/Akt signaling input to the pathway. These observations identify peripheral lysosome levels as a critical determinant of mTORC1 inactivation during nutrient stress and may have implications for diseases with aberrant mTORC1 signaling, including cancer.

Keywords:  Amino acid deprivation; Catabolically impaired lysosomes; Lysosome positioning; MTORC1; PI3K-Akt signaling; Rab7; Rap1

DOI:  https://doi.org/10.1186/s12964-026-02659-9
Nat Mater. 2026 Jan 19.

Cell viscosity influences haematogenous dissemination and metastatic extravasation of tumour cells.

Valentin Gensbittel, Zeynep Yesilata, Louis Bochler, Gautier Follain, Laurie Nemoz-Billet, Olivier Lefebvre, Klemens Uhlmann, Annabel Larnicol, Giulia E M Ammirati, Sébastien Harlepp, Ruchi Goswami, Salvatore Girardo, Laetitia Paulen, Vincent Hyenne, Vincent Mittelheisser, Tristan Stemmelen, Anne Molitor, Raphael Carapito, Guillaume Belthier, Julie Pannequin, Martin Kräter, Daniel J Müller, Daniel Balzani, Jochen Guck, Naël Osmani, Jacky G Goetz.

Metastases arise from a multistep process during which tumour cells face several microenvironmental mechanical challenges, which influence metastatic success. However, how circulating tumour cells (CTCs) adapt their mechanics to such microenvironments is not fully understood. Here we report that the deformability of CTCs affects their haematogenous dissemination and identify mechanical phenotypes that favour metastatic extravasation. Combining intravital microscopy with CTC-mimicking elastic beads, mechanical tuning in tumour lines and profiling of tumour-patient-derived cells, we demonstrate that the inherent mechanical properties of circulating objects dictate their ability to enter constraining vessels. We identify cellular viscosity as a rheostat of CTC circulation and arrest, and show that cellular viscosity is crucial for efficient extravasation. Moreover, we find that mechanical properties that favour extravasation and subsequent metastatic outgrowth can be opposite. Altogether, our results establish CTC viscosity as a key biomechanical parameter that shapes several steps of metastasis.

DOI: https://doi.org/10.1038/s41563-025-02462-w
Proc Natl Acad Sci U S A. 2026 Jan 27. 123(4): e2520399123

The molecular mechanism of lipid uptake by membrane-anchored bridge-like lipid transfer proteins.

Daniel Álvarez, Paige Chandran Blair, Cristian Rocha-Roa, Michael Davey, Elizabeth Conibear, Stefano Vanni.

  Lipid transport by bridge-like lipid transfer proteins (BLTPs) is emerging as a key process in lipid and cellular metabolism in both physiological and pathological conditions. However, the precise mechanism of lipid transport by BLTPs has remained elusive. Here, we use extensive all-atom molecular dynamics simulations to characterize the precise mechanism of lipid transfer into the BLTP hydrophobic cavity from donor membranes. For multiple BLTPs, we observe the ability to extract and solubilize lipids without lipid selectivity, and we identify membrane destabilization as a critical parameter to achieve effective lipid desorption. We rationally design a mutant BLTP with altered ability to destabilize lipid bilayers, and we show that this abolishes lipid desorption in silico and protein function in vivo. Taken together, our data provide an atomic-level description of the mechanism of lipid transport by BLTPs, ultimately suggesting alternative strategies to interfere with their activity.

Keywords:  lipid membranes; lipid transport; membrane trafficking; molecular dynamics; organelle

DOI:  https://doi.org/10.1073/pnas.2520399123
Proc Natl Acad Sci U S A. 2026 Jan 27. 123(4): e2511733123

Selective targeting of NRF2-high pancreatic ductal adenocarcinoma with an NQO1-activatable prodrug.

Laura Antonucci, Kosuke Watari, Yechen Feng, Jingjing Qi, Mandy Zhu, Tingya Wang, Isabella Ng, Emily A Vucic, Irene Riahi, Li Huang, Mojgan Hosseini, Evangeline Mose, Randall French, Jonathan Weitz, Dafna Bar-Sagi, David W Dawson, Beicheng Sun, Herve Tiriac, Jinyi Xu, Shengtao Xu, Andrew M Lowy, Michael Karin.

