bims-cagime 2026-07-12 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2026–07–12
27 papers selected by
Kıvanç Görgülü, Technical University of Munich

Lipid packing contributes to the confinement of caveolae to the plasma membrane.
Active regulation of intrinsic curvature by eukaryotic phospholipid metabolism.
Going beyond total skeletal muscle area at L3 (tSMA) to accurately assess pancreatic cancer cachexia.
Targeting lysosomes with a novel chloroquine derivative induces irreversible lysosomal damage and disrupts autophagosome and lysosome assembly in cancer.
Spatial multi-omics landscape of colorectal cancer macro- and micrometastases.
Accumulation of p62/sequestosome-1 in pancreatic cancer progression: association with inflammation and immune cell infiltration.
Aneuploidy selects for the acquisition of driver genes in breast cancer.
Tissue mechanopathology of cancer.
CODAvision: best practices and a user-friendly interface for rapid, customizable segmentation of medical images.
Sealing and healing: A two-step model for plasma membrane repair.
Metastasis as a breakdown of the multicellular social contract.
KRAS-G12D inhibitor HRS-4642 plus chemotherapy in advanced KRASG12D-mutant pancreatic cancer: a phase 1b/2 trial.
Neuron-tumor communication in solid tumors: from bona fide synapses to pseudo-synaptic neural interfaces.
Vertical inhibition of the autophagy pathway impairs growth and enhances sensitivity to mTORC1 inhibition in pancreatic ductal adenocarcinoma.
Nanomechanical Phenotyping of Circulating Tumor Cells with Atomic Force Microscopy.
Periodic Fracture of Active Tissues.
Metastasis in biological time.
Autophagy in cancer - functional plasticity, therapeutic paradox, and the road to precision modulation: a comprehensive review.
FerroScore: a statistical approach for quantifying tumor-related ferroptosis based on omics data.
De Novo Designed Minibinders Targeting the GDF15-GFRAL Axis Reverse Cancer Cachexia and Restore Anti-Tumor Immunity.
Glycan atlasing in cells and tissues.
Targeting Cystine Addiction Suppresses Breast Cancer Lung Metastasis.
Senescent cells accumulate lipid droplets.
Fibroblasts: a diverse population of cells balancing homeostasis, wound healing, regeneration, inflammation, fibrosis, and cancer across organs.
Intrinsic polyunsaturated fatty acid synthesis capacity dictates ferroptosis sensitivity under restricted arachidonic acid availability.
Multi-metal cooperation drives chemoresistance in lung cancer and is reversed by the membrane-permeable chelator MiADMSA.
Cell chirality in cancer: Emerging roles in malignant progression and tumor metastasis.

Elife. 2026 07 06. pii: RP108369. [Epub ahead of print]14

Lipid packing contributes to the confinement of caveolae to the plasma membrane.

Elin Larsson, Aleksei Kabedev, Hudson Pace, Jakob Lindwall, Fouzia Bano, James Rae, Robert G Parton, Christel A Bergström, Ingela Parmryd, Marta Bally, Richard Lundmark.

  Lipid packing is a fundamental characteristic of bilayer membranes. Yet, we lack detailed mechanistic understanding of how lipid packing directly affects membrane-associated cellular processes. Here, we address this by focusing on caveolae, small Ω-shaped invaginations of the plasma membrane, which serve as key regulators of cellular lipid sorting and mechano-responses. In addition to caveolae coat proteins, the lipid membrane is a core component of caveolae that critically impacts their biogenesis, morphology, and stability. We show that the small compound Dyngo-4a adsorbs and inserts into the membrane, resulting in a dramatic dynamin-independent inhibition of caveola dynamics. Analysis of model membranes in combination with molecular dynamics simulations revealed that a substantial amount of Dyngo-4a was inserted and positioned at the level of cholesterol in the bilayer, affecting lipid order in a cholesterol-dependent manner. Dyngo-4a treatment resulted in decreased lipid packing of the plasma membrane. This prevented caveolae internalization and lateral diffusion without affecting their morphology, associated proteins, or the overall cell stiffness. Artificially increasing plasma membrane cholesterol levels was found to counteract the block in caveola dynamics caused by Dyngo-4a. Therefore, we propose that the outer leaflet lipid packing of cholesterol in the plasma membrane critically contributes to the confinement of caveolae to the plasma membrane.

Keywords:  Dyngo-4a; caveolae; cell biology; computational biology; lipid packing; membrane curvature; none; systems biology

DOI:  https://doi.org/10.7554/eLife.108369
Cell Rep Phys Sci. 2026 May 20. pii: 103277. [Epub ahead of print]7(5):

Active regulation of intrinsic curvature by eukaryotic phospholipid metabolism.

Daniel Milshteyn, Jacob R Winnikoff, Elida Kocharian, Aaron M Armando, Edward A Dennis, Peter R Girguis, Itay Budin.

Membranes contain thousands of different lipids, but it is poorly understood why their compositions vary across cell types and environments. We report that lipid metabolism balances the molecular curvature of phospholipids, a parameter that describes their shape and propensity to destabilize flat sheets. We utilized extreme hydrostatic pressures-similar to those found in the deep ocean-to change the shape (reduce the curvature) of phospholipids in growing cells. Yeast and human cells respond to this stress by increasing synthesis of distinct high-curvature lipid species. The results support a model in which eukaryotic cells actively regulate lipid composition to maintain their membranes in a frustrated state, a dynamic that could be important for maintaining core functions in membrane trafficking.

DOI: https://doi.org/10.1016/j.xcrp.2026.103277
J Gastrointest Oncol. 2026 Jun 30. 17(3): 191

Going beyond total skeletal muscle area at L3 (tSMA) to accurately assess pancreatic cancer cachexia.

Rishi Surana, Kimberly J Perez.



Keywords:  Pancreatic cancer; cachexia; edema; sarcopenia

DOI:  https://doi.org/10.21037/jgo-2026-0221
Autophagy. 2026 Jul 06. 1-23

Targeting lysosomes with a novel chloroquine derivative induces irreversible lysosomal damage and disrupts autophagosome and lysosome assembly in cancer.

