bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2026–07–05
twenty-two papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Dysregulated sphingolipid metabolismdrives pancreatic carcinogenesis through plasma membrane Kras enrichment.
  2. Mechanistic studies of autophagic cargo recruitment and membrane shaping through in vitro reconstitution.
  3. Surface Complex V couples proton gradient across the plasma membrane to ATP production in cancer.
  4. A dietary switch promotes sensory neuron-dependent cancer-associated cachexia.
  5. Cell crowding initiates tumor invasion by triggering a nanoscale topography transition of plasma membranes.
  6. Pancreatic Cancer: Translating Tumor Biology into Actionability.
  7. Spatially Resolved Proteomic Cartography Illuminates the Earliest Molecular Programs in Pancreatic Cancer Evolution.
  8. Disentangling the response to lysosomal damage.
  9. Steatosis shapes prognosis-defining liver metastasis heterogeneity in CRC.
  10. Biochemistry at scale: Seeing both the forest and the trees.
  11. Early Metastatic Relapse in Resected Stage IB KRAS G12D Pancreatic Ductal Adenocarcinoma: Limitations of Anatomical Staging.
  12. Ferrosome Organelles Spatially Insulate a Redox-Active Ferrous Phosphate Biomineral from Cytosolic ROS Chemistry.
  13. Imaging the hallmarks of cancer.
  14. Seeing cachexia clearly: the evolution of body composition and radiological biomarkers in cancer wasting.
  15. Senescence in non-cancerous cells within the tumor: What is the real deal?
  16. Zonated mechanosensing by PIEZO1 controls liver regeneration.
  17. Use of liposomal irinotecan with 5-FU and oxaliplatin (NALIRIFOX) in neoadjuvant pancreatic adenocarcinoma: NEO-Nal-IRI trial.
  18. Label-Free All-Electrical Tracking of Individual and Collective Cell Migration on a Megapixel CMOS Capacitance Sensor.
  19. Turning perfusion into repair through ferroptosis blockade.
  20. Drugging Ras trafficking-are there new roads to travel?
  21. Restraint of melanoma progression by cells in the local skin environment.
  22. Ventral pallidal GABAergic neurons control hedonic feeding and obesity.
  1. Gut. 2026 Jul 03. pii: gutjnl-2025-337363. [Epub ahead of print]
    Dysregulated sphingolipid metabolismdrives pancreatic carcinogenesis through plasma membrane Kras enrichment.
    Ahmed Alnatsha, Jianying Xu, Tahib Habshi, Qi Li, Klea Rickú, Prince Allawadhi, Didem Saka, Ruoxan Dai, Yuxing Xue, Hang Nguyen, Helena Stadler, Theresa Weltermann, Quan Zhou, Nicole Schreiner, Yonggan Xue, Victoria Rittinghausen, Steffen Ormanns, Fredrick Klauschen, Danmei Zhang, Stefan Böck, Martin Benoit, Najib Ben Khaled, Shibojyoti Lahiri, Axel Imhof, Andreas Klingl, Anjali Jaiswal, Girija P Sahoo, Ivonne Regel, Sebastian Mueller, Rupert Öllinger, Roland Rad, Claus Belka, Tanja Bange, Kirsten Lauber, Julia Mayerle, Ujjwal M Mahajan.
       BACKGROUND: As key constituents of cellular sphingolipid pools, sphingomyelin (SM) and ceramide (CER) are central to the regulation of cancer cell death and survival. The metabolic flux between these two lipids is a vital component of the cellular stress response, yet the underlying regulatory mechanisms in cancer remain elusive. Acid sphingomyelinase (SMPD1) facilitates the conversion of SM to CER, functioning as a key enzymatic driver of CER-mediated signalling.
    OBJECTIVES: Herein, we aim to evaluate the role of SMPD1-driven sphingolipid metabolism in pancreatic carcinogenesis.
    DESIGN: A targeted quantitative analysis of the plasma metabolome was conducted involving patients with pancreatic ductal adenocarcinoma (PDAC, n=202) and matched control subjects (n=204). Multiplex immunohistochemistry was performed on resected PDAC (n=122) to identify expression of SMPD1 with tumour and immune cell markers. CRISPR/Cas9 driven Smpd1-deleted murine cell lines were generated and subsequently assessed for their carcinogenic potential in vitro. The effects of Smpd1 deletion on tumour formation were evaluated using both syngeneic orthotopic and metastatic murine models.
    RESULTS: Here, we demonstrate that tumour cell-autonomous expression of SMPD1, in pancreatic ductal adenocarcinoma (PDAC), is associated with poorer patients' outcomes. Smpd1 ablation in murine PDAC cells resulted in reduced proliferation and migration in vitro and decreased metastases and tumour burden in vivo. Integrated transcriptomic, metabolomic and proteomic studies revealed that SMPD1 abrogation impairs KrasG12D oncogenic signalling and, thus, reduces tumour burden. Reduced plasma membrane interaction of KrasG12D was associated with SMPD1-dependent sphingolipid metabolism. Notably, the SMPD1 inhibitor (ARC39) potently synergised with the KrasG12D inhibitor (MRTX1133).