  Activation of transcription factor NRF2 in pancreatic ductal adenocarcinoma (PDAC) promotes aggressive tumor phenotype and protection from therapy-induced oxidative stress. We postulated that NRF2high PDAC can be selectively targeted by C29h, a prodrug that is activated by the NRF2-induced enzyme NAD(P)H:quinone oxidoreductase-1 (NQO1), which is elevated in human pancreatic tumors. Initial evaluations of C29h alone or together with the standard-of-care chemotherapeutic drug gemcitabine were conducted on NQO1high human and mouse PDAC cell lines and patient-derived organoids. As PDAC is enriched in collagen-containing extracellular matrix (ECM) that activates NRF2 and induces NQO1 expression, we examined the ECM effect on the response to C29h, as well as in vivo tumor control in IKKα-deficient KrasG12D/IkkαΔPEC mice in which NRF2 is strongly activated, immunocompromised Nu/Nu mice orthotopically transplanted with human PDAC cells and C57BL/6n and NOD/SCID mice transplanted with mouse PDAC. C29h led to NQO1-dependent killing of human and mouse PDAC cell lines and organoids and acted additively with gemcitabine. Furthermore, ECM-plated PDAC cells were more susceptible to C29h cytotoxicity than cells grown on plastic. Importantly, C29h treatment induced tumor regression and increased the survival of PDAC-bearing mice and optimal C29h-induced tumor regression was dependent on CD8+ T lymphocytes whose tumoral recruitment was enhanced by drug treatment. This study supports the use of C29h alone or as part of a drug combination as an effective and promising strategy for selective eradication of NRF2high PDAC.

Keywords:  NQO1; PDAC; prodrugs

DOI:  https://doi.org/10.1073/pnas.2511733123
bioRxiv. 2025 Dec 05. pii: 2025.12.01.691614. [Epub ahead of print]

Longitudinal analysis of matched patient biospecimens reveals Neural Reprogramming of Cancer-Associated Fibroblasts Following Chemotherapy in Pancreatic Ductal Adenocarcinoma.

Aylin Z Henstridge, Nandini Arya, Ahmed M Elhossiny, Padma Kadiyala, Georgina Branch, Vaibhav Sahai, Nicole Peterson, Jorge Machicado, Richard Kwon, Allison Schulman, Erik Wamsteker, George Philips, Stacy Menees, Jonathan Xia, Arvind Rao, Jiaqi Shi, Timothy Frankel, Filip Bednar, Marina Pasca di Magliano, Costas A Lyssiotis, Mark Truty, Martin Fernandez-Zapico, Eileen S Carpenter.

Pancreatic ductal adenocarcinoma (PDAC) has poor response to chemotherapy with a strong likelihood of recurrence. While previous studies have examined patient samples collected before and after chemotherapy, few have analyzed matched samples from the same patients to allow for deconvolution of interpatient heterogeneity, a large limitation to PDAC studies. Here, we study the effects of chemotherapy on the tumor microenvironment using scRNA sequencing of matched pre- and post- treatment tissue biopsies from 5 patients. While immune subsets were heterogeneously affected by chemotherapy treatment, we found near-universal enrichment of axonal guidance genes in cancer associated fibroblasts (CAFs) post-treatment. We validated the in-situ expression of these genes in patient-derived PDAC tissues and observed that these neural CAFs localized near regions of perineural invasion, where tumor cells had increased proliferation. Furthermore, predicted ligand-receptor interactions between these CAFs and tumor cells further predicts that these CAFs have the potential to drive tumor progression.

DOI: https://doi.org/10.64898/2025.12.01.691614
J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70183

Distinct Metabolomic Alterations Are Associated With Physical Function, Weight Loss, and Muscle Mass in Men With Cancer.

Lindsey J Anderson, Lu Xia, Haiming Kerr, Marin Cabrera, Fabien Chu, Jaqueline Rose, Peter C Wu, Atreya Dash, Sina A Gharib, Jose M Garcia.