Nitish Chauhan, Ananda Guha Majumdar, Sujit Kumar Bhutia, Papiya Dey, Mahesh Subramanian, Birija Sankar Patro.

  Pancreatic ductal adenocarcinoma (PDAC) exhibits profound therapy resistance driven by lysosome-dependent nutrient recycling, metabolic adaptation, and stress tolerance. Current lysosome targeting agents such as chloroquine (CQ)/hydroxychloroquine (HCQ) show limited efficacy due to transient activity and dose-limiting-toxicities. To overcome these limitations, we developed lysostilbenes, a new class of hybrid small molecules combining the CQ pharmacophore with lysosome-disrupting stilbene analogs. Stilbene pharmacophore is the core structural component of resveratrol. Among the synthesized hybrids, lysostilbene-4 emerged as the lead candidate, demonstrating ~30-40-fold greater cytotoxicity against PDAC cells than parent compounds, while sparing nonmalignant cells. At nanomolar concentrations, lysostilbene-4 induced rapid, irreversible lysosomal membrane permeabilization (LMP), initiating a lysosome mitochondria apoptotic cascade via CTSB (cathepsin B) release, BID cleavage, BAX activation, and caspase-mediated apoptosis. In parallel, it abrogated lysosomal recovery by significantly reducing repair, lysophagy, autophagosome maturation, and uncoupling TFEB-driven transcriptional programs from effective lysosome biogenesis. Reduced TFEB mRNA expression correlated with poor overall-survival and disease-free-survival across multiple cancer patients, with a particularly strong association in pancreatic cancer patients. Using TFEB+/+ and TFEB-/- knockout pancreatic cancer cells we establish that lysostilbene-4 exerts severe cytotoxicity by inducing persistent lysosomal-damage and disrupting autophagosome-lysosome assembly, with vulnerability further amplified in TFEB-deficient cells. This finding underscores TFEB as a key determinant of lysosomal-resilience and a potential predictive biomarker. Importantly, lysostilbene-4 was well tolerated in preclinical mouse-models at supra-therapeutic doses without systemic-toxicity. These findings position lysostilbene-4 as a first-in-class lysosome-targeting therapeutic that enforces sustained lysosomal collapse while compromising adaptive recovery-mechanisms, providing a mechanistically precise and safe strategy against PDAC.Abbreviations: ALG: autophagy-lysosome genes; AMPK: AMP-activated protein kinase; CASM: conjugation of ATG8s to single membranes; CTSB: cathepsin B; LGALS3: galectin 3; LMP: lysosomal membrane permeabilization; LS: lysostilbene; MTOR: mechanistic target of rapamycin kinase; PDAC: pancreatic ductal adenocarcinoma; TCGA: The Cancer Genome Atlas; TFEB: transcription factor EB; ULK1: unc-51 like autophagy activating kinase 1.

Keywords:  Chloroquine; dihydroxystilbene; lysophagy; lysosome repair; lysostilbene; resveratrol

DOI:  https://doi.org/10.1080/15548627.2026.2693263
Cancer Cell. 2026 Jul 09. pii: S1535-6108(26)00296-5. [Epub ahead of print]

Spatial multi-omics landscape of colorectal cancer macro- and micrometastases.

Yang Liu, Akshaya S Jadhav, Yuwen Pan, Jianlong Liao, Isha Khanduri, Yunhe Liu, Riham Katkhuda, Wei Lu, Kyung Serk Cho, Zhimin Tong, Tieling Zhou, Kangyu Lin, Baohua Sun, Mei Jiang, Sharia D Hernandez, Idania Carolina Lubo Julio, Patrick Brennan, Guangsheng Pei, Kai Yu, Yibo Dai, Tian Chu, Fuduan Peng, Khaja Khan, Saxon Rodriguez, Ling Xia, Youming Guo, Alicia Mejia, Sean W Barnes, Ou Shi, Shreeya Indulkar, Alaa M T Mohamed, Natalie Wall Fowlkes, Timothy Newhook, Yun Shin Chun, Van K Morris, David Menter, Dadi Jiang, John Paul Shen, Ryan Sun, Jean-Nicolas Vauthey, Ruoyan Li, Humam Kadara, Luisa M Solis Soto, Scott Kopetz, Linghua Wang, Dipen Maru.

Colorectal cancer (CRC) metastases frequently recur due to minimal residual disease (MRD) and persistent micrometastases after therapy. Here, we performed spatial multimodal profiling using spot-level and high-resolution spatial transcriptomics, multi-regional whole-genome sequencing following laser-capture microdissection, and high-plex protein imaging to map 49 tumors from 19 patients, encompassing paired primary CRC and matched liver (CLiM) and lung (CLuM) metastases. Phylogenetic reconstruction revealed that liver micrometastases (CLiMi) arose from early clonal divergences and harbored a stem-like, quiescent state consistent with metastatic dormancy. Spatially, we uncovered distinct stromal barriers: macrometastases were encapsulated by myofibroblasts, whereas micrometastases were surrounded by immunosuppressive niches characterized by T cell exhaustion and distinct ligand-receptor signaling networks. Notably, we identified a CLiMi-specific six-gene signature associated with MRD status, disease-free survival, and chemotherapy resistance across multiple independent cohorts. These findings elucidate the spatial evolutionary landscape of CRC metastases and provide tissue-based spatially validated biomarkers for surveillance and therapeutic targeting.

DOI: https://doi.org/10.1016/j.ccell.2026.06.009
Pancreatology. 2026 Jul 07. pii: S1424-3903(26)00233-4. [Epub ahead of print]

Accumulation of p62/sequestosome-1 in pancreatic cancer progression: association with inflammation and immune cell infiltration.

Eva Philipson, Thayna Cruz, Cecilia Engström, Peter Naredi, Johan Bourghardt Fagman.

   BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer that develops from precursor lesions such as pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). The adaptor protein p62 links autophagy defects with oxidative stress and inflammatory signaling, but its role across disease stages is not well defined. We examined p62 expression together with markers of autophagy, metabolic stress responses, and inflammation in human pancreatic lesions and a Kras-driven mouse model.
METHODS: Formalin-fixed sections from 29 patients (PanIN2/3, n = 10; IPMN, n = 9; PDAC, n = 10) were analyzed by immunohistochemistry for p62, LC3B, NRF2, TFEB, phosphorylated NFκB p65, CD45, and CD3. Staining was quantified using digital pathology (QuPath). Parallel studies were conducted in Pdx1-Cre;LSL-KrasG12D mice aged 4-12 months, with blinded histological scoring.
RESULTS: p62 expression was higher in PDAC than in PanIN2/3 and IPMN (p < 0.01), while LC3B, NRF2, and TFEB showed no differences. Immune infiltration (CD45) was increased in PDAC versus PanIN2/3 (p < 0.01), whereas phosphorylated NFκB p65 did not differ between groups. Correlation analysis showed stage-specific associations: p62-LC3B in PanIN2/3, p62-CD45 in IPMN, and p62-TFEB in PDAC. In mice, p62 and phosphorylated NFκB p65 followed a biphasic pattern, peaking in early lesions, decreasing in PanIN, and rising again in PDAC.
CONCLUSION: These findings show that p62 accumulation is stage-dependent and is associated with inflammatory and immune changes during pancreatic cancer progression, suggesting a potential role in the transition to invasive PDAC.

Keywords:  Autophagy; Inflammation; Kras(G12D) mice; PDAC; p62

DOI:  https://doi.org/10.1016/j.pan.2026.07.005
Nature. 2026 Jul 08.

Aneuploidy selects for the acquisition of driver genes in breast cancer.

Khalid N Al-Zahrani, Ellen R Langille, Jocelyn Nurtanto, Andreea Obersterescu, Katie Teng, Christopher Lowden, Julien Dessapt, Cynthia H Chiu, Lauren V Caldwell, David P Cook, Miguel A Pérez-Castro, Jacob M Berman, Ricky Tsai, Alexander T Bahcheli, Geraldine Mbamalu, Shifei Wu, Masahiro Narimatsu, Adele G Lopes, Iosifina Fotiadou, Kin Chan, Linkang Zhang, K W Annie Bang, Michael J Parsons, Larissa Mourao, E Idil Temel, Liddy McCulla, Palavalasa Sravya, Li Zhang, Peter Sajjakulnukit, Costas A Lyssiotis, Alexander D Borowsky, Colinda L G J Scheele, Daniel R Wahl, Hartland W Jackson, Katherine S Stewart, Elaine Fuchs, Sean E Egan, Miguel Angel Pujana, Jüri Reimand, Jeffrey L Wrana, Daniel Schramek.

Chromosome instability is highly prevalent in cancer and drives large-scale chromosomal imbalances, known as aneuploidies1-4. How aneuploidy contributes to tumorigenesis remains difficult to study due to the vast numbers of genes affected. Here we established a CRISPR knockout- and activation-linked assay (CRISPR-KOALA), enabling high-throughput bidirectional genetic screens in immunocompetent mouse models of cancer. We developed a compendium of the ten most frequent human chromosome-arm-level alterations in basal-like breast cancer (BLBC), a disease type that is driven by large copy-number alterations (CNAs)5-8. Using CRISPR-KOALA, we screened the mouse orthologues of 3,752 genes on these arms and identified 90 cancer driver genes, the function of the vast majority of which is unknown. These genes drive distinct signalling pathways including MAPK, HIPPO and WNT, reflecting the high degree of BLBC heterogeneity. Manipulating the identified cancer driver genes overcomes the need for CNAs in Trp53-mutant BLBC mouse models. Mechanistically, we identify that PLGRKT is a potent oncogene that lies on chromosome 9p and show that its tumour-promoting activity is associated with highly stress-resistant mitochondria and an increased ability to detoxify reactive oxygen species. Together, our findings reveal that arm-level CNAs can function to select specific driver genes to promote heterogeneous biological processes.

DOI: https://doi.org/10.1038/s41586-026-10752-9
Dev Cell. 2026 Jul 08. pii: S1534-5807(26)00230-3. [Epub ahead of print]61(7): 1392-1406

Tissue mechanopathology of cancer.

Johanna Ivaska, Sarah Sale, Alpha S Yap.

Cancers are complex cellular communities comprising tumor cells and their microenvironment. Recent advances in cancer biology have emerged from efforts to analyze tumors as tissues, in which emergent properties arise as tumor cells interact with one another, their microenvironment, and the host tissue. In this review, we consider interactions involving mechanical forces and mechanosignaling pathways that detect changes in physical inputs to regulate cellular behavior. This rapidly developing field provides perspectives for understanding cancer biology and tumor interactions with the host ecosystem.

DOI: https://doi.org/10.1016/j.devcel.2026.06.006
Nat Protoc. 2026 Jul 07.

CODAvision: best practices and a user-friendly interface for rapid, customizable segmentation of medical images.

Valentina Matos-Romero, Jaime Gómez-Becerril, André Forjaz, Lucie Dequiedt, Tyler Newton, Saurabh Joshi, Yu Shen, Eban Hanna, Praful Nair, Arrun Sivasubramanian, Jenny S H Wang, Emily L Lasse-Opsahl, Alexander T F Bell, Diogo Fróis-Vieira, Julianna Czum, Charles Steenbergen, Dao-Fu Dai, Laura D Wood, Luciane T Kagohara, Elana J Fertig, Marina Pasca di Magliano, Joseph J Shatzel, Owen J T McCarty, Jamie O Lo, Avi Rosenberg, Ralph H Hruban, Arrate Muñoz-Barrutia, Denis Wirtz, Ashley L Kiemen.

Image-based machine learning tools are powerful resources for analyzing medical images, with deep learning-based semantic segmentation commonly utilized to enable the spatial quantification of structures visible in images. However, dataset generation and training of segmentation algorithms requires advanced programming skills and intricate workflows, limiting their accessibility to scientists without prior coding expertise. Here we present the step-by-step instructions to carry out automatic segmentation of medical images guided by a graphical user interface using the CODAvision algorithm. This workflow simplifies the process of semantic segmentation of microanatomical structures by enabling users to train highly customizable deep learning models without extensive coding expertise. The protocol outlines best practices for creating robust training datasets, configuring model parameters and optimizing performance across diverse biomedical image modalities. CODAvision enhances the usability of the CODA algorithm by streamlining parameter configuration, model training and performance evaluation, automatically generating quantitative results and comprehensive reports. We show the use of CODA to serial histology by demonstrating robust performance across numerous medical image modalities and diverse biological questions. We provide sample results in data types, including histology, magnetic resonance imaging and computed tomography. We demonstrate the diverse use of this tool in applications, including quantification of metastatic burden in in vivo models and deconvolution of spot-based spatial transcriptomics datasets. This protocol is designed for researchers with interest in rapid design of highly customizable semantic segmentation algorithms and a basic understanding of programming and anatomy.