    CONCLUSION: In summary, SMPD1 regulated plasma membrane sequestration of KrasG12D represents a potential therapeutic target within the Kras signalling pathway for intractable PDAC.
    Keywords:  BASIC SCIENCES; PANCREAS; PANCREATIC CANCER
    DOI:  https://doi.org/10.1136/gutjnl-2025-337363
  2. Autophagy. 2026 Jun 30.
    Mechanistic studies of autophagic cargo recruitment and membrane shaping through in vitro reconstitution.
    Wenxin Zhang, Thomas Litschel, Anne Schreiber, Rocco D'Antuono, Sharon A Tooze.
      Macroautophagy/autophagy, a conserved intracellular catabolic pathway, removes deleterious cytosolic material to maintain homeostasis and survival. Upon autophagy induction, a unique double-membraned structure, the phagophore, forms and engulfs cytosolic material, the cargo, as it closes to become an autophagosome. Mammalian Atg8-family proteins (ATG8s) are ubiquitin-like proteins which are essential for engulfment of the cargo and membrane closure. ATG8s are recruited to the phagophore by ATG12-ATG5-ATG16L1, an E3-like ligase which is recruited by PtdIns3P-binding WIPI proteins. Covalent lipidation of the ATG8s to phosphatidylethanolamine by the E3 ligase occurs specifically on the phagophore membrane allowing recruitment of cytosolic cargo and cargo receptors, such as SQSTM1/p62. While ATG8-cargo receptor interactions are well established, how the ATG8s bind cargo and cargo receptors on the inner membrane of the phagophore has not been studied. To recapitulate these events, we use giant unilamellar vesicles (GUVs) and encapsulate protein machinery and cargo, generating a membrane platform to which ATG8 proteins can be recruited. Inside the GUVs we reconstituted WIPI2B-directed and cargo-directed ATG8 lipidation revealing distinct roles of WIPI2B and SQSTM1 in initiating ATG8 conjugation. We show that SQSTM1 and SQSTM1 droplets are recruited to the GUV inner membrane through interaction with membrane bound ATG8s. Through the development of a bead-based membrane deformation assay, we show redistribution and local enrichment of membrane-bound ATG8s occurs upon binding to SQSTM1 droplets. Our work demonstrates fundamental molecular mechanisms into phagophore-ATG8-cargo interactions providing novel model systems to investigate ATG8-cargo interactions on the inner phagophore membrane.Abbreviations:ATG: autophagy related; cDICE: continuous droplet interface crossing encapsulation; DOPE: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine; GABARAP: GABA type A receptor-associated protein; GUV: giant unilamellar vesicle; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; LIR: LC3-interacting region; LUV: large unilamellar vesicle; NBD: 7-nitrobenz-2-oxa-1,3-diazol-4-yl; PE: phosphatidylethanolamine; PtdIns: phosphatidylinositol; PtdIns3P: phosphatidylinositol-3-phosphate; PolyUb: K63-linked polyubiquitin; POPC: 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine; POPE: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine; Rh-PE: 18:1 Liss Rhod PE; SQSTM1/p62: sequestosome 1; WIPI2B: WD repeat domain, phosphoinositide interacting 2B.
    Keywords:  ATG8 lipidation; giant unilamellar vesicles; in vitro reconstitution; liquid-liquid phase separation; membrane expansion
    DOI:  https://doi.org/10.1080/15548627.2026.2697432
  3. Res Sq. 2026 Jun 17. pii: rs.3.rs-10007862. [Epub ahead of print]
    Surface Complex V couples proton gradient across the plasma membrane to ATP production in cancer.
    Daniel Pelaez, Samantha McLaughlin, Kendall Knechtel, Zelia Correa, J William Harbour.
      Cancer cells alter their metabolism to support growth and survival, most notably by fermenting glucose to lactate even in the presence of oxygen, a phenomenon known as the Warburg effect. Although this metabolic state has been recognized for decades, its bioenergetic advantages remain unclear, as fermentation produces less net ATP than mitochondrial respiration. How aerobic fermentation contributes to cellular energy balance therefore remains unresolved. Here, we show that extracellular acidification generated by lactate export creates a proton gradient across the plasma membrane that is harnessed by ectopic ATP synthases to drive intracellular ATP production. We find that ATP synthase and proton-shuttling components of the mitochondrial respiratory chain translocate to the plasma membrane in cancer cells and are preferentially oriented to exploit this gradient, linking a hallmark of aerobic fermentation directly to energy supplementation. This work provides a mechanistic resolution to the apparent energetic inefficiency of the Warburg paradigm and identifies a previously unrecognized pathway for energy complementation in cancer.
    DOI:  https://doi.org/10.21203/rs.3.rs-10007862/v1
  4. Science. 2026 Jul 02. 393(6806): 90-97
    A dietary switch promotes sensory neuron-dependent cancer-associated cachexia.
