bims-cagime 2026-06-28 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2026–06–28
28 papers selected by
Kıvanç Görgülü, Technical University of Munich

Pancreatic cancer fibrosis activates protumorigenic Schwann cells through a nuclear mechanosensing mechanism.
Lipid transfer protein ORP3 mediates lysosomal repair via LC3B and ubiquitin-TAK1-p38 signaling.
Phosphatidylserine and RhoB connect PI4P and PA metabolism to maintain plasma membrane identity.
Phospholipid Remodeling as a Key Regulator of Ferroptosis.
Molecular phenotypes and spatial archetypes: A new framework for cancer-associated fibroblasts.
Mediator subunit MED4 enforces metastatic dormancy in breast cancer.
The metabolic basis of regulated cell death.
Tension TRAAKer: a chemigenetic fluorescent membrane tension reporter.
Adaptive mechanochemical mechanisms of the nucleus during confined cell migration.
A new sense for electrical fields.
Cancer cells adopt unprecedented strategies to produce a molecule that protects them from iron-dependent death.
Quantitative 3D histology reveals localized immune remodeling during early pancreatic cancer progression.
Endobody: Genetically Encodable Nanobody-CPP Chimeras for Degradation of Membrane and Extracellular Proteins.
A modeller's guide for biomedical discovery.
Iron-catalyzed active lipid peroxides drive ultrafast collective cell death in blooming algae.
The multifaceted inducers of cellular senescence.
Csf1 facilitates adaptive membrane lipid remodeling linked to ER-plasma membrane contact sites.
An immunological panacea for cancer-related cachexia.
Protein-enhanced small molecule disruptors of ordered membrane domains.
Beyond body surface area: CT-derived body composition as a predictor of chemotherapy toxicity and survival in pancreatic ductal adenocarcinoma: a systematic review.
Physiological media and oxygen levels modulate cancer hallmarks in cultured breast cancer cells.
Cuproptosis-immunity crosstalk informs strategy to overcome immunotherapy resistance.
A Micro-Quantitative and FFPE-Compatible Workflow for Immunohistochemistry-Guided Spatial Proteomic Analysis of Cellular Subpopulations Within the Tumor Microenvironment.
CLPTM1L modulates membrane lipid rafts to promote tumor EGFR signaling.
A membrane homeostatic response to lipid overload coordinates fatty acid metabolism.
Surveying the roles of NINJ1 in plasma membrane rupture.
Ex vivo assay for organ-specific cancer cell invasion.
Biomarker analysis from patients with metastatic PDAC treated with TGFβ antibody, NIS793, plus abraxane+gemcitabine vs. abraxane+gemcitabine alone in a phase II, open label, randomized study.

Gut. 2026 Jun 23. pii: gutjnl-2025-337316. [Epub ahead of print]

Pancreatic cancer fibrosis activates protumorigenic Schwann cells through a nuclear mechanosensing mechanism.

Pavel Stupakov, Golbahar Sadatrezaei, Ines Velazquez Quesada, Lillian A Boe, Chun-Hao Chen, Francesca Gaino, Efsevia Vakiani, Ihsan Ekin Demir, Boris Reva, Bojana Gligorijevic, Richard J Wong, Sylvie Deborde.

   BACKGROUND: Fibrosis and tumour innervation are two features of the tumour microenvironment (TME) that contribute directly to the lethality of pancreatic ductal adenocarcinoma (PDAC), but their potential interactions have not been explored. Moreover, although it is known that activated Schwann cells (SCs) stimulate cancer cell invasion, it remains unclear how SCs are activated.
OBJECTIVE: We determined how SCs are activated in the pancreatic fibrotic microenvironment.
DESIGN: The correlation between physical features of the microenvironment and SC activation was assessed in human patient samples and in mice by SC c-Jun phosphorylation monitoring, atomic force microscopy and multiphoton live imaging. Several in vitro models in which forces were applied to SCs expressing a reporter for c-Jun phosphorylation and RNA-Seq analysis were used to decipher the cellular and molecular mechanisms of SC activation.
RESULTS: Nerves surrounded by stiff stroma present higher SC activation. Intravital imaging shows a matrix-dependent SC activation. Mechanical forces on SCs induce c-Jun phosphorylation in SCs in a non-canonical manner that involves a nuclear sensing machinery with the pro-inflammatory enzyme phospholipase A2.
CONCLUSION: Fibrosis enhances the protumorigenic impact of innervation by activating SCs via a mechanism in which nuclear compression triggers non-canonical activation of the AP-1 transcription factor complex. Pancreatic fibrosis alone, without cancer cells, is sufficient to activate SCs, suggesting this mechanism may be common across non-malignant pancreatic diseases. Notably, SCs are more sensitive to mechanical activation than PDAC cells. These findings reveal TME interactions that may guide future microenvironment-targeted PDAC therapies.

