bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2026–11–08
35 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. KRAS Inhibitor Resistance Confers a Targetable Vulnerability to Ferroptosis in Pancreatic Ductal Adenocarcinoma.
  2. Dual mTORC1/2 and Scd1 inhibition uncovers a therapeutic vulnerability in pancreatic cancer.
  3. Safe lysosomal sequestration of ferrous iron is mediated via cholesterol shielding and drives senescence and ferroptosis resistance.
  4. Cancer cells differentially modulate mitochondrial respiration to alter redox state and enable biomass synthesis in nutrient-limited environments.
  5. Liver-Lung Organotropism in Pancreatic Ductal Adenocarcinoma: A Five-Stage Framework.
  6. A KRT17/GATA6 hybrid state marks unique vulnerability to MYC in pancreatic cancer.
  7. Lipid Changes due to Low O-GlcNAc and the Downstream Consequences.
  8. The multifaceted roles of lysosomes in cancer.
  9. Cancer cells acquire cysteine directly from a reduced tumor microenvironment.
  10. On the lethal mechanism of class III ferroptosis inducers.
  11. Bioprinted Stiffness‑Tunable Pancreatic Microniches to Decode Early Tumor Initiation Mechanisms.
  12. Fatty acid desaturation controls cellular fate decisions between senescence and ferroptosis.
  13. A selective TNKS2 inhibitor for tumor-restricted WNT suppression.
  14. The immune code of metal-dependent cell death.
  15. Corrigendum to "Intrinsic and extrinsic regulators of cancer dormancy and awakening" [Journal of the National Cancer Center 6 (2026) 211-218].
  16. Transmembrane PhoxID: photoproximity labelling across the plasma membrane in vivo.
  17. Lysosome-resident nanoreactor enables spatiotemporally controlled ferroptosis via cascade amplification of lipid peroxidation in breast cancer therapy.
  18. Leveraging induced cell states for cancer therapy: The case for dynamic synthetic lethality.
  19. Nutrients and Their Role in Autophagy Regulation.
  20. Reprogramming muscle proteostasis in cancer cachexia: Transcriptional mechanisms and therapeutic opportunities.
  21. Cytoplasmic crowding drives intracellular viscoelastic increase during epithelial maturation.
  22. Myeloid-derived TGFβ1 and oncostatin M establish two distinct stromal niches controlling late and hybrid EMT states.
  23. Remembering Stiffness: HCC Maintains Malignancy through Heritable Hyperacetylation Driven by Mechanically Mediated Acetyl-CoA Levels.
  24. CRISPR mutagenesis of the MYC locus reveals a druggable ultraconserved RNA element.
  25. Myosin heavy-chain 9 executes cuproptosis.
  26. Cellular responses to severe dehydration during spin-drying resemble hyperosmotic stress.
  27. A Phase 1 Trial of Low-dose Gemcitabine Combined with ATR Inhibitor Elimusertib for Advanced Solid Tumors.
  28. A History of Cancer Research: Mouse Models of Cancer Genetics.
  29. Isolation and lipidomic profiling of neuronal lipid droplets to unveil the lipid landscape of neurodegenerative disorders.
  30. Claudin-12-Expressing Fibroblasts Facilitate Metastatic Spread of Pancreatic Cancer Through Physical Interactions.
  31. Gastruloids reveal alternative morphogenetic routes for body-axis elongation with distinct cytoskeletal dependencies.
  32. HuBMAP Data Portal: a resource for multimodal spatial and single-cell data of healthy human tissues.
  33. Sludge-induced acute pancreatitis is linked to lower cholecystectomy rates than gallstone pancreatitis.
  34. Tryptophan Restores Recovery Competence Following Starvation in the Absence of Lysosomal Amino Acid Sensing.
  35. A Cell-Autonomous Cold Sensor Promotes Lipolysis Through Phase Separation.
  1. Cancer Res. 2026 Nov 03.
    KRAS Inhibitor Resistance Confers a Targetable Vulnerability to Ferroptosis in Pancreatic Ductal Adenocarcinoma.
    Sihan Huo, Hailong Zhao, Tong Liu, Ruoxuan Wang, Yuyao Guo, Wenqin Hao, Minghe Fan, Ziyang Zhang, Xiangying Fu, Yueran Zhang, Lina Wang, Jingfeng Tang, Hua Wang, Ying Zhao.
      KRAS inhibitors represent a promising therapeutic frontier in pancreatic ductal adenocarcinoma (PDAC) treatment. However, the clinical benefit of KRAS inhibitors in PDAC is limited by the frequent emergence of resistance. Here, we demonstrated that acquisition of resistance to KRAS inhibitors rendered PDAC cells hypersensitive to ferroptosis. Untargeted lipidomic profiling revealed that resistant cells underwent extensive lipid metabolic reprogramming characterized by selective enrichment of polyunsaturated fatty acid-containing phosphatidylcholines (PC-PUFAs) and a concomitant reduction in monounsaturated fatty acid-containing species (PC-MUFAs). The orphan nuclear receptor NR2F2 was a critical determinant of ferroptosis sensitivity in resistant cells. NR2F2 expression was markedly elevated upon acquisition of resistance, accompanied by substantial changes in its occupancy at regulatory elements of key lipid metabolic genes. By altering chromatin accessibility, NR2F2 drove PUFA biosynthesis and phospholipid remodeling, creating a ferroptosis-prone lipid state. Collectively, these findings establish NR2F2-driven lipid metabolic rewiring as an intrinsic ferroptosis liability in KRAS inhibitor-resistant PDAC and reveal ferroptosis induction as a therapeutic strategy to overcome resistance to KRAS-targeted therapies.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-1490
  2. Oncogene. 2026 Oct 31.
    Dual mTORC1/2 and Scd1 inhibition uncovers a therapeutic vulnerability in pancreatic cancer.
    Chao Fang, Yuanyuan Yu, Yiping Yin, Zhao Shi, Zhaiyue Xu, Britta Statz, Yina Qiao, Hongzhen Li, Yifeng Sun, Jingxiong Hu, Tamer Abdelaal, Kathleen Schuck, Lei Wang, Thomas Hank, Max Heckler, Martin Loos, Ingrid Herr, Franco Fortunato, Ihsan Ekin Demir, Helmut Friess, Shanshan Shen, Christoph W Michalski, Bo Kong.
      Hyperactivation of the mechanistic target of rapamycin (mTOR) complexes, mTORC1 and mTORC2, is common in pancreatic ductal adenocarcinoma (PDAC). However, clinical use of mTOR inhibitors has shown limited efficacy due to rapid adaptive resistance. Using inducible genetically engineered mouse models and matched organoids, we delineated distinct complex-specific adaptations. Loss of mTORC1 delayed tumor progression but induced compensatory PI3K/Akt signalling hyperactivation, while concurrently suppressing inflammatory cancer-associated fibroblasts and desmoplasia through Il-1ra. In contrast, mTORC2 loss impaired de novo sphingolipid synthesis, shifted lipid composition toward saturation, increased the saturated-to-monounsaturated fatty acid ratio, enriched plasma membrane lipid rafts, and amplified interferon-γ signaling. This lipid reprogramming generated a synthetic-lethal dependency on stearoyl-CoA desaturase 1 (Scd1). Pharmacological co-inhibition of mTORC1/2 and Scd1 prevented adaptive PI3K/Akt signalling rebound, remodelled the tumor stroma, enhanced interferon-γ responses, and synergized with anti-PD-1 therapy. These findings establish dual targeting of mTOR signaling and Scd1 as a rational therapeutic strategy for PDAC.