    Michael Cross, Stefan Kotschi, Warren Wu, Fedra Luciano-Mateo, Young-Yon Kwon, Ezequiel Dantas, Taha Niazi, Shijia Chen, Ali Rashidfarrokhi, Ray Pillai, Jack Sanford, Jeshua Kim, Juliya Hsiang, Begona Gamallo-Lana, Adam C Mar, Yuan Hao, Sahith Rajalingam, Annie Huang, Jackie Shan, Habon A Issa, Maria Gomez, Alice R Wang, Xiang Zhao, Tobias Janowitz, Eileen White, Yin Liu, Kwok-Kin Wong, Leopoldo N Segal, Sheng Hui, Marcus D Goncalves, Robert C Froemke, Thales Papagiannakopoulos.
      Sickness behaviors are common in cancer-associated cachexia and affect up to half of lung cancer patients. We demonstrate that among the most common cancer mutations, loss of liver kinase B1 (Lkb1) promotes the development of cachexia in preclinical models of lung cancer. In an effort to improve caloric intake with an obesogenic high-fat diet, we paradoxically observed worsened cachexia-associated sickness. We found that local production of prostaglandin E2 (PGE2), rather than circulating factors, promotes sickness and that genetic, dietary, and pharmacological inhibition of tumor-derived PGE2 suppresses sickness and cachexia. Notably, we demonstrate that lung sensory neuron abrogation prevents PGE2-dependent cachexia. Our study establishes localized tumor-derived signals to sensory neurons, rather than circulating factors, as drivers of cachexia and highlights a previously unknown role of the peripheral nervous system in cancer cachexia.
    DOI:  https://doi.org/10.1126/science.adz4196
  5. Acta Biomater. 2026 Jun 30. pii: S1742-7061(26)00433-2. [Epub ahead of print]
    Cell crowding initiates tumor invasion by triggering a nanoscale topography transition of plasma membranes.
    Xinbin Zhao, Min Tan, Long Li, Xubo Lin, Zekun Li, Xiaohuan Wang, Bingqi Song, Tailin Chen, Sen Hou, Jiehou Fan, Shijiang Wang, Zheng Guo, Yun Zhang, Jing Du.
      During the progression from epithelial neoplasms to invasive carcinoma, uncontrolled cellular growth within a confined space generates pronounced cell crowding. Despite its prevalence, how cancer cells sense and respond to crowding during the early stages of tumor invasion remains poorly understood. Here, using a spontaneous crowding model that mimics the progressive compressive stress produced by proliferating cells, we show that cell crowding induces an invasive phenotype in cancer cells. This phenotypic switch is accompanied by a nanoscale smooth-to-corrugated topography transition (nSCTT) of the plasma membrane. By combining biophysical measurements with mechanical modeling, we demonstrate that cell crowding elevates Laplace pressure while reducing membrane tension to drive the nSCTT of the plasma membrane. nSCTT promotes tumor invasion by disrupting the aggregation of lipid raft-like domains. Finally, we demonstrate that strengthening membrane-to-cortex attachment (MCA) effectively blocks the nSCTT and suppresses tumor invasion in both cell crowding models and mouse xenograft models. Together, these findings reveal that cell crowding initiates tumor invasion through a nanoscale plasma membrane topography transition, providing a framework for understanding how mechanical forces are converted into malignant behavior at the nanoscale. STATEMENT OF SIGNIFICANCE: This study reveals how physical crowding of cancer cells triggers invasion through a previously unknown nanoscale mechanism. We discovered that crowding forces cause the cell membrane to transform from smooth to corrugated at the nanoscale. This topography change breaks apart critical signaling hubs (lipid raft domains) on the membrane, ultimately activating invasive behavior. This work provides a framework for understanding how tumors become malignant under mechanical stress and identifies reinforcing the cell membrane as a potential strategy to block cancer invasion.
    Keywords:  Cell crowding; Invasion initiation; Lipid raft-like domains; Membrane-to-cortex attachment; Nanoscale topography transition
    DOI:  https://doi.org/10.1016/j.actbio.2026.06.062
  6. Cancer Discov. 2026 Jul 01. 16(7): 1262-1279
    Pancreatic Cancer: Translating Tumor Biology into Actionability.
    Fiyinfolu O Balogun, Mara H Sherman, Wungki Park, Kevin C Soares, Marsha Reyngold, Joshua D Schoenfeld, Anupriya Singhal, Christine A Iacobuzio-Donahue, Eileen M O'Reilly.
      Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of pancreatic cancers and has a very poor prognosis. Ten to 15% are staged as resectable at diagnosis, and 5% to 15% downstaged with therapy to where surgery is feasible. Chemotherapy is a mainstay for all stages of PDAC. Targeted therapies are available for patients with select but expanding actionable genomic alterations. The tumor microenvironment provides a dense stroma with an immunosuppressive milieu that contributes to inherent treatment resistance of PDAC. Herein, we review current management of PDAC with a focus on emerging treatment paradigms, including targeted and immunomodulatory agents.
    SIGNIFICANCE: PDAC is a complex disease with unique genomic, immunologic, and clinical features. Recent developments in understanding of the pathobiology of this disease are translating into targeted and immunomodulatory therapies that will alter treatment paradigms and improve outcomes for this recalcitrant malignancy.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-2014
  7. Cancer Discov. 2026 Jul 01. 16(7): 1255-1257
    Spatially Resolved Proteomic Cartography Illuminates the Earliest Molecular Programs in Pancreatic Cancer Evolution.
    Mingyu Yang, Rong Fan.