DOI: https://doi.org/10.1038/s41596-026-01404-3
Dev Cell. 2026 Jul 08. pii: S1534-5807(26)00236-4. [Epub ahead of print]61(7): 1345-1346

Sealing and healing: A two-step model for plasma membrane repair.

Athanasios Kournoutis, Harald Stenmark.

Plasma membrane damage can cause cell death and is associated with neurodegeneration. In this issue of Developmental Cell, Heffner et al. show that annexin A11 (ANXA11) first plugs membrane lesions, before ESCRT-III is recruited to extrude the damaged patch-a two-step repair mechanism compromised by ALS- and FTD-linked mutations.

DOI: https://doi.org/10.1016/j.devcel.2026.06.011
Cancer Metastasis Rev. 2026 Jul 07. pii: 45. [Epub ahead of print]45(3):

Metastasis as a breakdown of the multicellular social contract.

Laurine Lagache, Michel Salzet.

  Multicellular organisms are not just collections of cells; they are evolutionary compromises in which cell-level fitness is subordinated to organism-level integrity. Cancer begins when that compromise is locally subverted, but metastasis is the decisive escalation: malignant cells must cross tissue boundaries, survive a hostile systemic phase, condition remote organs, enter or escape dormancy and construct a new permissive ecology. This Perspective uses the social-contract metaphor as a disciplined heuristic, not as a claim of intention or moral agency, to integrate metastasis biology with eco-evolutionary thinking. We argue that the metastatic cascade can be read as serial failure of multicellular governance: local architecture loses territorial control; vascular and immune systems fail to exclude or destroy emigrant cells; distant tissues become preconditioned by tumour-derived signals; dormant disseminated cells persist as residual insurgencies and colonisation emerges when organ-specific restraint is converted into support. The framework becomes most useful when it also explains the paradox that cells which defect from host-level cooperation may cooperate locally with each other and with recruited stroma. Public goods, collective dissemination, metabolic exchange and premetastatic niche construction create dependencies that may be exploitable therapeutically. We give the Black Queen Hypothesis a precise but bounded role: it is a testable model for dependency-generating loss or outsourcing of costly shared functions, not a universal law of cancer evolution. Finally, we outline translational implications for metastasis: rearming immune enforcement, blocking niche education, maintaining or eradicating dormant disease, disrupting shared dependencies and using adaptive schedules to manage evolutionary escape. The social-contract lens is valuable only when it remains evidence-led and mechanistically anchored; used this way, it makes metastatic dormancy and colonisation a sharper target for ecological cancer therapy.

Keywords:  Adaptive therapy; Cancer evolution; Metastasis; Metastatic dormancy; Multicellularity; Public goods; Tumour ecology

DOI:  https://doi.org/10.1007/s10555-026-10352-z
Nat Med. 2026 Jul 09.

KRAS-G12D inhibitor HRS-4642 plus chemotherapy in advanced KRASG12D-mutant pancreatic cancer: a phase 1b/2 trial.

Jiujie Cui, Kuirong Jiang, Wei Li, Shuqin Ni, Hong Zong, Juan Du, Yifu He, Zhonghua Liu, Guoqiang Kong, Yanqiao Zhang, Xiaotong Li, Hongxia Han, Fen Yao, Yongwu Chen, Ming Zhou, Liwei Wang.

KRASG12D is the predominant oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). While most investigational KRAS-G12D inhibitors are oral small molecules limited by gastrointestinal toxicities and suboptimal tumor exposure, HRS-4642 is a new, high‑affinity, noncovalent KRAS-G12D inhibitor. Formulated as a liposomal nanoparticle for intravenous administration, it is designed to enhance tumor accumulation and prolong the duration of target inhibition. This phase 1b/2 study evaluated HRS-4642 in combination with nab-paclitaxel and gemcitabine (AG) in patients with advanced KRASG12D-mutant PDAC. As of 5 December 2025, 68 patients were screened and 31 (1 previously treated patient and 30 treatment-naive patients) were enrolled and treated. In the phase 1b portion, no dose-limiting toxicities were observed, and the starting dose (500 mg on day 1 and 1,200 mg on day 8, every 3 weeks) was selected as the recommended phase 2 dose. In the phase 2 portion, with a median follow-up of 12.3 months (95% confidence interval (CI) = 12.2-13.0), the primary endpoint was met-the confirmed objective response rate in 30 treatment-naive patients was 63.3% (95% CI = 43.9-80.1). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 90.3% patients, primarily hematologic toxicities consistent with AG chemotherapy. No TRAEs led to treatment discontinuation or death. In conclusion, HRS-4642 combined with AG demonstrates promising antitumor activity and a manageable safety profile in advanced KRASG12D-mutant PDAC, supporting further investigation. Clinicaltrials.gov registration: NCT06520488 .

DOI: https://doi.org/10.1038/s41591-026-04538-9
Trends Cancer. 2026 Jul 09. pii: S2405-8033(26)00136-6. [Epub ahead of print]

Neuron-tumor communication in solid tumors: from bona fide synapses to pseudo-synaptic neural interfaces.

Lei Ren, Chunfeng Liu, Wangsheng Chen, Yinchun Wang, Gerhard Rammes, Peter H Neckel, Andreas Klingl, Rouzanna Istvanffy, Helmut Friess, Güralp O Ceyhan, Qingqiang Yang, Ihsan Ekin Demir.