   BACKGROUND: Treatments for cancer cachexia, defined as involuntary weight and muscle mass loss leading to significant functional impairment, remain unavailable partly due to insufficient improvement of clinically meaningful outcomes in current trials. By reflecting downstream effects of cellular function, metabolomics may identify mechanisms contributing to poor functional performance. Previous metabolomic studies in cancer cachexia have identified alterations in amino acid metabolism with weight loss or low muscularity; none have examined perturbations with poor physical function. We hypothesized that distinct metabolic signals in plasma and muscle are associated with weight loss, low muscle mass, and impaired function in cancer cachexia.
METHODS: We enrolled patients planning elective laparotomy for gastrointestinal or genitourinary cancer. Handgrip strength (HGS), stair climb power (SCP), and fasting plasma were collected within 2 weeks prior to surgery; rectus abdominis samples were obtained during surgery. Metabolomic perturbations associated with physical function (HGS, SCP), muscularity (lumbar cross-sectional area 'CSA' from opportunistic CT), or weight loss (> 5% over previous 6 months) were examined in plasma and muscle. The Mann-Whitney U-test compared metabolite abundance between weight-losing and weight-stable patients, while Spearman's correlation tested associations of abundance with CSA, HGS, or SCP. The 'Globaltest' method assessed pathway alterations with weight loss, CSA, HGS, or SCP; the Benjamini-Hochberg adjustment was used to control for false discovery.
RESULTS: Patients (N = 72) were male, median age 65 [interquartile range: 59-70], with 57% genitourinary cancer. Plasma and skeletal muscle metabolomic data were collected (N = 64 and N = 68, respectively). Weight loss was associated with significantly altered microbial, amino acid/derivative, fatty acid/lipid, and caffeine-related metabolism pathways in plasma (adjusted p < 0.1). Lower CSA was associated with significantly altered fatty acid/lipid, galactose, glycerophospholipid, and histidine metabolism and bile secretion pathways in skeletal muscle (adjusted p < 0.1). Worse HGS was nominally associated with altered plasma branched chain amino acid biosynthesis and altered skeletal muscle glutathione metabolism (unadjusted p ≤ 0.05), while worse SCP was nominally associated with altered skeletal muscle amino sugar/nucleotide sugar metabolism and phenylalanine, tyrosine, and tryptophan biosynthesis (unadjusted p ≤ 0.05).
CONCLUSIONS: Significant metabolomic alterations in plasma and skeletal muscle characterized cancer-related weight loss and reduced CSA, respectively. Nominal, function-specific alterations were detected with worse HGS and SCP, which were distinct from those associated with weight loss or low CSA. Future larger studies may further characterize metabolomic profiles related to various functional outcomes and guide development of therapeutic targets to improve functional performance.

Keywords:  cancer cachexia; functional impairment; handgrip; metabolomics; skeletal muscle; stair climb

DOI:  https://doi.org/10.1002/jcsm.70183
Proc Natl Acad Sci U S A. 2026 Jan 27. 123(4): e2523465123

ER membrane receptors engage core autophagy machinery to initiate ER-phagy.

Cha Wu, Haixia Yang, Chen Wang, Peiqi Huang, Ning Yan, Ruobing Ren, Wei Liu, Yi Lu, Chunmei Chang.

  Endoplasmic reticulum (ER) phagy is the form of selective autophagy that governs ER abundance and integrity by targeting dysfunctional ER fragments for degradation. How the recognition of ER fragments as autophagy substrates is coupled to engagement of the core autophagic machinery is largely unknown. Here, using a combination of in vitro reconstitution systems, structural modeling, and cell biology, we demonstrate that ER membrane receptors directly engage the core autophagy component ATG9A, as well as the PI3P-binding protein WIPI2, to initiate ER-associated autophagosome biogenesis. ER-phagy receptor-ATG9A association nucleates the recruitment of the other key autophagy proteins required to initiate ER-phagy. In parallel, ER-phagy receptor-WIPI2 engagement promotes rapid LC3 lipidation for autophagic membrane expansion. These data show how ER-phagy receptors trigger the cascade of events leading to ER autophagosome formation.

Keywords:  ER-phagy; ER-phagy receptor; autophagosome biogenesis; autophagy machinery; in vitro reconstitution

DOI:  https://doi.org/10.1073/pnas.2523465123
Nat Commun. 2026 Jan 19.

Guardian ubiquitin E3 ligases target cancer-associated APOBEC3 deaminases for degradation to promote human genome integrity.