      Min, Schweizer, and colleagues use artificial intelligence-powered deep visual proteomics to generate a spatial proteomic atlas of pancreatic cancer precursor evolution, revealing that major metabolic and inflammatory reprogramming occurs long before overt histologic transformation. More broadly, the study highlights the emerging potential of spatial proteomics and multiomics to bridge histopathology with molecular pathology and precision oncology. See related article by Min et al., p. 1323.
    DOI:  https://doi.org/10.1158/2159-8290.CD-26-1022
  8. J Cell Sci. 2026 Jul 01. pii: jcs264806. [Epub ahead of print]139(13):
    Disentangling the response to lysosomal damage.
    Hemmo Meyer, Akiko Kuma, Shuhei Nakamura.
      The limiting membrane of lysosomes is prone to damage that can have deleterious consequences for cellular homeostasis. Cells respond to this damage with an array of molecular countermeasures, ranging from membrane repair mechanisms to elimination of terminally damaged lysosomes by selective macroautophagy. The various elements of this response therefore need to be carefully assessed in the context of the specific pathological or experimental conditions being studied. Emerging evidence has revealed further complexity within the lysosomal damage response, such as processes that contribute to initial membrane resealing as well as lysosome regeneration required to restore the lysosomal system. These mechanisms involve unusual ubiquitylation, non-canonical ATG8 lipidation, or modifications that govern lysosome tubulation or microlysophagy pathways. Therefore, caution is advised when using previously established lysosome damage reporters that might confound interpretation of the underlying events and outcomes. This Opinion article seeks to shed light on the emerging regulatory mechanisms of lysosomal regeneration and evaluate the appropriateness of various reporters and assays for studying the lysosomal damage response.
    Keywords:  ATG8; ESCRT; Lysosomes; Membrane permeabilization; Microautophagy; Ubiquitin
    DOI:  https://doi.org/10.1242/jcs.264806
  9. Nature. 2026 Jul 01.
    Steatosis shapes prognosis-defining liver metastasis heterogeneity in CRC.
    Yiming Peng-Winkler, Xiao-Zheng Liu, Sanne M L Verheul, Charlotte Girondel, Sebastian Igelmann, Sara Marie Rotter, Michail Doukas, Ming Liu, Anke Vandekeere, Mélanie Planque, Juan Fernández-García, Sébastien Tabariès, Marta Buetas-Arcas, Sandra Martínez-Martín, Florian Döbbe, Margherita Demicco, Ines Vermeire, Janine Theile, Johannes Ceuppens, Jonas Haesevoets, Emma Tobarra-López, Dorien Broekaert, Johannes Georg Bode, Tom Luedde, Peter Vermeulen, Daniele V F Tauriello, Raquel Perez-Lopez, Steve Stegen, Laura Soucek, Tiago De Oliveira, Lena-Christin Conradi, Peter M Siegel, Cornelis Verhoef, Sarah-Maria Fendt.
      Patients with colorectal cancer (CRC) frequently develop liver metastases1-3. The prognosis of these patients is skewed by the histopathological heterogeneity of their liver metastases4,5. Patients with 'replacement' metastases have a 5-year overall survival of less than 44.2%, compared with 73.4% in patients with 'encapsulated' (previously known as desmoplastic) metastases5; yet there are currently no approved therapies targeting replacement liver metastases. Here we show that treatment-naive patients with CRC with liver steatosis have an increased occurrence of replacement metastases compared with patients without steatosis. Mechanistically, we find that steatosis-promoted fatty acid oxidation increases formation of replacement metastases by increasing MYC stability through acetylation. In turn, MYC activates proline synthesis, fuelling collagen production, enabling growth of replacement metastases. Targeting MYC, P5CS or COL1A1 suppresses the occurrence and growth of replacement metastases in patient-derived organoids, mouse or patient-derived xenograft models. Spatial metabolite and protein analyses of liver metastases from patients with CRC further support this mechanism. In conclusion, we provide a mechanistic understanding of the emergence of liver metastases with poor prognosis in treatment-naive patients with CRC, identifying potential targets for therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41586-026-10686-2
  10. Trends Biochem Sci. 2026 Jul;pii: S0968-0004(26)00142-8. [Epub ahead of print]51(7): 661-672
    Biochemistry at scale: Seeing both the forest and the trees.
    Stefan A Harry, Chirag Vasavda, Adam Wahida, Reilly Stevens, Harshabad Singh, I David Goldman, Bruce Chabner, Liron Bar-Peled.
      Today, therapeutic drug discovery lies at the crossroads of mechanistic biochemistry and the rapidly growing fields of multi-omics and AI. How will traditionally reductionist biochemistry adapt to the increasing complexity of biological processes? We address this question by first examining historical cases in which biochemistry uncovered new biology in pathways targeted by small-molecule drugs, leading to the development of targeted disease treatments. We discuss how biochemistry is evolving with approaches such as chemical proteomics, which maps protein-drug interactions and is increasingly important for therapy development. Ultimately, the future of drug discovery will be defined by the ability to integrate high-content measurements into the process of defining actionable biochemical mechanisms: seeing both the forest and the trees through biochemistry executed 'at scale'.