  Neuron-tumor communication is emerging as a distinct layer of tumor-host interaction beyond conventional stromal, vascular, and immune regulation. Recent studies show that malignant cells can detect neuronal activity and convert neural signals into growth-promoting cellular responses. In the brain, glioma cells can become electrically integrated into neuronal circuits, where glutamatergic input drives depolarization, calcium influx, and downstream signaling. In extracranial tumors, neural influence appears more heterogeneous, involving spatially organized neurochemical niches, receptor-enriched cancer-nerve contacts ('pseudo-synapses'), autonomic pathways, and injury-associated neuroimmune remodeling. These findings raise important questions about how neural input regulates tumor cell state, metabolism, immune tone, and therapeutic adaptation. This review evaluates the evidence linking neural activity to cancer progression across anatomical contexts and outlines the experimental standards needed to distinguish structured neuron-tumor interfaces from broader neural effects within the tumor microenvironment.

Keywords:  cancer neuroscience; neural circuits; neuron–tumor communication; neuron–tumor synapse; pseudo-synaptic interface; tumor microenvironment

DOI:  https://doi.org/10.1016/j.trecan.2026.06.008
bioRxiv. 2026 Jun 29. pii: 2026.06.28.734981. [Epub ahead of print]

Vertical inhibition of the autophagy pathway impairs growth and enhances sensitivity to mTORC1 inhibition in pancreatic ductal adenocarcinoma.

Mallory K Roach, Seamus E Degan, Jonathan M DeLiberty, Lily M Pita, Noah L Pieper, Runying Yang, Khalilah E Taylor, Elyse G Schechter, Ryan Robb, Mariaelena Pierobon, Clint A Stalnecker, Emanuel F Petricoin, Kirsten L Bryant.

Pancreatic ductal adenocarcinoma (PDAC) is dependent on autophagy for growth. Chloroquine/Hydroxychloroquine (CQ/HCQ), the sole FDA-approved autophagy inhibitors, have shown limited clinical efficacy as cancer therapies. To identify approaches to improve PDAC response to CQ, we performed a CQ-anchored, CRISPR-Cas9 mediated loss-of-function screen. We identified that the loss of genes encoding proteins upstream in the autophagy pathway enhanced CQ-mediated growth suppression. This indicated that simultaneous targeting of two distinct nodes of the same pathway, vertical inhibition, may be a more effective strategy than single node inhibition. We demonstrated that genetic loss or pharmacological inhibition of VPS34, a protein necessary for autophagosome nucleation, sensitized PDAC cells to inhibitors of the terminal stage of the autophagy pathway, including CQ and an inhibitor of PIKfyve. We extended this concept to the initiation complex and demonstrated that ULK1/2 inhibition synergized with CQ and PIKfyve inhibition to impair PDAC cell growth and increase apoptosis. Anticipating mechanisms of resistance to vertical autophagy inhibition, we performed reverse-phase protein array profiling and identified that vertical inhibition of the autophagy pathway resulted in enhanced activation of the PI3K-AKT-mTORC1 signaling pathway. Increased mTORC1 signaling resulted in heightened sensitivity to bi-steric mTORC1 inhibition in both cell line and organoid models of PDAC. This study identifies novel anti-autophagy inhibitor combinations that may improve the clinical efficacy of autophagy inhibition for PDAC treatment.
IMPLICATIONS: Vertical inhibition of the autophagy pathway reduces pancreatic cancer cell growth, increases apoptosis, and enhances sensitivity to mTORC1 inhibition; thereby representing a novel therapeutic strategy for autophagy-driven pancreatic cancer.

DOI: https://doi.org/10.64898/2026.06.28.734981
Methods Mol Biol. 2026 ;2999 111-125

Nanomechanical Phenotyping of Circulating Tumor Cells with Atomic Force Microscopy.

Pawel A Osmulski, Yusheng Qian, Maria Gaczynska.

  Tumor cells shed into the bloodstream are exposed to significant mechanical forces that are distinct from the native environment of epithelial-like cells. The surviving circulating tumor cells (CTCs) respond to circulation conditions with a range of mechanical adaptations resulting in their "mechanical fitness." Multiparameter nanomechanical phenotyping with atomic force microscopy (AFM)-based force spectrometry provides a comprehensive way to characterize these adaptations in a single-cell manner, in live CTCs isolated from the blood of cancer patients. Here, we describe the PeakForce Quantitative Nanomechanical (PF-QNM) phenotyping method for the determination of mechanical properties of CTCs in a fast and non-destructive way, permissive for additional downstream single-cell analyses.

Keywords:  Adhesion; Atomic force microscopy; Circulating tumor cells; Deformability; Elasticity; Force spectrometry; Mechanical properties; Stiffness

DOI:  https://doi.org/10.1007/978-1-0716-5050-9_10
Phys Rev Lett. 2026 Jun 19. 136(24): 248402

Periodic Fracture of Active Tissues.

Yue Qian, Yue Li, Bo Li.

Fracture typically signifies mechanical failure in engineering materials, whereas controlled cracking may actively sculpt tissues through precise biological regulation. Here, we establish a multiscale nonlinear peridynamic theory that accounts for cellular mechanosensing to decipher the spontaneous fracture of active tissues. We show that tissues cultured in a ring-shaped domain can undergo periodic fracture to generate multicellular aggregates with regular spacing, recapitulating prior morphogenetic experiments on avian dermal cell collectives. It is found that the number of cracks varies nonmonotonically with the substrate stiffness. We predict that a narrow tissue favors equally spaced radial cracking, while such ordered cracks deflect, branch, and randomize increasingly as the tissue broadens, attributable to the anisotropy-isotropy transition of tissue stresses induced by the interplay of active contraction and domain geometry. Backed by energetic arguments, we identify the factors that control the characteristic size of tissue fracture. Our Letter reveals a synergy of physics, geometry, and cellular mechanosensing in controlling active tissue fracture to achieve tissue-level organization.

DOI: https://doi.org/10.1103/hw7t-kf32
Front Cell Dev Biol. 2026 ;14 1845678

Metastasis in biological time.

Jhommara Bautista, Sofía Ojeda-Mosquera, Camila Beltrán-Flores, David Palacios-Zavala, Andrés López-Cortés.