    DOI:  https://doi.org/10.1038/s41388-026-04026-x
  3. EMBO J. 2026 Nov 02.
    Safe lysosomal sequestration of ferrous iron is mediated via cholesterol shielding and drives senescence and ferroptosis resistance.
    Izumi Yanatori, Tasuku Hirayama, Raku Son, Yasuhiro Murakawa, Yuta Matsuoka, Yuki Sugiura, Masato Niwa, Tatsuya Katsuno, Masahiko Tsujimoto, Hiroyuki Yasui, Atsuyasu Sato, Makoto Nakanishi, Kazuhiro Iwai.
      Iron accumulation is a conserved hallmark of cellular as well as organismal aging, yet its mechanistic role in senescence remains largely elusive. Here we show that the accumulation of ferrous iron (Fe2+) in lysosomes, a unique feature of senescent cells, is crucial for the induction of multiple senescence-associated phenotypes. Intriguingly, we found that this lysosomal Fe2+ sequestration is rendered "safe" by a dual metabolic adaptation that confers robust resistance to ferroptosis. First, Fe2+ accumulation triggers lysosomal alkalinization and subsequent cholesterol accumulation, which reinforces the lysosomal membrane against permeabilization. Second, senescent cells partition polyunsaturated fatty acids into lipid droplets, thereby depleting these ferroptosis-prone substrates from cellular membranes. Our findings establish that such cholesterol-enabled safe sequestration of Fe2+ serves as a central modulator linking senescence-associated remodeling to ferroptosis resistance. Modulating this lysosomal iron-centered pathway may provide new opportunities to target and control the behavior of senescent cells.
    DOI:  https://doi.org/10.1038/s44318-026-00939-1
  4. Elife. 2026 Nov 04. pii: RP107123. [Epub ahead of print]14
    Cancer cells differentially modulate mitochondrial respiration to alter redox state and enable biomass synthesis in nutrient-limited environments.
    Sarah M Chang, Muhammad Bin Munim, Sonia E Trojan, Huel Cox, Anna Shevzov-Zebrun, Keene L Abbott, Renee Chang, Matthew G Vander Heiden.
      The cell NAD+/NADH ratio can constrain biomass synthesis and influence proliferation in nutrient-limited environments. However, which cell processes regulate the NAD+/NADH ratio is not known. Here, we find that some cancer cells elevate the NAD+/NADH ratio in response to serine deprivation by increasing mitochondrial respiration. Cancer cells that elevate mitochondrial respiration have higher serine production and proliferation in serine-limiting conditions than cells with no mitochondrial respiration response, independent of serine synthesis enzyme expression. Increases in mitochondrial respiration and the NAD+/NADH ratio promote serine synthesis regardless of whether serine is environmentally limiting. Lipid deprivation can increase the NAD+/NADH ratio via mitochondrial respiration in some cells, including cells that do not increase respiration following serine deprivation. Thus, in cancer cells where lipid depletion raises the NAD+/NADH ratio, proliferation in serine-depleted environments improves when lipids are also depleted. Taken together, these data suggest that changes in mitochondrial respiration in response to nutrient deprivation can influence the NAD+/NADH ratio in a cell-specific manner to impact oxidative biomass synthesis and proliferation. Given the complexity of tumor microenvironments, this work provides a metabolic framework for understanding how levels of more than one environmental nutrient affect cancer cell proliferation.
    Keywords:  NAD+/NADH ratio; biochemistry; cancer biology; cancer metabolism; chemical biology; human; lipid depletion; mitochondria; serine
    DOI:  https://doi.org/10.7554/eLife.107123
  5. Cancer Manag Res. 2026 ;18 644548
    Liver-Lung Organotropism in Pancreatic Ductal Adenocarcinoma: A Five-Stage Framework.
    Baodan Cong, Kunfei Deng, Yu Du, Kaidi Sun.
      Liver and lung metastases in pancreatic ductal adenocarcinoma (PDAC) differ in timing, molecular features, and clinical course. We propose that these differences emerge through five interacting processes: pre-existing predisposition, anatomical delivery, premetastatic conditioning, organ-specific selection, and adaptive colonization. This narrative review integrates clinical observations with genetically engineered mouse models (GEMMs), lineage tracing, and functional perturbation to explain liver-lung divergence. The framework organizes organ preference around the states available before dissemination, the cells delivered to each organ, and their subsequent survival and growth. It connects each process to an experimental readout, allowing recurrent-site associations and causal mechanisms to inform a common biological question. GEMM studies reveal early dissemination, heterogeneous metastatic competence, polyclonal seeding, and changes in tumor-cell and stromal organization across metastatic lesion sizes. Genetic manipulation of epithelial adhesion and tissue-specific signaling further identifies distinct requirements for hepatic and pulmonary colonization. Complementary transplantation experiments demonstrate organ-dependent responses to SMAD4 restoration and PCSK9 perturbation. Together, these findings support a probabilistic interpretation in which the same tumor-cell program can confer different advantages according to the target organ and stage of progression. Clinical recurrence patterns provide a complementary view of this biology, with isolated pulmonary disease often associated with a more indolent course. By linking evidence to the process it measures, the framework identifies opportunities to reduce dissemination, disrupt organ conditioning, or inhibit established metastatic growth and guides the design of prospective studies of organ-specific risk and treatment response.
    Keywords:  liver metastasis; lung metastasis; metastatic fitness; metastatic organotropism; pancreatic ductal adenocarcinoma; premetastatic niche; tumor microenvironment; tumor-cell plasticity
    DOI:  https://doi.org/10.2147/CMAR.S644548
  6. Res Sq. 2026 Nov 01. pii: rs.3.rs-11519779. [Epub ahead of print]
    A KRT17/GATA6 hybrid state marks unique vulnerability to MYC in pancreatic cancer.
    Lyanne Delgado, Andrew Resnick, Jonathan Ogata, Jorge Villar-Samaniego, Qian Lin, Michael Horowitz, Thomas Beggs, Tristan Kwai, Anastasia Terbaci, Kayla Schwartz, Jeremy Loffredo, Katlin Wilson, Nicholas W Bateman, Kelly A Conrads, Jacky D Lin, Anika Porwal, Fjord Deda, Bo Chen, Sruthi Babu, Natalia Marchenko, Emanuel F Petricoin Iii, Thomas P Conrads, Scott Powers, Luisa Escobar-Hoyos, Kenneth Shroyer.
      Pancreatic ductal adenocarcinoma (PDAC) progression is driven by a poorly understood continuum of plastic malignant cell states between the "classical" (GATA6⁺) and "basal-like" (KRT17⁺) subtypes. Here, we integrate \(\:scRNA\text{-}seq\) with quantitative proteomics from laser-capture microdissected patient tissue and targeted mechanistic perturbations to establish a framework that simplifies this continuum and defines malignant programs linked to tumor progression, metastasis, and therapy resistance. We identify a transcriptionally and proteomically distinct KRT17⁺/GATA6⁺ hybrid cell state. Spatial analyses show that hybrid cells are enriched among de-differentiating populations, concentrate at the invasive front of primary tumors, and are significantly overrepresented in lethal liver and lung metastases, indicating that this plastic phenotype is selected during the metastatic cascade. Proteomic deconstruction reveals that the hybrid state is governed by a MYC-driven oncogenic program coupled to a metabolic shift toward oxidative phosphorylation. By individually reducing KRT17 and GATA6 expression, we establish a direct KRT17→c-MYC regulatory axis that promotes broad resistance to standard therapies while creating a specific, targetable vulnerability to MYC inhibition. Together, these findings identify the KRT17⁺/GATA6⁺ hybrid phenotype as a key node of PDAC aggressiveness and therapeutic resistance and support the use of KRT17/GATA6 as biomarkers to stratify patients for clinical trials of MYC inhibitors.