    Keywords:  AI; chemical proteomics; drug discovery; multi-omics
    DOI:  https://doi.org/10.1016/j.tibs.2026.05.005
  11. Cureus. 2026 May;18(5): e109660
    Early Metastatic Relapse in Resected Stage IB KRAS G12D Pancreatic Ductal Adenocarcinoma: Limitations of Anatomical Staging.
    Vaishna Anilkumar.
      Pancreatic ductal adenocarcinoma (PDAC) is associated with poor survival, although patients with localized resectable disease are generally expected to achieve improved outcomes following surgery and adjuvant chemotherapy. Increasing evidence, however, suggests that tumor biology may outweigh anatomical staging in determining prognosis. This case report describes the case of a 36-year-old male with low-risk factors diagnosed with stage IB pancreatic tail adenocarcinoma following evaluation for persistent dyspeptic symptoms. The patient underwent distal pancreatectomy with splenectomy and achieved a margin-negative, node-negative resection. Histopathology demonstrated lymphovascular and perineural invasion, while delayed molecular profiling identified a KRAS G12D mutation. Despite apparently favorable pathological staging and adjuvant FOLFIRINOX chemotherapy, the patient developed early biochemical progression with rapidly rising carbohydrate antigen 19-9 (CA 19-9) levels, followed by widespread metastatic dissemination involving the liver, lung, spine, skeletal muscle, and multiple visceral sites. Notably, disease progression occurred despite a transient biochemical response to second-line chemotherapy, highlighting discordance between tumor marker kinetics and true disease burden. The patient died 13 months after diagnosis. This case highlights the limitations of anatomical staging in PDAC and emphasizes the prognostic importance of tumor biology, including KRAS mutation status, lymphovascular invasion, and perineural invasion. It also demonstrates the potential limitations of CA 19-9 as a solitary marker of treatment response in biologically aggressive disease.
    Keywords:  early-stage cancer; kras mutation; metastasis; pancreatic adenocarcinoma; pancreatic cancer; pancreatic tail tumor; perineural invasion; vascular invasion
    DOI:  https://doi.org/10.7759/cureus.109660
  12. bioRxiv. 2026 Jun 17. pii: 2026.06.16.732667. [Epub ahead of print]
    Ferrosome Organelles Spatially Insulate a Redox-Active Ferrous Phosphate Biomineral from Cytosolic ROS Chemistry.
    Kewei Zhao, Kristina M Ferrara, Yixuan Liu, Macon J Abernathy, Ritimukta Sarangi, Hualiang Pi.
      Ferrosomes are recently discovered lipid-bound bacterial organelles that store iron as iron-phosphate biominerals, yet the chemical nature and physiological consequences of ferrosome-stored iron remain poorly understood. Here, we combined X-ray absorption spectroscopy (XAS), electron microscopy, inductively coupled plasma mass spectrometry (ICP-MS), and physiological analyses to characterize ferrosome iron in Clostridioides difficile . XAS analysis of isolated ferrosomes revealed an amorphous iron-phosphate biomineral containing mixed Fe(II)/Fe(III), consistent with partial oxidation during aerobic isolation. In contrast, whole-cell XAS of intact anaerobically maintained cells demonstrated that ferrosomes predominantly contain a structurally disordered ferrous phosphate biomineral with local Fe-O-P coordination features similar to those of vivianite. Upon air exposure, this ferrous biomineral rapidly oxidized to a ferric phosphate-like state, revealing a highly oxygen-sensitive iron-storage phase. Despite containing abundant redox-active Fe(II), ferrosome-stored iron contributed minimally to the cytosolic labile iron pool. Consistent with this observation, isolated ferrosomes exhibited little ROS-generating activity, and ferrosome-overproducing cells displayed no substantial increase in sensitivity to oxygen, peroxide, or paraquat stress relative to ferrosome-deficient controls. Together, these results establish ferrosomes as iron-storage organelles that sequester redox-active Fe(II) in a mineralized ferrous phosphate phase, limiting its participation in cytosolic ROS chemistry and providing a mechanism for the safe storage of reactive iron.
    Significance Statement: Iron is essential for life but can also damage cells because ferrous iron drives oxidative stress. How cells store large amounts of ferrous iron while limiting toxicity therefore remains a fundamental biological question. Ferrosomes are recently discovered bacterial organelles that store iron as iron-phosphate biominerals, but the chemical nature and physiological consequences of ferrosome-associated iron remained unknown. Using Fe K-edge X-ray absorption spectroscopy, we show that ferrosomes in Clostridioides difficile contain a redox-sensitive ferrous phosphate biomineral. Physiological analyses demonstrate that this iron is largely inaccessible to cytosolic reactive oxygen species (ROS) chemistry. These findings reveal that bacteria can combine biomineralization and subcellular compartmentalization to maintain large intracellular iron reservoirs while limiting iron-dependent oxidative damage.
    DOI:  https://doi.org/10.64898/2026.06.16.732667
  13. Nat Rev Cancer. 2026 Jun 29.
    Imaging the hallmarks of cancer.