Irene Schwartz, Valentina Budroni, Mathilde Meyenberg, Zuzana Hodakova, Harald Hornegger, Kathrin Hacker, Siegfried Schwartz, Daniel B Grabarczyk, Julian F Ehrmann, Sara Scinicariello, David Haselbach, Jörg Menche, Tim Clausen, G Elif Karagöz, Gijs A Versteeg.

APOBEC family members play crucial roles in antiviral restriction. However, certain APOBEC3 (A3) proteins drive harmful hypermutation in humans, contributing to cancer. The cancer-associated A3 proteins are capable of transiting from the cytosol to the nucleus, where they can cause genome mutations. Here, we uncover a specific set of cellular pathways that protect genomic DNA from the major cancer-associated A3 proteins. Through genetic and proteomic screening, we identify UBR4, UBR5, and HUWE1 as key ubiquitin E3 ligases marking cancer-associated A3B and A3H-I for degradation, thereby limiting A3-driven hypermutation. Mechanistically, UBR5 and HUWE1 recognize A3s in the absence of their RNA binding partner, thus promoting proteasomal degradation of APOBEC3 protein that is not engaged in its antiviral cellular function. Depletion or mutation of the E3 ligases in cells and human cancer samples increases A3-driven genome mutagenesis. Our findings reveal that UBR4, UBR5, and HUWE1 are crucial factors in a ubiquitination cascade that maintains human genome stability.

DOI: https://doi.org/10.1038/s41467-026-68420-5
Cytokine Growth Factor Rev. 2026 Jan 13. pii: S1359-6101(26)00004-3. [Epub ahead of print]88 47-57

GDF15 in the tumor microenvironment: A central mediator of cancer immunometabolism and therapeutic resistance.

Lingeng Lu, Caroline H Johnson, Sajid A Khan, Melinda L Irwin.

  Growth differentiation factor 15 (GDF15), a divergent member of the transforming growth factor-β (TGFβ) superfamily, has emerged as a pivotal cytokine linking cancer metabolism, immune suppression, and systemic energy balance. Initially characterized as a stress-induced cytokine with roles in appetite regulation and cachexia, GDF15 was first identified in activated macrophages and is also secreted by tumor cells, stromal cells and stressed epithelial cells across multiple tissues. Functionally, GDF15 exerts pleiotropic effects on both immune and nonimmune cell populations, modulating T cells, dendritic cells, and macrophages in the tumor microenvironment (TME), and metabolic tissues such as liver, adipose and muscle, thereby promoting tumor progression, therapeutic resistance, and cancer-associated metabolic dysregulation. In several human cancers of such as colorectal, pancreatic, breast and brain, elevated GDF15 levels correlate with poor prognosis, immune evasion, and chemoresistance. Mechanistically, GDF15 modulates fatty acid metabolism, promotes epithelial-mesenchymal transition, and suppresses anti-tumor immunity by impairing dendritic cell maturation and excluding CD8+ T cell infiltration. Targeting GDF15 may reprogram immunometabolic suppression and enhance checkpoint blockade efficacy. This review synthesizes current knowledge on GDF15's multifaceted roles in tumor biology, emphasizing its function as a central node of cancer immunometabolism. We highlight advances in spatial multi-omics, integrating transcriptomics and immune imaging, that reveal GDF15 spatially restricted immunosuppression in the tumor microenvironment.

Keywords:  Cancer immunotherapy; Colorectal cancer; GDF15; Immunometabolism; Obesity; Pancreatic cancer; Spatial metabolomics; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.cytogfr.2026.01.004
Mol Cancer. 2026 Jan 17.

Ferroptosis in cancer toward molecular insights and clinical translation in pancreatic cancer.

Qun Chen, Fengyuan Liu, Yufeng Zhang, Lingtao Yan, Yang Wu, Dong Xu, Pengfei Wu, Hao Yuan, Kuirong Jiang.



Keywords:  Cancer metabolism; Ferroptosis; Molecular mechanism; Regulated cell death; Therapeutic significance; Translational medicine

DOI:  https://doi.org/10.1186/s12943-025-02567-5
Nano Lett. 2026 Jan 22.

Dual-Color Expansion Microscopy of Membrane Proteins Using Bioorthogonal Labeling.