    DOI:  https://doi.org/10.21203/rs.3.rs-11519779/v1
  7. bioRxiv. 2026 Oct 31. pii: 2026.10.13.758586. [Epub ahead of print]
    Lipid Changes due to Low O-GlcNAc and the Downstream Consequences.
    George Q Fei, Victoria M Marando, Kellen L Olszewski, Bettine E Gibbs, Wyatt G Jensen, Alexander M J Hall, Marco Jost, Suzanne Walker.
      O -GlcNAc transferase (OGT) is an essential mammalian glycosyltransferase that installs O -GlcNAc onto thousands of cytosolic and nuclear proteins. Dysregulated glycosylation by OGT is associated with disease states, including cancer and neurodegeneration. However, cellular consequences of acute loss of O -GlcNAc remain poorly understood. Here, we employed a cell-permeable small molecule inhibitor of OGT, OSMI-4, coupled with transcriptomic and lipidomic analyses to characterize the effects of O -GlcNAc depletion in human cell lines. Loss of O -GlcNAc led to changes in expression of lipid metabolism genes and remodeling of the lipidome, with unsaturated phosphatidylcholines (PCs), saturated lysophosphatidylcholines (LPCs) and unsaturated storage lipids accumulating. We also observed increased lipid droplets. Our results suggest that polyunsaturated fatty acids (PUFAs) accumulate in the membrane under low O -GlcNAc conditions and that cells buffer this accumulation by removing PUFAs from membrane lipids and sequestering them in lipid droplets. We found that treatment with OSMI-4 sensitizes cells to ferroptosis inducers, likely because accumulated cell membrane PUFAs undergo peroxidation. Taken together, our results highlight lipid remodeling as an important process that mediates the downstream effects of loss of O -GlcNAc. It may be possible to exploit the synergy between OGT inhibitors and ferroptosis inducers for therapeutic benefit.
    DOI:  https://doi.org/10.64898/2026.10.13.758586
  8. Mol Oncol. 2026 Nov 04.
    The multifaceted roles of lysosomes in cancer.
    Jia Li, Kevin M Ryan.
      Cancer cells proliferate rapidly and require sustained supplies of nutrients and biosynthetic precursors. Lysosomes are more than terminal degradation sites: they recycle amino acids, sugars, lipids, nucleosides and ions, while also coordinating nutrient sensing, organelle communication and immune regulation. Consequently, lysosomal capacity can become selectively advantageous in tumours by linking nutrient salvage with growth control, organelle communication and inflammatory signalling. Enhanced lysosomal function can support tumour growth, invasion and therapy resistance. Here, we review four cancer-relevant dimensions of lysosomal capacity: catabolism and transport; mTORC1- and AMPK-linked nutrient sensing; membrane contact sites with the ER, mitochondria, and Golgi; and immune regulation spanning innate and adaptive responses and inflammatory control. These functions are context dependent: lysosomal quality control can restrain tumour initiation, whereas established cancers often exploit increased lysosomal capacity to support proliferation, invasion, metastasis and therapy resistance. Finally, we discuss lysosome-state biomarkers and lysosome-targeted strategies for patient stratification and rational combination therapy.
    Keywords:  cancer; lysosome; membrane contact sites; metabolism; nutrient sensing; tumour immunity
    DOI:  https://doi.org/10.1002/1878-0261.70349
  9. bioRxiv. 2026 Oct 27. pii: 2026.10.25.761647. [Epub ahead of print]
    Cancer cells acquire cysteine directly from a reduced tumor microenvironment.
    Feroza K Choudhury, Basma A Yasseen, Paloma González-Sánchez, Meredith Long, Samantha Caldwell, Pritin N Soni, Suehelay Acevedo-Acevedo, Yun Huang, Elsa R Flores, Chang Jiang, Nathan P Ward, Gina M DeNicola.
      The metabolic environment of a tumor is shaped by the nutrients available in its interstitial fluid, yet the redox composition of that fluid is poorly defined. Measuring sulfur metabolites in the interstitial fluid of tumors, matched healthy organs, and serum across three mouse models of cancer, we find that the tumor microenvironment (TME) is a chemically reduced compartment in which free cysteine predominates over its oxidized form, cystine. This is especially pronounced in the lung TME, where cystine is nearly absent. We further show that lung cancer cells take up cysteine and cystine with comparable efficiency and proliferate on cysteine alone, and that the abundant glutathione in the TME helps keep cysteine reduced through disulfide exchange. In a medium formulated to match the sulfur composition of the lung tumor interstitial fluid, cells become independent of cystine import through xCT. Cells cultured in this medium were resistant to glutaminase inhibitors, oxidants and ferroptosis inducers, and better maintained NADPH levels under oxidative challenge. These findings suggest that standard culture conditions overestimate the dependence of cancer cells on cystine uptake and their vulnerability to oxidative stress-targeting therapies.
    DOI:  https://doi.org/10.64898/2026.10.25.761647
  10. Ferroptosis Oxid Stress. 2026 ;2(4): 202615
    On the lethal mechanism of class III ferroptosis inducers.
    Alby Joseph, Scott J Dixon.
      Ferroptosis is an oxidative form of non-apoptotic cell death that is important for human biology. This process can be induced in cultured cells by at least four structurally and mechanistically distinct classes of ferroptosis inducing (FIN) small molecules. These four classes of FINs are distinguished based on molecular target and mechanism of action. The lethal mechanism of the prototypic oxime-containing class III FIN, FIN56, is unique and poorly understood. FIN56 is proposed to cause ferroptosis by depleting coenzyme Q10 and degrading glutathione peroxidase 4 (GPX4). Curiously, the FIN56 analogs caspase independent lethal 56 (CIL56) and tegavivint also trigger non-apoptotic cell death but not ferroptosis. Tegavivint is a drug candidate currently being tested in humans for the treatment of cancer. Here, we review our understanding of the FIN56 lethal mechanism with a view to guiding future investigations into a privileged chemical scaffold that possesses unusual lethal activity in cancer cells.
    Keywords:  CIL56; FIN56; Lipid peroxidation; RSL3; erastin; necrosis; tegavivint
    DOI:  https://doi.org/10.70401/fos.2026.0028
  11. Adv Healthc Mater. 2026 Nov 05. pii: e71938. [Epub ahead of print]
    Bioprinted Stiffness‑Tunable Pancreatic Microniches to Decode Early Tumor Initiation Mechanisms.
    Aurelien Mazet, Charles Handschin, Theo Desigaux, Nathalie Dusserre, Marie-Laure Stachowicz, Shane Fennell, Malou Lea, Silvia Arcucci, Benoît Thibault, Jean-Christophe Fricain, Julie Guillermet-Guibert, Hugo Oliveira.
      Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest human cancers, driven in 90% of cases by KRAS mutations and characterized by an intense desmoplastic reaction, early metastasis, and therapy resistance. The mechanisms driving PDAC initiation, however, remain poorly understood because early acinar transformation is difficult to model in a controlled microenvironment. Here, we introduce a microvalve-bioprinted 3D pancreatic cancer initiation niche that supports culture of primary acini from wild-type and Kras-mutant mice, up to 14 days, within gelatin-methacryloyl (GelMA) hydrogels. Our printing strategy enables tuning of hydrogel stiffness to cover the range reported for healthy murine pancreas and early stages of desmoplastic remodelling. In this system, wild-type acini retain a predominantly acinar phenotype, whereas intermediate GelMA conditions cooperate with pre-existing oncogenic Kras to promote acinar-to-ductal metaplasia and proliferative programs associated with early neoplastic reprogramming. Multimodal readouts revealed a stiffness-permissive window in which mechanical cues cooperated with oncogenic Kras to promote acinar transdifferenciation, proliferation and distinct stiffness-dependent secretory programs, including inflammatory and stromal-associated factors with previously reported relevance to PDAC biology. The deterministic droplet geometry supported reproducible, high-throughput, and longitudinal analysis under conditions inaccessible to conventional extrusion or laser‑assisted bioprinting, providing an experimental framework to study early Kras-driven acinar reprogramming.
    Keywords:  bioprinting; cancer 3D models; cancer initiation; microvalve bioprinting; pancreatic cancer; precancerous niche
    DOI:  https://doi.org/10.1002/adhm.71938
  12. Cell. 2026 Nov 02. pii: S0092-8674(26)01139-6. [Epub ahead of print]
    Fatty acid desaturation controls cellular fate decisions between senescence and ferroptosis.
    Chisaka Kuehnemann, Samantha T Jezak, Bronwyn A Mogck, Niharika Kura, Rushmeen Tariq, Yuheng Che, Maija Vaittinen, Ioannis Siokas, Sharvari Deshpande, Carlyn Guthrie, Xuejuan Tan, Eliezer Aimontche, Aleksandra Aljakna Kahn, Peter Reifsnyder, Gung Lee, Amene Majidipur, Andrew H Kung, Qiaoling Wang, Diana Jurk, Tong Zheng, Andrew S Greenberg, Xiang-Dong Wang, Koji Kitazawa, Gregory Dolnikowski, Yong Cheng, Nirupa R Matthan, Arvind Ramanthan, Jennifer Lee, Daniel Roh, Howard H Chen, Jussi Pihlajamaki, Ron Korstanje, Christopher D Wiley.
      When subject to damage or stress, cells develop responses in order to maintain tissue homeostasis. Two such responses are ferroptosis and cellular senescence, but how cells decide between these outcomes remains unclear. Here, we show that senescent cells increase import and membrane levels of multiple polyunsaturated fatty acids (PUFAs), but a specific intermediate PUFA, dihomo-gamma-linolenic acid (DGLA, 20:3ω-6), is reduced. Exogenous repletion of DGLA instead results in cell death by ferroptosis. Senescent cells manifest additional features associated with ferroptosis, including labile iron and expression of lipoxygenases as well as low-level membrane peroxidation. Oral DGLA supplementation lowers markers of senescence in aged mice and improves age-related functional outcomes. Finally, obese humans with lowered DGLA desaturation rates have lower markers of adipose tissue senescence. Together, our data implicate shifts in PUFA metabolism as a driver of decisions between senescence and ferroptosis.
    Keywords:  DGLA; PUFA; aging; desaturation; ferroptosis; lipid peroxidation; metabolism; obesity; senescence; senolytic
    DOI:  https://doi.org/10.1016/j.cell.2026.09.036
  13. Nat Chem Biol. 2026 Nov 02.
    A selective TNKS2 inhibitor for tumor-restricted WNT suppression.
    Jill Zimmerman, Brandon F Malone, Kevan Chu, Efrat Finkin-Groner, Shan Sun, Rui Liang, Sher Bahadur, Miguel Foronda, Emma M Schatoff, Elizabeth Granowsky, Florencia Madorsky, Sukanya Goswami, Alyna Katti, Benjamin Leach, Heather Alcorn, Tuomas Tammela, Benjamin Hopkins, Yoshiyuki Fukase, Tanweer Khan, David J Huggins, John Ginn, Nigel Liverton, Richard K Hite, Lukas E Dow.
      Hyperactive WNT signaling is a potent cancer driver but clinical translation of WNT inhibitors has been hampered by on-target toxicities. WNT signaling can be constrained through inhibition of the PARP-family enzymes tankyrase 1 (TNKS1) and TNKS2; however, existing TNKS inhibitors suppress WNT signaling in both tumor and healthy tissues. In this Article, we show that genomic loss of TNKS1 on chromosome 8p creates a collateral vulnerability that drives a tumor-restricted dependency on TNKS2 for cellular TNKS activity. Through structure-guided design, we identify a flexible loop in TNKS2 that can be exploited to enable TNKS2-selective drug targeting and we generate a first-in-class TNKS2 inhibitor to drive selective WNT inhibition in TNKS1-deficient cell and organoid models. This work demonstrates a targetable cancer-specific vulnerability in multiple cancer types, providing a new approach for WNT-targeted therapies.
    DOI:  https://doi.org/10.1038/s41589-026-02358-z
  14. Trends Immunol. 2026 Nov 06. pii: S1471-4906(26)00297-8. [Epub ahead of print]
    The immune code of metal-dependent cell death.
    Jiao Liu, Daolin Tang, Rui Kang.
      Metal-dependent cell death can provoke, suppress, or evade immune recognition. We propose that these divergent outcomes reflect two interacting sources of information: signals generated by dying cells and changes in metal availability and localization that shape their perception. Their integration, rather than the death pathway alone, may determine immunogenicity.
    Keywords:  cuproptosis; ferroptosis; immunogenic cell death; metal homeostasis; metal-dependent cell death
    DOI:  https://doi.org/10.1016/j.it.2026.10.007
  15. J Natl Cancer Cent. 2026 Oct;6(5): 512
    Corrigendum to "Intrinsic and extrinsic regulators of cancer dormancy and awakening" [Journal of the National Cancer Center 6 (2026) 211-218].
    Jingwei Zhang, Md Imtiaz Khalil, Ranjan Mishra, Hao Li, Luigi Perelli, Robert A Weinberg.
      [This corrects the article DOI: 10.1016/j.jncc.2026.03.007.].
    DOI:  https://doi.org/10.1016/j.jncc.2026.08.001
  16. Nat Commun. 2026 Oct 05. pii: 11323. [Epub ahead of print]17(1):
    Transmembrane PhoxID: photoproximity labelling across the plasma membrane in vivo.
    Fátima Yuri Tanimura Valor, Mikiko Takato, Ayane Araki, Seiji Sakamoto, Tomonori Tamura, Itaru Hamachi.
      Transmembrane proteins perform essential roles in cellular transport, signalling, and communication. The function and dynamics of these proteins are precisely regulated by interactions on both sides of the plasma membrane; thus, mapping the composition of these interactomes is a fundamental challenge in molecular biology. Proximity labelling methods are powerful tools for this purpose; however, existing approaches that rely on membrane-impermeable reactive species generally focus on either the extracellular or the intracellular region of transmembrane proteins. Here, we capitalise on the membrane permeability of singlet oxygen to carry out simultaneous proximity labelling of both the extra- and intracellular sides of transmembrane proteins using an extracellularly anchored photosensitiser. We apply this method, termed transmembrane PhoxID (tmPhoxID), to several receptors (GRID2, GABAAR, and GRM1) in the living mouse brain and successfully determine their specific membrane-proximal intracellular interactomes. Notably, network analysis of the identified proteins reveals that this method can characterise the native components of transsynaptic nanocolumns formed at parallel fibre-Purkinje cell synapses. Furthermore, our study reveals a previously uncharacterised GABAAR-CAMKV interaction in mice and human brains. Our results provide a proof of concept for transmembrane and transcellular proximity labelling, establishing a powerful platform for analysing the interactomes of transmembrane proteins.