    Jan Grimm, Fabian Kiessling, Kevin M Brindle, Douglas Hanahan, Sanjay K Jain, Philippe Lambin, Twan Lammers, King C Li, I Jolanda M de Vries, Wolfgang A Weber, Bettina Weigelin, Bernd J Pichler.
      The hallmarks of cancer were introduced by Hanahan and Weinberg as a conceptual organizing framework to distil the complexity of tumours. This concept of cancer hallmarks has become an enduring theme in cancer research. Moreover, an increasing number of therapeutic strategies are being aimed at targeting these hallmarks. However, translating them into the clinic requires technologies to monitor their effectiveness and biomarkers that can stratify patients for the choice of specific therapies. Tumour heterogeneity and the ability of tumour cells to rapidly mutate and develop evasion strategies makes the development of non-invasive imaging capabilities to interrogate these hallmarks as biomarkers and monitor them longitudinally and quantitatively particularly important. This Review presents a holistic discussion of non-invasive diagnostic imaging capabilities related to the hallmarks of cancer; some hallmarks can be assessed with imaging probes that directly target biomolecules, whereas others can be interrogated indirectly by imaging pathophysiological processes. Additionally, visualizing the hallmarks of cancer can be addressed with artificial intelligence-assisted, multiparametric image analysis (for example, radiomics, radiogenomics and deep learning). The approaches discussed have been evaluated in a translational context, and some of them already have a substantial role in clinical practice, for example, to guide treatment strategies, including surgical resections, radiotherapy and molecularly targeted chemo-, immuno- and radiopharmaceutical therapies.
    DOI:  https://doi.org/10.1038/s41568-026-00950-y
  14. Curr Opin Clin Nutr Metab Care. 2026 Jul 03.
    Seeing cachexia clearly: the evolution of body composition and radiological biomarkers in cancer wasting.
    Maria Soupashi, Richard J E Skipworth, Leo R Brown.
       PURPOSE OF REVIEW: Cancer cachexia is a highly prevalent multifactorial syndrome with huge prognostic influence. It is primarily characterised by progressive tissue wasting and imaging can be a powerful tool for noninvasive, longitudinal assessment.
    RECENT FINDINGS: Ongoing exploration and development of imaging modalities such as computed tomography (CT) and magnetic resonance imaging (MRI), as well as emerging radiological biomarkers, will deepen our understanding of distinct cachexia phenotypes.
    SUMMARY: Bioelectrical impedance (BIA) and dual-energy X-ray absorptiometry (DEXA) were amongst the earlier modalities used to assess body composition. They are accessible and easy to use; however, concerns remain regarding their accuracy, and a paucity of detail provided in their estimates. CT provides more granular muscle and adipose tissue measurements, and analyses can be augmented with the use of automated segregation systems and multislice volumetric analysis. This could be key for supporting its integration in clinical practice. Beyond conventional quantitative assessments, MRI may aid in characterising emerging, clinically important markers of cachexia such as muscle inflammation, fat infiltration or fibrosis. Positron emission tomography (PET) CT may also become important tools for exploring how specific tissue-level pathophysiology can be accurately detected.
    Keywords:  body composition; cancer cachexia; computed tomography; magnetic resonance imaging; radiological marker
    DOI:  https://doi.org/10.1097/MCO.0000000000001246
  15. Biochim Biophys Acta Rev Cancer. 2026 Jul 01. pii: S0304-419X(26)00126-5. [Epub ahead of print] 189654
    Senescence in non-cancerous cells within the tumor: What is the real deal?
    Aida Perramon-Güell, Carlos Anerillas.
      Senescence is a dynamic stress response that not only enforces growth arrest in damaged cells but also profoundly reshapes the tissue microenvironment through secretory programs, immune modulation, and extracellular matrix remodeling. In the context of cancer, senescence occurs not only in malignant cells but also in non-cancerous populations, where it can actively influence tumor initiation, progression, and therapy response. This review focuses on senescent non-malignant cells within tumors, exploring how oncogene-induced senescence, therapy-induced senescence, and age-associated niches drive senescence in these compartments and remodel the tumor microenvironment. Finally, we discuss senotherapies (senolytics and senomorphics) and highlight that achieving lineage- and context-selective targeting of senescent non-malignant niches remains a key translational goal that could improve therapy response and reduce relapse.
    Keywords:  Aging; Cellular senescence; SASP; Senotherapies; Therapy-induced senescence; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189654
  16. Science. 2026 Jul 02. 393(6806): eaef0825
    Zonated mechanosensing by PIEZO1 controls liver regeneration.
    Ying Zhang, Yuzhuo Sun, Guangkui Xu, Yue Wu, Zhijun Shi, Zhuo Chang, Junjun Liu, Kaidan Pang, Siyu Liu, Han Wang, Weixin Rong, Zehua Shao, Xingqian Liu, Yu He, Yang Yan, Bin Zhou, Zuyi Yuan, Xu-Feng Zhang, Stefan Offermanns, Shengpeng Wang.