Steven Edwards, Birthe Meineke, Sebastian Bauer, Hans Blom, Simon Elsässer, Hjalmar Brismar.

  With recent advances in fluorescence microscopy, resolution is often limited by the size of the label and the resulting linkage error, rather than the microscope itself. Site-specific incorporation of noncanonical amino acids (ncAAs) combined with bioorthogonal click chemistry provides a powerful tool for fluorescent protein labeling, overcoming the spatial uncertainty inherent to antibody-based probes. Here, we present a method to further improve labeling precision by combining ncAA labeling with expansion microscopy (ExM) for dual-color super-resolution imaging. After optimizing labeling procedures and fluorophore selection, we visualize and resolve the nanoscale distribution of Na,K-ATPase α1 and β1 subunits in expanded HEK 293T cells. We validate our approach by super-resolution STED imaging of the ncAA labeled β1 subunit in unexpanded cells. This work presents a strong framework for multiplexed, high-resolution imaging, suggesting that ncAA labeling combined with ExM enables biological imaging at the nanometer scale.

Keywords:  Bioorthogonal chemistry; Expansion microscopy; Linkage error; Noncanonical amino acids; Site-specific labeling; Super-resolution microscopy

DOI:  https://doi.org/10.1021/acs.nanolett.5c05301
J Cell Biol. 2026 Mar 02. pii: e202504025. [Epub ahead of print]225(3):

Mechanometabolism of cell adhesion: Vinculin regulates bioenergetics via RhoA-ROCK.

Emily D Fabiano, Elle P Techasiriwan, Lindsey N Sabo, Nathaniel Seluga, Brenton D Hoffman, Cynthia A Reinhart-King.

Cell migration and cytoskeletal remodeling are energetically demanding processes. Reorganizing the cytoskeleton requires ATP to fuel the actomyosin complex, enabling cells to adhere to and migrate through a matrix. While it is known that energy is required for cell migration, the mechanism by which cell-extracellular matrix adhesion influences cell energetics is unclear. Here, we investigated the relationship between cell-extracellular matrix adhesion and cellular metabolic state with a focus on vinculin given its role in connecting the cytoskeleton to focal adhesions and extracellular space. Knocking out vinculin increases the metabolic activity in cells and results in fast, frequent Rho kinase activity-dependent changes in cell shape and protrusions. The cellular protrusion dynamics and bioenergetics are interrelated processes, as stimulating RhoA/Rho kinase activity increases dynamic blebbing protrusions and energy production, and inhibiting metabolism decreases the frequency of blebbing cell protrusions. This link between cell-extracellular matrix adhesion and bioenergetics provides a novel basis by which cellular metabolism and cell migration could be controlled.

DOI: https://doi.org/10.1083/jcb.202504025
Sci Adv. 2026 Jan 23. 12(4): eadz9227

Aberrant methylation limits antitumoral inflammation in lung adenocarcinoma by restricting RIPK3 expression.

Deepti Agrawal, Katarina Cisarova, Sebastian Vosberg, Fabian Allmendinger, Enkhtsetseg Munkhbaatar, Nadia Dandachi, Francisco Jose Fernandez Hernandez, Marta Tonietto, Vanessa Jäger, Martina Anton, Eva C Keller, Moritz Jesinghaus, Anna-Lena Meinhardt, Verena Haefner, Tobias Stoeger, Katja Steiger, Nicholas McGranahan, Michael A Dengler, Adam Wahida, Philipp J Jost.

Evasion of programmed cell death is a critical hallmark of cancer. However, the contribution of inflammatory forms of cell death in lung carcinogenesis and their effects on the composition of the tumor-immune microenvironment remain unclear. Our multi-omics analyses of samples from patients with primary lung adenocarcinoma revealed that necrosome signaling is repressed because of reduced expression of receptor-interacting protein kinase 3 (RIPK3). Distinct methylation signatures, both in the RIPK3 promoter and nonpromoter regions, correlated with lower transcription levels of RIPK3. This resulted in limited expression of inflammatory genes, advanced histologic features, reduced immune cell invasion, and decreased patient survival. Mechanistically, we confirmed the tumor-suppressive role of necrosome signaling through the genetic deletion of Ripk3 in two independent, clinically relevant mouse models of lung adenocarcinoma. Functionally, RIPK3 shaped a diverse immune environment by promoting the invasion of innate and adaptive immune cells in patient samples and experimental mice. Thus, RIPK3-mediated inflammatory signaling enhances a diverse immune microenvironment and hinders progression in lung adenocarcinoma.