    DOI:  https://doi.org/10.1038/s41467-026-78135-2
  17. J Control Release. 2026 Nov 01. pii: S0168-3659(26)00914-4. [Epub ahead of print] 115510
    Lysosome-resident nanoreactor enables spatiotemporally controlled ferroptosis via cascade amplification of lipid peroxidation in breast cancer therapy.
    Tian-Jiao Zhou, Li-Ling Huang, Hao-Bin Che, Meng-Meng Zhang, Rui Long, Qiang Dai, Yan Wang, Wen-Yan Yang, Jing Zhang, Yi Wang, Jin-Jian Lu, Jee-Heon Jeong, Xian Wu Cheng, Lei Xing, Hu-Lin Jiang.
      Ferroptosis induced by Fenton-reaction holds great promise in triple-negative breast cancer (TNBC) therapy. However, its efficacy is severely constrained by limited endogenous hydrogen peroxide (H2O2) substrates and poor Fenton reaction efficiency. To overcome these limitations, we propose a strategy to initiate a heterogeneous photo-Fenton-like reaction in H2O2-rich lysosomes and design a reaction engine for amplified cascade toxic oxidative radical propagation (REACTOR), which can confine the reaction to lysosomes for light triggering and accelerate it with p-benzoquinone (DMBQ). The REACTOR nanoplatform encapsulates copper-enriched Prussian blue (CuPB) and a redox-active DMBQ within thermosensitive liposomes, enabling preferential accumulation in lysosomes. Under irradiation, REACTOR triggers lipid phase transition, exposing the co-encapsulated CuPB and DMBQ to the lysosomal H2O2 pool and initiating a highly efficient Fenton reaction that induces lysosomal membrane lipid peroxidation. Concurrently, ferrous ions released from lysosomal stores, together with CuPB-catalyzed quinone redox cycle, propagate oxidative damage to mitochondrial membranes, culminating in an explosive burst of lipid peroxides that efficiently triggers ferroptosis. REACTOR combined with irradiation significantly inhibits tumor growth, even achieving complete tumor regression and effectively suppressing metastasis in a TNBC-model. This light-activatable REACTOR transitions from a ready to a reactive state by mimicking the bombardier beetle's defense strategy, leveraging the lysosomal compartment to trigger, amplify, and sustain oxidative damage, offering a highly efficient and low-toxicity platform for precision cancer therapy.
    Keywords:  Copper-enriched Prussian blue; Fenton reaction; Ferroptosis; Lipid peroxidation; Lysosome-resident; Nanoreactor
    DOI:  https://doi.org/10.1016/j.jconrel.2026.115510
  18. Cell Metab. 2026 Nov 03. pii: S1550-4131(26)00369-4. [Epub ahead of print]38(11): 2173-2177
    Leveraging induced cell states for cancer therapy: The case for dynamic synthetic lethality.
    Christina Mayerhofer, David T Scadden.
      Metabolic differences between cancer and normal cells are accentuated by the selection pressure of therapy. Persisting cells enter a therapy-induced state of heightened, time-limited metabolic dependency. We argue that this interval can be exploited with metabolic modifiers to achieve persister cell death and improve cancer outcomes.
    DOI:  https://doi.org/10.1016/j.cmet.2026.08.017
  19. Biochemistry. 2026 Nov 03. 65(21): 3349-3370
    Nutrients and Their Role in Autophagy Regulation.
    Niall Wilson, Gamze Kocak, Sovan Sarkar, Yoana Rabanal Ruiz, Viktor I Korolchuk.
      Autophagy is a fundamental catabolic pathway that maintains cellular homeostasis through the degradation and recycling of intracellular components in response to nutrient limitation and metabolic stress. Increasing evidence indicates that autophagy is tightly regulated by cellular metabolism, with nutrients and metabolites acting not only as energy substrates and biosynthetic intermediates, but also as signaling molecules that directly modulate the autophagic machinery. In this review, we discuss how different metabolites regulate autophagy through interconnected nutrient- and energy-sensing pathways. We further examine how these metabolic signals coordinate distinct stages of autophagosome biogenesis and autophagic flux under conditions of nutrient deprivation or energy stress. Collectively, metabolite-autophagy crosstalk emerges as a central mechanism that enables cells to balance metabolic demand with intracellular resource availability, while its dysregulation contributes to metabolic imbalance and age-associated pathology.
    Keywords:  autophagy; cellular homeostasis; endoplasmic reticulum (ER); metabolism; phagophore assembly site (PAS)
    DOI:  https://doi.org/10.1021/acs.biochem.6c00482
  20. Cancer Lett. 2026 Nov 03. pii: S0304-3835(26)00708-1. [Epub ahead of print]664 218944
    Reprogramming muscle proteostasis in cancer cachexia: Transcriptional mechanisms and therapeutic opportunities.
    Bowen Xu, Aishwarya Jaiswal, Silin Liu, Ashok Kumar, Meiricris Tomaz da Silva.
      Cancer cachexia is a multifactorial syndrome characterized by progressive skeletal muscle wasting that impairs quality of life, limits responses to anticancer therapies, and increases mortality. Although excessive protein degradation has traditionally been viewed as a primary driver of muscle loss, cachectic muscle undergoes broader disruptions in proteostasis involving protein turnover, organelle quality control, stress adaptation, metabolism, and regenerative capacity. Accumulating evidence suggests that diverse tumor- and host-derived signals converge on interconnected transcriptional networks that coordinate these processes. Rather than functioning independently, transcription factors integrate inflammatory, metabolic, hormonal, and cellular-stress signals to orchestrate catabolic, stress-responsive, anabolic, and regenerative programs, with effects that vary with disease stage and cellular context. Importantly, these transcriptional responses are not uniformly pathological but can represent causal, adaptive, or compensatory programs. Epigenetic, post-transcriptional, and post-translational mechanisms add further regulatory layers that shape the activation and magnitude of these transcriptional programs. Emerging single-cell and multi-omic approaches have further revealed myofiber- and cell-specific regulatory networks that contribute to the heterogeneous response of skeletal muscle to tumor growth. In this review, we propose that transcriptional reprogramming represents a central integrative mechanism through which diverse catabolic signals remodel skeletal muscle proteostasis, and we examine how network-level regulation contributes to muscle adaptation and wasting in cancer cachexia. Defining which regulatory programs are causal, maladaptive, adaptive, or compensatory may reveal more precise biomarkers and therapeutic targets for preserving skeletal muscle mass and function in patients with cancer cachexia.
    Keywords:  Cancer cachexia; FOXO; Muscle atrophy; NF-κB; Proteostasis; STAT3; Skeletal muscle; Transcriptional regulation
    DOI:  https://doi.org/10.1016/j.canlet.2026.218944
  21. Sci Adv. 2026 Nov 06. 12(45): eaeh7786
    Cytoplasmic crowding drives intracellular viscoelastic increase during epithelial maturation.