      The liver exhibits a marked regenerative capacity organized through distinct zones, yet how tissue mechanics coordinate zonated proliferation remains elusive. We reveal that mechanical cues critically contribute to mouse liver regeneration in a highly region-specific manner through sensing by a subpopulation of mid-lobular hepatocytes, which are characterized by dipeptidyl peptidase-4 (DPP4) expression and represent the key proliferative pool of hepatocytes. PIEZO1 is a primary mechanosensor enriched in zone 2 DPP4+ hepatocytes that integrates biomechanical cues to drive liver regrowth by insulin-like growth factor binding protein 2 (IGFBP2). Genetic disruption of PIEZO1 restrains hepatocyte proliferation and compromises liver regeneration, whereas zonated PIEZO1 gain of function enhances proliferation and accelerates recovery. These findings reveal that DPP4+ mechanosensitive hepatocytes orchestrate liver regrowth through PIEZO1-mediated mechanosensing, establishing a link between tissue mechanics and liver regeneration.
    DOI:  https://doi.org/10.1126/science.aef0825
  17. Oncologist. 2026 Jun 29. pii: oyag250. [Epub ahead of print]
    Use of liposomal irinotecan with 5-FU and oxaliplatin (NALIRIFOX) in neoadjuvant pancreatic adenocarcinoma: NEO-Nal-IRI trial.
    Thomas J George, Tuo Lin, Ibrahim Nassour, Sherise C Rogers, Tim Jang, Ilyas Sahin, Brian H Ramnaraign, Jesus Fabregas, Kathryn Hitchcock, Gonghao Liu, Karen B Russell, Anita A Turk, Omar Kayaleh, Z Hugh Fan, David L DeRemer, Ryan M Thomas, Ji-Hyun Lee, Steven J Hughes.
       BACKGROUND: While neoadjuvant FOLFIRINOX is an effective regimen for pancreatic ductal adenocarcinoma (PDAC), toxicity frequently limits its use. Nanoliposomal irinotecan (nal-IRI) offers improved pharmacokinetic properties and may mitigate some of the side effects. We conducted a multi-institutional, phase II study to evaluate the safety and clinical activity of neoadjuvant NALIRIFOX (nal-IRI, 5-fluorouracil, leucovorin, and oxaliplatin) in patients with resectable and borderline resectable (R/BR) PDAC.
    METHODS: Patients with untreated R/BR PDAC received eight cycles of neoadjuvant NALIRIFOX. The primary endpoint was the 30-day post-operative major complication rate among resected patients. Secondary endpoints included treatment completion rate, R0 resection rate, objective response rate (ORR), biochemical (CA19-9) and radiographic responses, nodal downstaging, and quality of life (QoL by FACT-G).
    RESULTS: Of the 45 enrolled patients, 73% completed all eight cycles of neoadjuvant NALIRIFOX. 34 patients (76%) underwent attempted surgery, of whom 29 (64%) had complete resection (15 BR patients and 14 R patients). The 30-day post-operative major complication rate was 10% (95% CI, 2.2-27%, p = 0.012), meeting the pre-specified threshold. R0 resection was achieved in 90% of resected patients. The radiographic ORR was 45% (95% CI, 29-62%), and the clinical benefit rate was 73% (95% CI, 58-85%).
    CONCLUSION: Neoadjuvant NALIRIFOX is a safe and active regimen in R/BR PDAC with a low post-operative complication rate, high treatment completion and R0 resection rates, and meaningful clinical responses. These findings support further investigation of NALIRIFOX as part of a total neoadjuvant therapy (TNT) approach in PDAC. [ClinicalTrials.gov identifier: NCT03483038].
    Keywords:  Liposomal irinotecan; NALIRIFOX; Pancreatic ductal adenocarcinoma; Phase II clinical trial; Resectable and borderline resectable pancreatic cancer; Total neoadjuvant therapy
    DOI:  https://doi.org/10.1093/oncolo/oyag250
  18. bioRxiv. 2026 Jun 17. pii: 2026.06.16.731623. [Epub ahead of print]
    Label-Free All-Electrical Tracking of Individual and Collective Cell Migration on a Megapixel CMOS Capacitance Sensor.
    Hyuntae Jeong, Pushkaraj Joshi, Yinshi Hu, Jiwon Kim, Anh Hoang Vu, Jacob K Rosenstein, Ian Y Wong.
      Label-free tracking of adherent cell migration could enable important insights into biological processes such as tissue repair, inflammatory response, or cancer progression. Nevertheless, visualizing unlabeled animal cells using optical microscopy remains challenging due to low contrast as well as frequent changes in cell shape and number. A promising alternative uses electrical capacitance measurements, which are sensitive to cell adhesion to electrode surfaces. However, prior examples often utilized electrodes with areas larger than single cells, resulting in averaged readouts over multiple cells. Here, we demonstrate label-free, live-cell tracking using a capacitance sensor array with more than 1 million pixels on a 10 micron pitch across an area larger than 1 square centimeter. We show that single cell morphology can be clearly segmented, and then used to reconstruct migration and proliferation dynamics using optical flow. We further track the spreading of multicellular spheroids, revealing fast-moving peripheral regions led by a collective leader cell "front." Finally, we demonstrate label-free imaging of millimeter-scale honeycomb-shaped tissues without the multi-image stitching often required for conventional microscopy. We utilize mutual capacitance measurements with electrically-programmable electrode spacing to reconstruct topographical features of these engineered tissues. Overall, CMOS capacitance imaging arrays enables label-free imaging spanning from single cells to large tissues, in a portable and scalable format for settings where optical microscopy may be difficult to access.