DOI: https://doi.org/10.1126/sciadv.adz9227
bioRxiv. 2025 Dec 03. pii: 2025.12.01.691659. [Epub ahead of print]

TGFβ signaling regulates the response of the skeleton to phosphate.

Emily K Zhu, Dylan P Kuennen, Long Tran, Parthena E Kostalidis, Michael Mannstadt, Lauren E Surface.

Inorganic phosphate (Pi) homeostasis is crucial to organismal health, yet the mechanisms underlying the regulation of it remain unclear. Critically, we lack a clear understanding of the Pi response circuitry in osteogenic cells that identifies altered serum Pi levels and transmits this information to changes in serum FGF23 levels, a key hormone regulating circulating Pi. We utilized genome-wide CRISPR screens in osteogenic Pi-responsive fluorescent reporter cell lines to identify regulators of the response to high phosphate, intersecting those results with loci associated with circulating FGF23 levels by genome-wide association studies (GWAS) and identified a potential role for TGF-β2. We found that each of the three ligands (TGF-β1, 2, 3) can enhance the response to Pi in osteogenic cell lines and ex vivo cultures of calvariae, while inhibitors of TGFβ receptor signaling dampen it. Co-treatment of Pi with TGFβ ligands led to an elevated, synergistic transcriptional induction of Slc20a1 , which encodes a key Pi importer, which corresponded with an increased intracellular uptake of phosphate. Furthermore, in mice, blocking TGFβ signaling disrupted the induction of FGF23 in mice on a high phosphate diet, resulting in disrupted downstream endocrine control of phosphate homeostasis. Together, these findings reveal a role for TGFβ signaling in the regulation of phosphate homeostasis in osteogenic cells through regulation of cellular phosphate uptake, which in turn contributes to the maintenance of organismal phosphate homeostasis.

DOI: https://doi.org/10.64898/2025.12.01.691659
Cancer Lett. 2026 Jan 19. pii: S0304-3835(26)00015-7. [Epub ahead of print] 218252

The vulnerabilities of chemotherapy resistant pancreatic cancer revealed by organoids of pre- and post- neoadjuvant therapy.

Huan Wang, Yunguang Li, Shijie Tang, Yikai Li, Yehan Zhang, Xiaoyi Yin, Juan He, Yiqin Zhu, Yi Zhang, Xiaohan Shi, Maoyuan Sun, Suizhi Gao, Bo Li, Lingyu Zhu, Shuai Yuan, Yaqi Pan, Meilong Shi, Penghao Li, Chuanqi Teng, Chaoliang Zhong, Xiaolu Yang, Zhendong Fu, Xinyu Liu, Xiaochao Kang, Yining Kang, Wenjie Li, Kailian Zheng, Bin Song, Wei Jing, Xiongfei Xu, Shiwei Guo, Luonan Chen, Dong Gao, Gang Jin.

Pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to intrinsic and acquired chemotherapy resistance, particularly after neoadjuvant therapy (NAT). To uncover therapy-induced vulnerabilities, we established matched patient-derived organoids from PDAC tissues obtained before and after NAT, creating a unique platform to track treatment-driven evolution. Comparative analysis of these organoids revealed negligible variation in key driver gene mutations but identified a transition from classical to basal-like subtype in one patient after neoadjuvant therapy. Notably, albumin-bound paclitaxel and gemcitabine (AG) treatment induced the resistance to paclitaxel, accompanied by elevated KRAS and MAPK signaling, which was confirmed by transcriptomic comparison of PDAC patient samples with (30 cases) and without (60 cases) AG treatment. Single-cell RNA sequencing of the organoid-derived xenografts revealed AG treatment promoted the emergence of resistant cell clusters characterized by KRAS and MAPK signaling activation. Importantly, EGFR/KRAS/BRAF signaling inhibitors effectively suppressed the growth of AG-resistant PDAC organoids. In a validation cohort of 29 organoids, pan-KRAS inhibitors exhibited superior efficacy against the residual organoids after AG treatment. These results provided insights into molecular changes in PDAC during treatment process and demonstrate that AG chemotherapy can activate the KRAS and MAPK signaling, presenting a potential target for therapeutic intervention.