    Gregory Arkowitz, Olivier Destrian, Anis Aggoun, Marc-Antoine Fardin, Pascal Berto, Gilles Tessier, René-Marc Mège, Jean-François Berret, Benoit Ladoux.
      The cytoplasm is a crowded, active medium whose mechanical properties underpin essential cellular functions, yet how intracellular rheology adapts during tissue maturation remains unclear. Here, we examine the evolution of cytoplasmic viscoelasticity in Madin-Darby canine kidney epithelial monolayers as cell density increases. Using magnetic rotational spectroscopy, an active microrheology technique, we quantify zero-shear viscosity and elastic modulus throughout monolayer maturation. We uncover a substantial enhancement of intracellular viscoelasticity correlated with increasing cell density and a concomitant rise in cellular dry mass concentration. Hyperosmotic perturbations on subconfluent monolayers reproduce this effect, confirming cytoplasmic crowding as a driver of rheological changes. Notably, intracellular viscoelasticity scales linearly with dry mass concentration, suggesting a direct coupling between internal mechanics and cytoplasmic concentration during epithelial maturation. These findings establish a link between tissue-level organization and intracellular mechanics, highlighting cytoplasmic crowding as a regulator of epithelial homeostasis and providing a framework to connect rheology with tissue behavior.
    DOI:  https://doi.org/10.1126/sciadv.aeh7786
  22. Nat Cancer. 2026 Nov 02.
    Myeloid-derived TGFβ1 and oncostatin M establish two distinct stromal niches controlling late and hybrid EMT states.
    Anqi Dong, Sebastiaan Vanuytven, Andrea Pérez González, Kevin Bévant, Lieselot Van de Putte, Zahra Zahedi, Justine Allard, Christine Dubois, Isabelle Salmon, Sandrine Rorive, Cédric Blanpain.
      Epithelial-to-mesenchymal transition (EMT) regulates tumor progression, metastasis and resistance to therapy. EMT encompasses a continuum of tumor states displaying different functions. The precise dialog between the tumor microenvironment and the different EMT states remains poorly understood. Using single-cell and spatial transcriptomics of mouse skin tumors, we uncover that different EMT states are associated with different niches. Neutrophils are more abundant in niches associated with hybrid EMT and secreted oncostatin M, which partially activates EMT while sustaining the epithelial program, promoting hybrid EMT states and metastasis formation. Macrophages are more abundant in niches associated with more advanced EMT states, which, together with other stromal cells, express TGFβ1 that promotes the late EMT state. Oncostatin M and TGFβ1 function in a feed-forward manner by creating distinct inflammatory niches to maintain specific EMT states. Together, our results reveal that distinct niches are associated with specific EMT states and that signaling pathways sustain their own niche's identity by recruiting specific myeloid cell populations.
    DOI:  https://doi.org/10.1038/s43018-026-01259-3
  23. Cancer Res. 2026 Nov 03. 86(21): 5313-5315
    Remembering Stiffness: HCC Maintains Malignancy through Heritable Hyperacetylation Driven by Mechanically Mediated Acetyl-CoA Levels.
    Kristopher A Kilian.
      Hepatocellular carcinoma (HCC) typically arises within fibrotic, mechanically rigid microenvironments where matrix stiffness directly drives primary tumor proliferation and invasion. However, whether and how tumor cells retain these mechanical adaptations upon disseminating to softer metastatic sites has remained unclear. In this issue of Cancer Research, Luo and colleagues demonstrate that HCC cells retain a "mechanical memory" of matrix stiffness that persists even after metastasizing to soft secondary niches, such as the lungs. Mechanistically, this memory is mediated by contractility-dependent suppression of mitochondrial fission. The resulting accumulation of acetyl-CoA fuels sustained histone hyperacetylation, preserving a proliferative state across subsequent cell generations. These findings uncover a novel mechano-metabolic-epigenetic axis that sustains HCC proliferation during metastatic dissemination. See related article by Luo et al., p. 5354.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-3004
  24. Cell. 2026 Nov 04. pii: S0092-8674(26)01213-4. [Epub ahead of print]
    CRISPR mutagenesis of the MYC locus reveals a druggable ultraconserved RNA element.
    Peiguo Shi, Feiyue Yang, Tala Fnu, Wesley Huang, Linqing Xing, Shah Alam, Wangyang Dai, Alexis O Aparicio, Colin H Kalicki, Aditi Trehan, Michael R Murphy, Esther R Rotlevi, Prajish Iyer, Lili Wang, Sara Zaccara, Muredach P Reilly, Ya Cheng Liao, Chaolin Zhang, Jianwen Que, Xuebing Wu.
      Noncoding sequences comprise most of the human genome; however, their functional significance remains largely elusive. Using CRISPR tiling mutagenesis with near-PAMless, high-fidelity SpRY-Cas9, we mapped the fitness landscape of an entire human gene, the 10-kb MYC locus, at base-pair resolution. This unbiased interrogation revealed that 67% of functionally essential base pairs are noncoding. Essential noncoding base pairs are under strong constraint in the human population but show limited evolutionary conservation across species. Within this landscape, we identified an ultraconserved noncoding RNA element in the 3' untranslated region (UTR) that promotes perinuclear localization of MYC mRNA and nuclear localization of MYC protein through interaction with hnRNP L. Steric-blocking antisense oligonucleotides (ASOs) targeting this element selectively eliminate diverse MYC-dependent cancer cells and inhibit growth of patient-derived tumor organoids. Together, these findings establish noncoding sequences as major carriers of functional genetic information and identify a therapeutically actionable RNA element whose targeting disrupts MYC-driven cancer.
    Keywords:  CRISPR; MYC; antisense oligonucleotides; cancer; hnRNP L; mRNA localization; noncoding; tiling mutagenesis; ultraconserved
    DOI:  https://doi.org/10.1016/j.cell.2026.10.002
  25. Mol Cell. 2026 Nov 05. pii: S1097-2765(26)00736-7. [Epub ahead of print]86(21): 4323-4324
    Myosin heavy-chain 9 executes cuproptosis.
    Anushka Ray, Andreas Linkermann.
      The pathophysiological relevance of cuproptosis has recently been demonstrated. In a study published in Cell, Wu et al. now identified myosin heavy-chain 9 (MYH9) as a critical molecule that oligomerizes in the presence of copper ions and causes the loss of plasma membrane integrity.1.
    DOI:  https://doi.org/10.1016/j.molcel.2026.10.016
  26. Cryobiology. 2026 Nov 01. pii: S0011-2240(26)00323-8. [Epub ahead of print]125 105904
    Cellular responses to severe dehydration during spin-drying resemble hyperosmotic stress.
    Fang Song, Saaya Yamane, Narumi Toyoda, Marie Shinohara, Takeshi Katsuda, Yasuyuki Sakai, Masaki Nishikawa.
      Dry preservation could potentially eliminate the need for low-temperature storage and cytotoxic cryoprotective agents. However, mammalian cells are sensitive to desiccation, and the cellular processes associated with drying-induced injury remain poorly understood. Drying and hyperosmotic stress both cause cellular dehydration, and previous studies have revealed similarities in these stresses. Here, we characterized drying injury by spin-drying HepG2 cells. We found that drying induced cellular responses closely resembled those caused by hyperosmotic dehydration, including cell shrinkage, membrane blebbing, cytoskeleton disruption, and widespread protein aggregation. In addition, trehalose suppressed extracellular salt crystallization during drying. Notably, cell death occurred within a narrow time window, suggesting that direct exposure to the gas phase and consequent rapid intracellular water loss may cause lethal injury. This work may guide future studies toward improved dry preservation strategies.