Keywords:  FIBROSIS; NEUROBIOLOGY; PANCREATIC CANCER; PANCREATIC FIBROSIS; Schwann Cells

DOI:  https://doi.org/10.1136/gutjnl-2025-337316
bioRxiv. 2026 Jun 10. pii: 2026.06.09.731146. [Epub ahead of print]

Lipid transfer protein ORP3 mediates lysosomal repair via LC3B and ubiquitin-TAK1-p38 signaling.

Christopher J Bott, Martyna O Iwaniek, James E Casanova.

Lysosomal membrane damage triggers a multi-stage repair response essential for cellular homeostasis. Here we identify the oxysterol-binding protein-related protein ORP3 as a critical mediator of late-stage lysosomal membrane repair. Following lysosomal damage induced by L-leucine-leucine methyl ester (LLOME) or cationic amphiphilic drugs (CADs), ORP3 is phosphorylated and recruited to ER-lysophagosome contact sites via a signaling cascade initiated by lysosomal membrane ubiquitination, TAK1, p38 MAPK, and, to a lesser extent, IKK. p38-dependent phosphorylation promotes direct interaction between ORP3 and LC3B, which together with PI(4,5)P₂ binding, is required for autophagic lysosome recruitment. ORP3 depletion impairs late-stage lysosomal recovery, elevates lysosomal lipid peroxidation, and reduces cell survival. A lipid transfer-deficient ORP3 mutant fails to restore lysosome function despite normal recruitment, indicating that ER-to-lysophagosome transfer of phosphatidylcholine by ORP3 is functionally required. ORP3 activity is subsequently terminated by VCP/p97-mediated deubiquitination of lysosomes. These findings define ORP3 as a MAPK regulated lipid transfer protein during the late autophagic phase of the endolysosomal damage response.
Summary: Lysosomal membrane damage triggers ubiquitination that activates a TAK1-p38 signaling cascade, phosphorylating the lipid transfer protein ORP3 and recruiting it to damaged lysosomes via LC3B interaction. ORP3-mediated phosphatidylcholine transfer from the ER is essential for late-stage lysosomal repair and cell survival.
Abstract Figure:

DOI: https://doi.org/10.64898/2026.06.09.731146
J Cell Biol. 2026 Aug 03. pii: e202509213. [Epub ahead of print]225(8):

Phosphatidylserine and RhoB connect PI4P and PA metabolism to maintain plasma membrane identity.

Shiying Huang, Yeun Ju Kim, Xiaofu Cao, Timothy W Bumpus, Mira Sohn, Matthew Tyler Menold, Ryan K Dale, Jin Joo Kang, Saori Uematsu, Shagun Gupta, Shu-Bing Qian, Haiyuan Yu, Tamas Balla, Jeremy M Baskin.

Proper functions of cellular organelles require tight control of membrane phospholipid composition, yet the mechanisms by which lipid imbalances are sensed and corrected remain largely unknown. Here, we present evidence of an unexpected metabolic connection between plasma membrane (PM) phosphoinositide metabolism and two key anionic lipids, phosphatidylserine (PS) and phosphatidic acid (PA). Prolonged depletion of PM phosphatidylinositol 4-phosphate (PI4P) by pharmacological inhibition of PI 4-kinase IIIα (PI4KIIIα/PI4KA) increases phospholipase D (PLD) activity and PA levels in the PM. Using lipidomics, RNA-seq, and proximity proteomics, we find that PI4P loss induces a concomitant decrease in PS, activating a reciprocal relationship between PS synthesis and PLD-mediated PA generation. These changes also drive transcriptional and translational upregulation of the small GTPase RhoB, which enhances PLD-mediated PA synthesis and actin cytoskeletal remodeling. Because reduced PI4KA activity underlies numerous hereditary diseases, our studies reveal how perturbation of PM phosphoinositide synthesis triggers an integrated response that maintains the anionic character and structural integrity of the PM.