DOI: https://doi.org/10.1016/j.canlet.2026.218252
Cancer Discov. 2026 Jan 21.

Preclinical Characterization and Clinical Activity of RNK08954, a Highly Selective and Orally Bioavailable KRAS G12D Inhibitor.

Ling Xie, Chunwei Xu, Han Si, Xiaoshuang Fu, Xiangcai Yang, Jianan Jin, Xiaoqing Yu, Zhiying Shao, Yanling Wang, Tianqing Chu, Jun Zhang, Rong Liang, Rui Meng, Yuchen Fei, Haolin Song, Chenghao Ying, Yan Dai, Yaya Wang, Iman Ei-Hariry, Guoqiang Wang, Weiwen Ying, Zhengbo Song.

KRAS G12D is the most prevalent subtype of KRAS mutation across solid tumors, but no drug is available in the clinic. RNK08954 is a potent and selective KRAS G12D inhibitor that inhibits proliferation of KRAS G12D-mutant cells and demonstrates significant tumor regressions in mouse xenograft models while inhibiting KRAS-mediated signaling. The in vivo effects of RNK08954 are explained by its unique pharmacokinetic (PK) profile and significantly prolonged retention time in tumor tissues. RNK08954 shows synergy with immune check blockade (ICB). In a Phase 1a study, the median follow-up was 4.85 months for 36 evaluable patients. In patients with non-small cell lung cancer (NSCLC), the objective response rate (ORR, unconfirmed) is 58.33%, and in patients with pancreatic ductal adenocarcinoma (PDAC) the ORR (unconfirmed) was 33.33% in the 1000-1200mg cohort. This study supports the clinical potential of RNK08954 in patients with KRAS G12D mutation either as a single agent or in combination.

DOI: https://doi.org/10.1158/2159-8290.CD-25-1346
J Physiol. 2026 Jan 20.

Lactate sensing by Carotid Bodies: Is it necessary for ventilatory responses to exercise?

Pedro F Spiller, Davi J A Moraes.



Keywords:  carotid body; exercise physiology; lactate

DOI:  https://doi.org/10.1113/JP290374
Nat Commun. 2026 Jan 19.

Disruption of iron homeostasis sensitizes pancreatic cancer to irreversible electroporation.

Linrong Li, Shihao Su, Zhishan Wang, Shuguo Sun, Yugang Wang, Hui Xu, Xin Long, Tao Yin, Jun Zhao.

Irreversible electroporation (IRE) is an ablative treatment for pancreatic cancer. It utilizes high-intensity pulsed electric field (PEF) to eliminate cancer cells by irreversibly disrupting cell membranes. However, PEF intensity is distributed unevenly; and cancer cells may survive in regions where it falls below the threshold of complete ablation. We find that iron-base metal organic framework nanoparticles (MOF-Fe) sensitize pancreatic cancer cells to PEF by inducing iron overload and ferroptosis. But their efficacy is diminished by the upregulation of ferritin heavy chain 1 (FTH1), a cellular response to restore iron homeostasis. C20U4V, a proteolysis targeting chimera (PROTAC) derived from arachidonic acid, degrades FTH1 and potentiates MOF-Fe-induced ferroptosis. It is then encapsulated in reactive oxygen species (ROS)-responsive micelles. The resulting M-C20U4V, when combined with MOF-Fe, efficiently induces ferroptosis and boosts PEF ablation efficacy. Therefore, disruption of iron homeostasis represents a potential strategy to lower the risk of tumor recurrence after IRE.

DOI: https://doi.org/10.1038/s41467-026-68585-z
Nat Chem Biol. 2026 Jan 22.

Targeting thymine DNA glycosylase induces synthetic lethality in p53-deficient cancers.

Jia-Xin Zhou, Zhen-Yu Shao, Lin Zhang, Jian-Nan Guo, Meng Wang, Qin Xu, Yi-Qin Wang, Qing Xu, Dan Zhou, Sheng-Xiang Ren, Yan-Hao Yu, Zhi-Hao Lu, Guo-Zheng Pang, Yao Cao, Yi-Lin Liu, Bin Zhou, Hong-Bin Ji, Yi-Han Chen, Hai-Ping Wu, Guo-Liang Xu, Liang Zhang, Ya-Rui Du.