    Keywords:  Cellular dehydration; Cytoskeleton; Desiccation; Dry preservation; Hyperosmotic stress; Membrane blebbing; Protein aggregation; Trehalose
    DOI:  https://doi.org/10.1016/j.cryobiol.2026.105904
  27. Cancer Res Commun. 2026 Nov 03.
    A Phase 1 Trial of Low-dose Gemcitabine Combined with ATR Inhibitor Elimusertib for Advanced Solid Tumors.
    Thejus Jayakrishnan, Rebecca Porter, Alice Chen, Ningxuan Zhou, Julianne L Holleran, Massimiliano Russo, Douglas A Rubinson, Brandon M Huffman, Nabihah Tayob, Lorenzo Trippa, Kaitlyn Ramsey, Mckenzie Kelly, Leah H Biller, Panagiotis A Konstantinopoulos, Carolyn Krassner, Elizabeth K Lee, Ursula A Matulonis, Kimberly J Perez, Renata R Almeida, Srivatsan Raghavan, Alexi A Wright, Brian M Wolpin, Jonathan A Nowak, Alan D D'Andrea, Andrew J Aguirre, Steven Gore, Geoffrey I Shapiro, Jan H Beumer, James M Cleary.
       PURPOSE: Preclinical data suggest that the anti-cancer efficacy of ATR inhibitors can be synergistically enhanced by low-dose gemcitabine. To test the clinical feasibility of this regimen, we conducted a phase 1 trial of low-dose gemcitabine combined with the ATR inhibitor elimusertib (BAY1895344).
    PATIENTS AND METHODS: This phase 1 study evaluated the combination of gemcitabine and elimusertib in patients with previously treated, incurable solid tumors. The primary objective was to assess the safety and tolerability of this regimen and to determine the maximum tolerated dose (MTD). Secondary objectives included assessment of objective response rate (ORR) per RECIST v.1.1 and characterization of the pharmacokinetic (PK) profile.
    RESULTS: Fourteen patients were enrolled; most patients had pancreatic cancer (n=6) or ovarian cancer (n=6). The median age was 63.5 years of age, and the median number of prior therapies was 2. The regimen caused significant toxicity, and four patients (28%) discontinued the trial due to treatment-related adverse events. The trial was stopped prior to establishing an MTD due to the pharmaceutical company's decision to halt development of the agent. A confirmed partial response was observed in one patient with platinum-refractory ovarian cancer harboring a gain in CCNE1. Another patient with pancreatic adenocarcinoma harboring biallelic ATM loss remained on trial for 9.5 months with stable disease, with an 85% decrease in CA19-9.
    CONCLUSIONS: The combination of low-dose gemcitabine combined with elimusertib was not tolerable. Although evidence of anti-tumor activity was observed, significant improvements in tolerability are required for future ATR inhibitor combinations to be clinically feasible.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-26-0505
  28. Cold Spring Harb Perspect Med. 2026 Nov 02. pii: a035915. [Epub ahead of print]16(11):
    A History of Cancer Research: Mouse Models of Cancer Genetics.
    Joseph Lipsick.
      Studies of genetically engineered mice have contributed significantly to our understanding of tumor biology, and there are now countless mouse models of different human cancers. Breeding of mice for cancer research began more than 100 years ago. This provided early insights into cancer genetics, but it was the development of techniques for generating transgenic and knockout mice that transformed the field in the 1980s. The advent of CRISPR-Cas technology 30 years later made mouse models even easier to generate. In this excerpt from his forthcoming book on the history of cancer research, Joe Lipsick looks back at a century of advances in mouse cancer genetics, from the early pioneering work of Abbie Lanthrop to the Nobel-winning discoveries that now allow researchers to manipulate potential cancer genes in mice and explore their roles in tumorigenesis.
    DOI:  https://doi.org/10.1101/cshperspect.a035915
  29. Nat Protoc. 2026 Nov 03.
    Isolation and lipidomic profiling of neuronal lipid droplets to unveil the lipid landscape of neurodegenerative disorders.
    Mukesh Kumar, Rachel McAllister, Souvik Roy, Justin A Knapp, Kallol Gupta, Timothy A Ryan.
      Recent advances have expanded the role of lipid droplets (LDs) beyond passive lipid storage, implicating their involvement in various metabolic processes across mammalian tissues. Neuronal LDs, whose existence has long been debated, have now been identified in several neural structures, raising questions about their contribution to neurodegenerative disorders. Elucidating the specific chemical makeup of these organelles within neurons is critical for understanding their role in neural pathologies. However, the inherent submicron size and low abundance in neurons have posed challenges in their isolation and physical and biochemical characterization. Here, we present our Protocol that overcomes this obstacle: we blocked neuron-specific triglyceride lipase to enlarge LDs, rendering them amenable to flotation in a sucrose gradient. We further used an improved methodology of lipidomic analysis on the LDs purified from cultured primary neurons, offering insights into their unique lipid composition. This Protocol can be implemented by researchers with basic expertise in neuronal culture, imaging, ultracentrifuge handling and liquid chromatography-mass spectrometry analysis. The complete workflow requires 3-4 weeks, from neuronal culture to lipidomics analysis. Future integration of this method with high-throughput techniques holds promise for uncovering disease-specific alterations in lipid metabolism, providing new avenues for potential therapeutic interventions.
    DOI:  https://doi.org/10.1038/s41596-026-01451-w
  30. MedComm (2020). 2026 Nov;7(11): e71114
    Claudin-12-Expressing Fibroblasts Facilitate Metastatic Spread of Pancreatic Cancer Through Physical Interactions.
    Qingcui Li, Xiangjing Miao, Yuanyuan Yang, Ruoyang Chen, Qingqing Fang, Xixi Duan, Xiaohan Lou, Xiaohan Yao, Lijing Zhang, Rainer Glauben, Zhihai Qin, Chen Ni.
      Claudins (CLDNs), as major components of tight junctions in epithelial cells, are emerging as attractive non-mutant targets for controlling the growth and metastasis of various cancers. However, the mechanisms by which CLDNs modulate tumor progression remain largely unclear. Here, we unexpectedly found that CLDN12 is expressed in cancer-associated fibroblasts (CAFs), which are generally not considered tight junction-forming cells. CLDN12 expression in fibroblasts increased their motility and, importantly, promoted direct adhesion to pancreatic cancer cells through homophilic CLDN12-CLDN12 interactions. This CLDN12-dependent physical interaction between fibroblasts and tumor cells markedly enhanced cancer cell invasion. Moreover, TGF-β produced by cancer cells further induced the upregulation of CLDN12 expression in fibroblasts. In vivo, CLDN12-positive fibroblasts facilitated distant metastasis of pancreatic cancer to liver and diaphragm. Targeting CLDN12 with the synthetic peptide C12-pm efficiently decreased the liver metastasis of pancreatic cancer. Taken together, these findings reveal a previously unrecognized role of CLDN12-expressing fibroblasts in promoting pancreatic cancer metastasis through direct physical interactions with tumor cells and highlight CLDN12-mediated interactions as a potential therapeutic target for metastatic pancreatic cancer.