    DOI:  https://doi.org/10.64898/2026.06.16.731623
  19. Trends Mol Med. 2026 Jul 01. pii: S1471-4914(26)00144-9. [Epub ahead of print]
    Turning perfusion into repair through ferroptosis blockade.
    Yajing Wang, Usama Ahmad, Xiaojun Cai, Quazi T H Shubhra.
      By identifying graft ferroptosis as a druggable vulnerability, Veeckmans et al. show that FXT-001 intercepts lipid-radical injury during machine perfusion and improves liver and lung graft function. This work supports rather than proves machine perfusion as a therapeutic window for preimplantation graft repair, a concept that now requires postimplantation validation.
    Keywords:  ferroptosis; graft protection; lipid peroxidation; machine perfusion; organ transplantation
    DOI:  https://doi.org/10.1016/j.molmed.2026.06.008
  20. NPJ Drug Discov. 2025 Jun 04. pii: 9. [Epub ahead of print]2(1):
    Drugging Ras trafficking-are there new roads to travel?
    Elisabeth Schaffner-Reckinger, Atanasio Gómez-Mulas, Daniel Kwaku Abankwa.
      Inhibition of Ras trafficking was the first approach to target Ras in the clinic. With the advent of direct Ras inhibitors, trafficking inhibition may appear obsolete. However, targeting certain trafficking hubs may still offer unexpected opportunities. To exploit these, we need to learn more about the functioning of Ras in specific organelles, which are associated with e.g., cell differentiation. We here discuss future opportunities in that regard.
    DOI:  https://doi.org/10.1038/s44386-025-00012-7
  21. Elife. 2026 Jun 30. pii: RP101974. [Epub ahead of print]13
    Restraint of melanoma progression by cells in the local skin environment.
    Yilun Ma, Mohita Tagore, Miranda V Hunter, Ting-Hsiang Huang, Emily Montal, Joshua M Weiss, Yingxiao Shi, Tuulia Vallius, Peter K Sorger, Richard M White.
      Keratinocytes, the dominant cell type in the melanoma microenvironment during tumor initiation, exhibit diverse effects on melanoma progression. Using a zebrafish model of melanoma and human cell co-cultures, we observed that keratinocytes undergo an epithelial-mesenchymal transition (EMT)-like transformation in the presence of melanoma, reminiscent of their behavior during wound healing. Surprisingly, overexpression of the EMT-transcription factor Twist in keratinocytes led to improved overall survival in zebrafish melanoma models, despite no change in tumor initiation rates. This survival benefit was attributed to reduced melanoma invasion, as confirmed by human cell co-culture assays. Single-cell RNA-sequencing revealed a unique melanoma cell cluster in the Twist-overexpressing condition, exhibiting a more differentiated, less invasive phenotype. Further analysis nominated homotypic jam3b-jam3b and pgrn-sort1a interactions between Twist-overexpressing keratinocytes and melanoma cells as potential mediators of the invasive restraint. Our findings suggest that EMT in the tumor microenvironment may paradoxically limit melanoma invasion through altered cell-cell interactions.
    Keywords:  EMT; cancer biology; invasion; keratinocytes; melanoma; microenvironment; zebrafish
    DOI:  https://doi.org/10.7554/eLife.101974
  22. bioRxiv. 2026 Jun 23. pii: 2026.06.18.733195. [Epub ahead of print]
    Ventral pallidal GABAergic neurons control hedonic feeding and obesity.
    Justin G Wang, Chang S Xu, Chantelle L Murrell, Mason R Barrett, Gargi C Basu, Lisa Z Fang, Yiru Chen, Florian Schoukroun, Thomas Topilko, Johanna Perens, Jacob Hecksher-Sørensen, Meaghan C Creed, Alexxai V Kravitz.
      Food intake is governed by two interacting drives. The homeostatic hunger drive regulates food intake to fulfill caloric needs while the hedonic drive promotes intake of palatable foods outside of caloric need. It is unclear which neural substrates can control the hedonic drive and thereby reduce overeating of palatable foods and associated obesity. Here, we show that ventral pallidal GABAergic neurons (VP GABA ) preferentially control hedonic feeding and are necessary for diet-induced obesity in mice. Stimulating VP GABA neurons drove robust consumption of high-fat diet and liquids, but not regular laboratory chow. Despite driving intake of palatable foods, VP GABA neurons are relatively insensitive to homeostatic signals - they express few hunger-hormone receptors and are not activated by ghrelin administration or fasting. Single-cell calcium imaging revealed stronger engagement of VP GABA neurons during long vs short feeding bouts, suggesting control over bout duration, which has been linked to palatability. This was confirmed with closed-loop optogenetic stimulation. Finally, taCasp3-mediated ablation of VP GABA neurons reduced intake of palatable liquids and blocked high-fat diet-induced obesity without impacting homeostatic feeding. Together, these findings establish VP GABA neurons as a neural population that preferentially controls hedonic over homeostatic feeding and can be leveraged to block obesity in mice.
    DOI:  https://doi.org/10.64898/2026.06.18.733195
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