DOI: https://doi.org/10.1083/jcb.202509213
J Lipid Res. 2026 Jun 25. pii: S0022-2275(26)00117-3. [Epub ahead of print] 101091

Phospholipid Remodeling as a Key Regulator of Ferroptosis.

Tomoyoshi Shingaki, Junken Aoki, Nozomu Kono.

  Ferroptosis is an iron-dependent form of regulated cell death characterized by the accumulation of lipid peroxides in cellular membranes. Cellular susceptibility to ferroptosis is strongly influenced by membrane phospholipid composition, which is dynamically regulated through phospholipid remodeling. Phospholipid remodeling, also known as the Lands' cycle, drives the replacement of fatty acyl chains in phospholipids through the coordinated actions of phospholipases A, acyl-CoA synthetases (ACSLs), and lysophospholipid acyltransferases (LPLATs). Phospholipid remodeling critically influences ferroptosis sensitivity by regulating the balance between phospholipid species containing polyunsaturated fatty acids (PUFAs), which promote lipid peroxidation, and those containing saturated/monounsaturated fatty acids, which confer resistance. Recent studies have identified key remodeling enzymes, including ACSL4 and LPLAT12, as central drivers of ferroptosis through the generation of PUFA-containing phospholipids, while other enzymes suppress ferroptosis by limiting lipid peroxidation or removing oxidized phospholipids. In parallel, specific phospholipid species-including arachidonic acid- and adrenic acid-containing phospholipids, di-PUFA phospholipids, and other oxidizable lipid classes-have emerged as critical contributors to ferroptosis. Collectively, these findings highlight phospholipid remodeling as a central determinant of ferroptosis by shaping the membrane lipid landscape.

Keywords:  acyl-CoA synthetase; ferroptosis; lysophospholipid acyltransferase; phospholipase A; phospholipid; phospholipid remodeling

DOI:  https://doi.org/10.1016/j.jlr.2026.101091
Cancer Cell. 2026 Jun 25. pii: S1535-6108(26)00288-6. [Epub ahead of print]

Molecular phenotypes and spatial archetypes: A new framework for cancer-associated fibroblasts.

Yunhe Liu, Xiongfeng Chen, Yibo Dai, Yiyue Jia, Yann Kieffer, Luyu Xie, Zhuan Zhou, Lauren Tyler, Alex C Kim, Giulia Biffi, Akshay T Krishnamurty, Fatima Mechta-Grigoriou, Ruth Scherz-Shouval, Mara H Sherman, Shannon J Turley, Linghua Wang, Huocong Huang.

  Cancer-associated fibroblasts (CAFs) form a dynamic ecosystem that critically influences tumor progression and therapeutic response. Although recent advances in single-cell and spatial omics have uncovered profound stromal diversity, interpreting the mechanistic relevance of this complexity remains a challenge. Here, we propose a more unifying conceptual framework to bridge high-dimensional data with experimental biology. By categorizing CAFs into conserved molecular phenotypes and distinct spatial archetypes, this model illustrates how CAF identities are intimately linked to local tissue contexts. This refined framework brings the complexity of the tumor stroma into greater focus, underscoring the necessary transition from broad stromal targeting toward precision, context-specific modulation. Ultimately, we hope this integrated effort will aid in the collaborative development of next-generation therapies that selectively target pathogenic stroma in cancer to improve patient outcomes.

Keywords:  cancer-associated fibroblasts; stroma; stroma-targeted therapy; tumor microenvironment

DOI:  https://doi.org/10.1016/j.ccell.2026.06.001
Nat Cell Biol. 2026 Jun 22.

Mediator subunit MED4 enforces metastatic dormancy in breast cancer.

Seongyeon S Bae, Hsiang-Hsi Ling, Jiankang Zhang, Yi Chen, Hong Chen, Dhiraj Kumar, Ajay K Saw, Kunal Rai, Aaron D Viny, Ronald A DePinho, Filippo G Giancotti.