    Keywords:  Claudin‐12; cancer‐associated fibroblast; homophilic adhesion; metastasis; pancreatic cancer
    DOI:  https://doi.org/10.1002/mco2.71114
  31. Proc Natl Acad Sci U S A. 2026 Nov 10. 123(45): e2606813123
    Gastruloids reveal alternative morphogenetic routes for body-axis elongation with distinct cytoskeletal dependencies.
    Guillermo Serrano Nájera, Apolline Delahaye, Benjamin J Steventon.
      Morphogenesis requires cells to integrate genetic and environmental information to pattern and shape tissues. Recent studies in vivo and in vitro have shown how alterations in environmental cues can induce alternative morphogenetic programs. However, what determines which morphogenetic strategy cells deploy in different environments remains unknown. Using gastruloids, a model for mammalian posterior body-axis elongation where environmental cues can be controlled in vitro, we show that substrate availability determines which force-generation strategy cells employ to build the body axis. In free-floating conditions, gastruloids self-assemble a single posterior body axis, presumably through cell-cell interactions. When plated on laminin, gastruloids acquire a flat morphology, break symmetry multiple times, and produce several independently elongating cell streams with anterior-posterior polarity through collective cell migration. On laminin, formin activity and focal adhesion-mediated traction are required for tissue elongation, yet both are functionally dispensable in free-floating conditions. Transcriptomic analysis shows that formin inhibition blocks elongation on laminin without any detectable transcriptional changes, indicating that these cytoskeletal components play primarily a mechanical role that is only required when cells engage a substrate. Furthermore, laminin biases cells toward posterior migratory fates while preserving similar Hox expression. Together, these results show that mammalian body-axis elongation can proceed through different morphogenetic modes that engage distinct mechanical effectors depending on substrate availability. These findings have implications for understanding how evolution explores morphological diversity and how tissue engineering might achieve desired forms through precise environmental control.
    Keywords:  developmental plasticity; extracellular matrix; gastrulation; gastruloids
    DOI:  https://doi.org/10.1073/pnas.2606813123
  32. Nat Commun. 2026 11 02. pii: 11125. [Epub ahead of print]17(1):
    HuBMAP Data Portal: a resource for multimodal spatial and single-cell data of healthy human tissues.
    HuBMAP Consortium
      The NIH Human BioMolecular Atlas Program (HuBMAP) Data Portal ( https://portal.hubmapconsortium.org/ ) serves as a comprehensive repository for multimodal, multi-scale spatial and single-cell data from healthy human tissues. As of August 2026, the portal hosts 9,316 public datasets from 26 data types spanning 29 organ classes across 501 donors. Portal infrastructure and user interfaces support data search and discovery, visualization, and analysis directly in web browsers. These capabilities include metadata- and data-driven search, collaborative Workspaces with access to high-performance compute, and interactive Vitessce visualizations across non-spatial, 2D, and 3D spatial datasets. Data-type-specific uniform processing pipelines and rigorous quality control processes ensure comparability of results across laboratories, organs, and donors, while externally processed community-contributed datasets provide complementary perspectives. Here we describe portal functionality, infrastructure, and design, and highlight its role as a platform for large-scale spatial single-cell research across diverse data types, organs, and scales.
    DOI:  https://doi.org/10.1038/s41467-026-77835-z
  33. Pancreatology. 2026 Oct 30. pii: S1424-3903(26)01566-8. [Epub ahead of print]
    Sludge-induced acute pancreatitis is linked to lower cholecystectomy rates than gallstone pancreatitis.
    Max Ole Hubert, Yujun Xu, Maria Valeria Demattè, Arlett Schäfer, Katarzyna Osokin, Katharina Bretthauer, Eric Hohmann, Mali Junge, Mahmood Ahmad, Michal Żorniak, Georg Beyer, Julia Mayerle, Simon Sirtl.
      
    Keywords:  Acute pancreatitis; Biliary pancreatitis; Biliary stones; Cholecystectomy; Secondary prevention
    DOI:  https://doi.org/10.1016/j.pan.2026.10.032
  34. bioRxiv. 2026 Oct 28. pii: 2026.10.27.762351. [Epub ahead of print]
    Tryptophan Restores Recovery Competence Following Starvation in the Absence of Lysosomal Amino Acid Sensing.
    John T Murphy, Ryan Chang, Ziang Bi, Siana Kapoor, Haoying Zhang, David Seamons, Agastya Diwan, Micklaus Garcia, Moydul Islam, Kenji Rowel Q Lim, Daniel L Schneider, Brian M Egan, David Rawnsley, Xiucui Ma, Kerry Kornfeld, Abhinav Diwan.
      How organisms recover from starvation to nutrient-replete physiology remains poorly understood. In C. elegans , we previously observed that transcription factor hlh-30 or a combination of glucose and linoleic acid in its absence are essential for survival with refeeding following starvation, i.e. recovery competence. A forward genetic screen to evaluate mechanisms identified depd-5 , which encodes a GATOR1 subunit, loss of which is expected to impair amino acid sensing with unrestrained raga-1 and mTOR activation. Surprisingly, glucose refeeding reduced recovery competence in depd-5(lf , loss-of-function) animals, which was rescued by amino acids, specifically tryptophan. Increasing tryptophan levels in depd-5(lf) worms through supplementation, reduced tryptophan catabolism with tdo-2 ablation and prolonged starvation restored recovery competence. raga-1(gf , gain-of-function) recapitulated whereas raga-1(lf) rescued the impaired recovery competence in starved depd-5(lf) worms. An analogous DEPDC5 mutation in mammalian cells impaired starvation-induced mTOR inactivation. We conclude that tryptophan counters unrestrained mTOR activity to restore recovery competence following starvation.
    DOI:  https://doi.org/10.64898/2026.10.27.762351
  35. bioRxiv. 2026 Oct 27. pii: 2026.10.22.760470. [Epub ahead of print]
    A Cell-Autonomous Cold Sensor Promotes Lipolysis Through Phase Separation.
    Yong Chen, Li Chen, Zezhou Zhao, Tian Lu, Youchen Guan, Zinger Yang Loureiro, Shingo Kajimura.
      Temperature is a fundamental determinant of mammalian metabolism. The canonical cold-adaptation pathway involves cold sensing by peripheral sensory neurons, which activate sympathetic outflow, β-adrenergic signaling, and lipolysis in adipose tissue. In contrast, we report here a cell-intrinsic mechanism by which physiologically relevant cooling temperatures (27-31 °C) enhance lipolysis in subcutaneous adipose tissue. Mechanistically, cooling drives liquid-liquid phase separation (LLPS) of perilipin 1 (PLIN1), the dominant lipid droplet coat protein, promoting its condensation and the local recruitment of PKA to the droplet surface. This spatial reorganization selectively amplified PKA-mediated perilipin 1 phosphorylation, CGI-58 release, and ATGL-dependent lipolysis. The process depends on the intrinsically disordered region (IDR) of perilipin1, where four aromatic residues, conserved in endotherms but not in ectotherms, are required for cooling-induced LLPS and lipolysis in vivo. Notably, targeted delivery of an LLPS-competent perilipin 1 variant to the inguinal adipose tissue of mice enhanced local lipolysis and reduced depot mass. Together, these findings uncover a cell-intrinsic thermosensitive mechanism that can tune lipolytic responsiveness, offering a possible strategy for targeted depot-selective fat reduction.
    DOI:  https://doi.org/10.64898/2026.10.22.760470
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