Thymine DNA glycosylase (TDG) is a multifaceted protein involved in base-excision repair, DNA demethylation and transcriptional regulation, with key roles in embryonic development and tumorigenesis. However, the mechanisms underlying its role in cancer progression and the therapeutic applications targeting TDG remain largely unknown. Here we demonstrate that targeting TDG induces synthetic lethality in p53-deficient cancers. We developed C-271, a first-in-class, small-molecule inhibitor that covalently binds to TDG, disrupting its DNA-binding capability. C-271 exhibits potent therapeutic efficacy in suppressing p53-deficient tumors. Mechanistically, TDG and p53 redundantly promote the transcription of DHX9, an RNA helicase that resolves double-stranded RNA (dsRNA). TDG inhibition in p53-deficient cancer cells leads to DHX9 downregulation and, thus, aberrant dsRNA accumulation, which activates the RIG-I/MDA5-MAVS sensing pathway, resulting in tumor suppression and enhanced antitumor immunity. These findings highlight the synthetic lethality between TDG and p53, positioning TDG inhibition as a promising therapeutic strategy for p53-deficient cancers.

DOI: https://doi.org/10.1038/s41589-025-02100-1
Neuron. 2026 Jan 19. pii: S0896-6273(25)00886-4. [Epub ahead of print]

CLN3 mediates chloride efflux from lysosomes.

Yayu Wang, Kai Li, Wei Chen, Chao Chen, Adeline J H Yong, Xiaofan Zhang, Marena Tynan-La Fontaine, Yuh Nung Jan, Lily Yeh Jan.

  Neurodegenerative diseases, which pose significant challenges for effective treatment, often involve risk variants of lysosomal gene products that disrupt lysosomal function, leading to the accumulation of indigestible materials and damage to brain cells. The lysosome is a degradative organelle and a signaling hub that senses nutrient availability. How lysosomal dysfunction contributes to neurodegenerative diseases is an important open question. In this study, we identified CLN3 (ceroid lipofuscinosis, neuronal 3), an endolysosomal protein that is linked to Batten disease, as an evolutionarily conserved protein that facilitates lysosomal chloride efflux. Additionally, we report that a natural compound with anti-inflammatory properties-the curcumin analog C1, which is a TFEB (transcription factor EB) activator-could enhance CLN3 activity and improve lysosomal function. These findings provide new insight into the role of CLN3 in lysosomal ion homeostasis and raise the possibility that modulation of the TFEB-CLN3 signaling axis may hold therapeutic potential for lysosomal storage disorders.

Keywords:  Batten disease; CLN3; chloride channel; lysosome; neurodegenerative disease

DOI:  https://doi.org/10.1016/j.neuron.2025.11.013
QRB Discov. 2026 ;7 e2

Infrared nanoscopy for subcellular chemical imaging.

Katerina Kanevche, David Joll Burr, Janina Drauschke, Jacek Kozuch, Carlos Baiz, Andreas Elsaesser, Joachim Heberle.

  Infrared (IR) nanoscopy represents a collection of imaging and spectroscopy techniques capable of resolving IR absorption on the nanometer scale. Chemical specificity is leveraged from vibrational spectroscopy, while light-matter interactions are detected by observing perturbations in the optical near field with an atomic force microscopy probe. Therefore, imaging is wavelength independent and has a spatial resolution on the nanometer scale, well beyond the classical diffraction limit. In this perspective, we outline the recent biological applications of scattering type scanning near-field optical microscopy and nanoscale Fourier-transform IR spectroscopy. These techniques are uniquely suited to resolving subcellular ultrastructure from a variety of cell types, as well as studying biological processes such as metabolic activity on the single-cell level. Furthermore, this review describes recent technical advances in IR nanoscopy, and emerging machine learning supported approaches to sampling, signal enhancement, and data processing. This emphasizes that label-free IR nanoscopy holds significant potential for ongoing and future biological applications.

Keywords:  O-PTIR; machine learning; organelle mapping; super resolution; vibrational spectroscopy

DOI:  https://doi.org/10.1017/qrd.2025.10014