  Metastasis is the leading cause of cancer-related death, yet it is still interpreted largely through genetic, spatial, and microenvironmental models that treat the host as temporally uniform. Emerging evidence challenges this view by showing that metastatic progression unfolds within a hierarchically organized circadian system in which tumour cells, vascular interfaces, immune compartments, and distant organs operate in biological time. In this review, we examine how circadian regulation shapes multiple stages of the metastatic cascade, including tumour metastatic competence, circulating tumour cell release, vascular trafficking, immune-mediated seeding, niche permissiveness, colonization, and metastatic outgrowth. We discuss how tumour-intrinsic clocks influence invasive and secretory programmes, how endothelial and stromal rhythms create time-dependent windows of tissue access, and how circadian immune dynamics determine whether disseminated tumour cells are eliminated or licensed for persistence. We further highlight the role of systemic zeitgebers, including light-dark cycles, feeding-fasting rhythms, glucocorticoids, autonomic signalling, and body temperature, in coordinating or disrupting temporal alignment across metastatic compartments. Together, these observations support a conceptual shift: metastasis should be understood not only as a disease of space and state, but also as a disease of biological time. This framework may help explain metastatic heterogeneity and inform future precision oncology strategies.

Keywords:  biological time; circadian immune dynamics; circadian system; metastasis; precision oncology; stromal rhythms; tumour-intrinsic clocks; zeitgebers

DOI:  https://doi.org/10.3389/fcell.2026.1845678
Mol Cancer. 2026 Jul 08.

Autophagy in cancer - functional plasticity, therapeutic paradox, and the road to precision modulation: a comprehensive review.

Jingjing Liu, Peng Wu, Dongyu Li, Xuanyu Gu, Bohui Zhao, Ruijie Ma, Binghua Tan, Dexin Shang, Junhan Zhou, Chuqi Lin, Nan Sun, Chaoqi Zhang, Jie He.

  Autophagy is an evolutionarily conserved lysosomal degradation pathway. In cancer, its role is paradoxical: it functions as a tumor-suppressive gatekeeper during initiation in part by preserving genomic stability, but it is frequently co-opted by established tumors to maintain metabolic fitness and therapeutic resistance. Early clinical efforts using broad, non-selective lysosomal inhibition (e.g., chloroquine) produced mixed outcomes and toxicities, prompting a paradigm shift toward modular, context-specific modulation.This review synthesizes the dynamic spatiotemporal evolution of autophagy in tumorigenesis, and characterizes it as an adaptable evolutionary trajectory governed by stress, tumor genotype, and microenvironmental context. We outline four conceptual pillars: genotype-defined modular networks, dynamic spatiotemporal adaptation, autophagy as an immunometabolic rheostat, and rational therapeutic modulation. Importantly, autophagy exerts cell-type-specific effects-promoting immune evasion in tumor cells while remaining indispensable for lymphocyte fitness. To address this paradox, we evaluate the transition from empirical global blockade to precision-guided intervention, including pathway-selective modulators, exploitation of selective vulnerabilities, and advanced targeted degradation technologies. Autophagy in cancer is a highly dynamic, context-dependent variable. Therapeutic control requires movement beyond universal flux inhibition toward pathway-specific, biomarker-guided interventions that match a tumor's distinct autophagic dependencies. Integration of dynamic monitoring with precise delivery systems may allow active modulation of the tumor microenvironment, transforming autophagy from a tumor resilience mechanism into an exploitable therapeutic vulnerability.

Keywords:  Autophagy plasticity; Cancer metabolism; Immune regulation; Precision oncology; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12943-026-02633-6
Brief Bioinform. 2026 Jul 03. pii: bbag368. [Epub ahead of print]27(4):

FerroScore: a statistical approach for quantifying tumor-related ferroptosis based on omics data.

Jiaqi Teng, Qi Gong, Zhaohang Cai, Tianshou Zhou.

  Ferroptosis is a novel form of programmed cell death driven by iron-dependent lipid peroxidation, and can significantly influence the progression of complex diseases such as cancer. Current methods of detecting ferroptosis rely primarily on experimental techniques that are typically low-throughput and costly, limiting their clinical applications. Here we develop an effective statistical method, FerroScore, to quantify ferroptosis by generating a score that integrates the activities of three core pathways-iron, glutathione, and lipid metabolism. This method enables the cross-resolution assessment of ferroptosis and provides mechanistic insights into tumor, immune, and neurodegenerative diseases, thus having potential applications in targeted therapy and drug discovery. When applied to pancreatic cancer transcriptomic data, FerroScore reveals: (i) a U-shaped relationship between ferroptosis and patient survival; (ii) heterogeneous ferroptosis activity across cell types in the tumor microenvironment, with high sensitivity to Macrophages, CD8 Tcm cells, and a population of nCAFs; (iii) the role of ferroptosis-active cells in reshaping the immunosuppressive and pro-metastatic microenvironment through intercellular communication.

Keywords:  computational biology; ferroptosis; network; single-cell RNA sequencing; tumor

DOI:  https://doi.org/10.1093/bib/bbag368
Adv Sci (Weinh). 2026 Jul 07. e76202

De Novo Designed Minibinders Targeting the GDF15-GFRAL Axis Reverse Cancer Cachexia and Restore Anti-Tumor Immunity.

Haitao Wang, Tianzhen Hua, Meiling Wang, Bingbing Meng, Yue Zhang, Chengxu Jiang, Yunhe Gao, Hongqi Yang, Jian Bo.

  Cancer-associated cachexia is a devastating syndrome characterized by progressive weight loss, reduced survival, and impaired responses to anticancer therapies. Growth differentiation factor 15 (GDF15), acting through its receptor GFRAL, has emerged as a key mediator of cachexia, yet effective and mechanistically defined strategies to neutralize this pathway remain limited. Here, we applied structure-guided de novo protein design to generate compact minibinders that selectively target the GDF15-GFRAL interaction interface. Using an integrated computational pipeline combining RFdiffusion, ProteinMPNN, and AlphaFold 3 structure prediction, we designed and experimentally validated high-affinity GDF15 minibinders with picomolar-range binding affinities and exceptional structural stability. Mutagenesis and charge-complementary rescue experiments confirm that these minibinders neutralize GDF15 through precisely engineered interface contacts. Functionally, the minibinders suppress GDF15-GFRAL signaling, inhibit downstream transcriptional responses, and robustly reverse cachexia in vivo across multiple tumor models, resulting in significant improvements in body weight and survival. Importantly, neutralization of GDF15 also restores sensitivity to anti-PD-1 immunotherapy in a GDF15-driven resistant tumor model. Combination treatment enhances CD8+ T cell infiltration and effector function within tumors, and its antitumor efficacy is strictly dependent on CD8+ T cells. Together, these findings demonstrate that de novo designed GDF15 minibinders can achieve potent, mechanism-defined neutralization of the GDF15-GFRAL axis in vivo, translating into robust physiological benefits and restoration of immunotherapy efficacy.

Keywords:  GDF15; RFdiffusion; cancer cachexia; de novo protein design; immune checkpoint blockade

DOI:  https://doi.org/10.1002/advs.76202
Nat Methods. 2026 Jul;23(7): 1285

Glycan atlasing in cells and tissues.

Aparna Anantharaman.

DOI: https://doi.org/10.1038/s41592-026-03166-y
Cancer Res. 2026 Jul 07.

Targeting Cystine Addiction Suppresses Breast Cancer Lung Metastasis.

Josep Tarragó-Celada, Asad S Mahmood, Yulia Panina, Sakshi Lalwani, Samantha Atkinson, Amy Spicer, Michael Kossifos, Weigang Cai, Ersa Gjelaj, Sharavan Vishaan Venkateswaran, Saidu Sesay, Izadora Furlani, Nathalie Michelle Legrave, Tegan Gilmore, Richard Mitter, Jayanta Bordoloi, Avinash Ghanate, Vincen Wu, Zoltán Takáts, Bin Yan, Alex Dexter, Rory T Steven, Josephine Bunch, George Georgiou, Everett M Stone, Míriam Tarrado-Castellarnau, James I MacRae, Richard J Burt, Mariia Yuneva.

Metastatic disease remains a major cause of cancer-related mortality. Recent studies suggest that dissemination to other organs comes with metabolic changes that allow the metastasizing cancer cells to adapt to new microenvironments. A deeper knowledge of these specific metabolic features and associated vulnerabilities could lead to the development of more effective therapies against metastasis. We used in vivo and ex vivo models of MYC-driven breast tumorigenesis to explore the key metabolic pathways that change when mammary gland tumor cells metastasize to the lung. Stable isotope-resolved metabolomics, mass spectrometry imaging, and single-cell RNA sequencing demonstrated that mammary gland tumor-derived lung metastases have increased synthesis of glutathione fueled by increased cystine uptake. Metastatic cells relied heavily on the availability of extracellular cysteine or cystine, possibly due to downregulated intracellular cysteine synthesis through the transsulfuration pathway. When combined with focal radiotherapy, the amino acid degrader cyst(e)inase effectively reduced metastatic burden in the lungs. Together, these findings show that targeting cystine/cysteine exploits a metabolic dependency that is unique to metastatic cells and acts as a sensitizer to radiotherapy-induced oxidative stress, offering a promising targeted strategy.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-3883
Aging (Albany NY). 2026 Jul 01. 18(1): 768-786

Senescent cells accumulate lipid droplets.

Noa Rachmian-Cooper, Riva Shmulevich, Hagay Akiva, Sarka Pokorna, Bareket Dassa, Ulysse Cherqui, Sergey Malitsky, Maxim Itkin, Binyamin Amichai Kliger, Inna Goliand, Tomer Meir Salame, Valery Krizhanovsky.

  Senescent cells (SnCs) are growth-arrested yet remain metabolically active and undergo extensive reprogramming to support their survival and the Senescence-Associated Secretory Phenotype (SASP). SnCs undergo key metabolic changes, including increased glycolysis, altered mitochondrial function and dysregulated lipid metabolism. While these metabolic changes are increasingly recognized, a comprehensive understanding of how they contribute to the pathophysiological effects of SnCs is still lacking. Here, through metabolic profiling, we identified elevated levels of glycolytic metabolites in SnCs, which coincided with an increased presence of lipid metabolites, specifically triacylglycerol derivatives, the precursors of lipid droplets (LDs). We show that SnCs accumulate LDs in a classical primary human fibroblast model, and that senescent microglia upregulate LDs markers in a mouse model of Alzheimer's disease (AD), where they play a pathological role. Single-nucleus analysis of brains from AD patients further revealed an elevated levels of LDs markers in senescent brain cells, including microglia. Previous studies implicated both lipid droplet-containing microglia and senescent microglia in AD pathology. Our findings provide evidence that these may represent the same cell population, in which the co-occurrence of LDs accumulation and the senescent state jointly contribute to their disease-promoting properties.

Keywords:  Alzheimer’s disease; aging; lipid droplets; metabolism; senescence

DOI:  https://doi.org/10.18632/aging.206390
JCI Insight. 2026 Jul 08. pii: e202529. [Epub ahead of print]11(13):

Fibroblasts: a diverse population of cells balancing homeostasis, wound healing, regeneration, inflammation, fibrosis, and cancer across organs.

Xiaochun Yang, Marcella Steffani, Sandeep Nadella, Dean Sheppard, Florian Rieder, Yuval Rinkevich, Rafael Kramann, David A Tuveson, Robert F Schwabe.

As the principal ECM-producing cell type, fibroblasts are essential regulators of tissue architecture and function in development, homeostasis, and disease. While their disease-promoting functions in fibrosis have long been the center of attention, it is increasingly recognized that fibroblasts exert critical homeostatic roles across organs, acting as sentinels that regulate the function, proliferation, and recruitment of epithelial, endothelial and immune cells in health and disease. Here, we will review the roles of fibroblasts and fibroblast-like cells in tissue maintenance, physiological wound healing, regeneration, maladaptive fibrosis, and cancer across major organs, including the skin, lung, liver, intestine, and kidney, and highlight organ-specific and shared populations and functions. We will discuss the role of PI16+ and COL15A1+ universal fibroblasts, organ-specific fibroblasts, and pericyte and pericyte-like stellate cells as cellular sources for the majority of CTHRC1+ activated fibroblasts and αSMA+ or LRRC15+ myofibroblasts and highlight the functions of specialized subpopulations, such as inflammatory fibroblasts, antigen-presenting fibroblasts, and fibroblast-like cells, including mesothelial and smooth muscle cells. A refined understanding of fibroblast heterogeneity holds promise for novel therapeutic concepts, aimed at targeting pathogenic subpopulations while preserving or enhancing homeostatic functions.

DOI: https://doi.org/10.1172/jci.insight.202529
Cell Death Discov. 2026 Jul 11.

Intrinsic polyunsaturated fatty acid synthesis capacity dictates ferroptosis sensitivity under restricted arachidonic acid availability.

Min Wook Kim, Seo Young Jang, Ji-Yoon Lee, Jong Woo Kim, Woosung Jung, Yeon-Mi You, Jooeun Kim, Kyoung-Jin Oh, Won Kon Kim, Baek-Soo Han, Kwang-Hee Bae, Mi-Young Kim, Geum-Sook Hwang, Eun-Woo Lee.

Ferroptosis is an iron-dependent type of regulated cell death driven by lipid peroxidation, in which polyunsaturated fatty acids (PUFAs) in membrane phospholipids serve as key substrates. Here, we identify PUFA biosynthetic capacity as a key determinant of ferroptosis sensitivity under arachidonic acid (AA)-limited conditions. Lipidomic and stable isotope-tracing analyses in human lung adenocarcinoma cell lines revealed that H1299 cells that harbor wild-type KEAP1 and are sensitive to ferroptosis have unexpectedly impaired PUFA biosynthesis and consequently low PUFA levels. Nevertheless, ferroptosis sensitivity in H1299 cells is maintained under normal culture conditions owing to an exogenous supply of AA. Culturing cells in the B27 supplement, which provides only essential fatty acids such as linoleic acid, in the presence of 1% dialyzed FBS reduced AA-containing phospholipids and rendered H1299 cells resistant to ferroptosis. In contrast, A549 cells with a KEAP1 mutation retained ferroptosis sensitivity under B27 conditions, enabled by their endogenous PUFA-synthesizing capacity. Strikingly, pharmacological inhibition of FADS2 or deletion of ELOVL5 in A549 cells phenocopied H1299 cells, conferring resistance under B27-AO conditions that was reversed by AA supplementation. These findings demonstrate that ferroptosis susceptibility is dictated by intrinsic PUFA biosynthetic capacity under AA-limited conditions resembling physiological lipid availability. Therefore, intrinsic PUFA biosynthetic capacity should be considered in ferroptosis-based cancer therapies.

DOI: https://doi.org/10.1038/s41420-026-03240-6
Cell Death Discov. 2026 Jul 06.

Multi-metal cooperation drives chemoresistance in lung cancer and is reversed by the membrane-permeable chelator MiADMSA.

Hannah L Richards, Steven J Bell, Katherine E V Deck, Anaïs M T Y Wiech, Emma Tarrant, Carissa M Lloyd, Juan A Aguilar, Dan Gelvan, William D G Brittain, Patricia A J Muller.

Elevated levels of transition metals are a common feature of solid tumours and are associated with poor clinical outcomes. However, tumour cells are exposed to complex metal mixtures rather than individual ions, and the functional consequences of such multi-metal exposure remain poorly defined. Here, we show that subtoxic combinations of metals cooperate to drive robust chemoresistance in lung cancer cells. This phenotype is not recapitulated by any single metal, demonstrating that resistance arises from coordinated multi-metal activity rather than individual metal effects. We further find that endogenous metal pools contribute to this response, and that metal-induced reactive oxygen species (ROS) are required but not sufficient, indicating that additional metal-dependent signalling mechanisms underpin chemoresistance. Because resistance emerges from collective metal activity, targeting individual metals fails to restore chemosensitivity. We therefore evaluated a pan-metal chelation strategy and identify monoisoamyl dimercaptosuccinic acid (MiADMSA) as a membrane-permeable chelator capable of targeting intracellular metal pools. Using complementary biochemical and cellular approaches, including a fluorinated derivative to track intracellular activity, we demonstrate that MiADMSA acts within cells to reverse metal-induced chemoresistance across multiple lung cancer models. Importantly, MiADMSA suppresses tumour growth in metal-exposed xenografts. Together, these findings identify multi-metal cooperation as a previously underappreciated driver of chemoresistance and establish intracellular pan-metal chelation as a potentially actionable strategy to restore chemotherapy sensitivity.

DOI: https://doi.org/10.1038/s41420-026-03222-8
Biochim Biophys Acta Rev Cancer. 2026 Jul 08. pii: S0304-419X(26)00130-7. [Epub ahead of print]1881(4): 189658

Cell chirality in cancer: Emerging roles in malignant progression and tumor metastasis.

Tongyao Hu, Jueyao Zou, Ziyan Zhu, Zhengyu Zhang, Yanhong Pan, Yin Lu, Wenxing Chen.

  Cell chirality is a newly discovered cellular characteristic that is phenotype-specific and is associated with cell migration, cell differentiation, organelle positioning, and organ asymmetry. The maintenance of normal cellular chirality is fundamental for preserving physiological functions in organisms. In recent years, cellular chirality has been increasingly investigated in tumor research, especially metastasis. During tumor metastasis, tumor cells acquire migratory and invasive capabilities through epithelial-mesenchymal transition (EMT), a process that is intricately linked to the dynamic reprogramming of cell chirality. The alterations in the chirality of both tumor cells and other surrounding cells significantly enhance metastatic efficiency not only by regulating cell-extracellular matrix interactions, collective migration patterns, and immune escape but also by increasing vascular permeability. This article provides a comprehensive and systematic exploration of the intricate relationship between cell chirality and tumor metastasis. It meticulously summarizes the molecular mechanisms that govern cell chirality, outlines the commonly employed detection methods, and delves into the potential therapeutic strategies targeting cellular chirality. Given the pivotal role of cell chirality in regulating metastasis, further research in this area holds great promise for revolutionizing cancer treatment and is expected to pave the way for the development of novel therapeutic strategies targeting tumor metastasis.

Keywords:  Cell chirality assays; Cellular chirality; Therapeutic strategies; Tumor metastasis

DOI:  https://doi.org/10.1016/j.bbcan.2026.189658