Long-term survival in breast cancer is often limited by metastatic recurrence arising from disseminated cancer cells that persist in a dormant state. The mechanisms that enable these dormant cells to survive and subsequently reawaken remain incompletely understood. Here an unbiased genome-scale genetic screen identified Med4 as a cancer cell-intrinsic gatekeeper in metastatic reactivation. Correspondingly, MED4 haploinsufficiency was found to be prevalent in metastatic breast cancer and associated with poorer clinical outcomes. Syngeneic mouse metastasis models revealed that MED4 enforces metastatic dormancy. Mechanistically, and unexpectedly given the canonical role of the Mediator complex in transcriptional activation, MED4 suppresses enhancer priming (H3K4me1) and activation (H3K27ac). Loss of a single Med4 allele disrupts enhancer poise, leading to extracellular matrix remodelling and integrin-mediated mechanotransduction programmes that ultimately drive metastatic outgrowth. Together, these findings establish MED4 as a key regulator of breast cancer cell dormancy and nominate MED4 haploinsufficiency as a potential predictive biomarker for patients at high risk of metastatic relapse.

DOI: https://doi.org/10.1038/s41556-026-01984-y
Cell Metab. 2026 Jun 25. pii: S1550-4131(26)00227-5. [Epub ahead of print]

The metabolic basis of regulated cell death.

Jiao Liu, Jiayi Wang, Rui Kang, Guido Kroemer, Daolin Tang.

Regulated cell death (RCD) has long been conceptualized as a genetically encoded signaling process, yet its outcome is ultimately dictated by cellular metabolism. Here, we propose that cellular metabolism functions as a gatekeeper of RCD, establishing permissive or restrictive states that determine cell fate. Bioenergetic capacity, redox balance, lipid composition, and metal availability impose metabolic constraints that bias cells toward survival or distinct death modalities. At the systems level, organelle-resolved metabolism and inter-organelle communication coordinate the spatial control of death processes. We further position RCD pathways along a metabolic continuum, ranging from energy-dependent apoptosis to chemistry-driven ferroptosis. This framework explains the plasticity of death responses and suggests that metabolic reprogramming can redirect cell fate. Targeting metabolic dependencies thus offers a strategy to control cell death in disease.

DOI: https://doi.org/10.1016/j.cmet.2026.06.001
bioRxiv. 2026 Jun 10. pii: 2026.06.08.730921. [Epub ahead of print]

Tension TRAAKer: a chemigenetic fluorescent membrane tension reporter.

Anna V Elleman, Nels Gerstner, Benjamin E Smith, Evan W Miller, Richard H Kramer, Stephen G Brohawn.

Mechanical force transduction is essential to survival, underlying biological processes as fundamental as morphogenesis, somatosensation, audition, and interoception; and driving pathologies as diverse as hypertension and cancer metastasis. Exogenous forces are translated to intracellular signals through transient changes in membrane tension which are currently not possible to directly monitor in situ . To remedy this, we have designed and validated Tension TRAAKer, a chemigenetic fluorescent membrane tension reporter for the visualization of tension induction, propagation, and dissipation in living cells. Tension TRAAKer is derived from inserting a tension-sensitive nonconductive variant of the mechanosensitive potassium ion channel TRAAK into a self-labelling HaloTag. Increasing membrane tensions effect conformational changes in the TRAAK channel that are optically monitored by a HaloTag-conjugated fluorogenic (environment-sensitive) dye. EGFP incorporation C-terminal to the HaloTag enables unambiguous tension reporting in mobile membranes via dual-color ratiometric imaging that controls for variations in sensor density. Tension TRAAKer reports membrane tension changes rapidly, reversibly, and with spatiotemporal precision-its fluorescence scaling to both stimulus magnitude and area, with consistent effect sizes observed between diverse cell types. It better distinguishes among elevated membrane tensions than do available indirect chemical reporters, with the additional advantage of being readily genetically targetable. We thus expect Tension TRAAKer to be a powerful tool for the study of membrane tension across biological systems and disease states.

DOI: https://doi.org/10.64898/2026.06.08.730921
Proc Natl Acad Sci U S A. 2026 Jun 30. 123(26): e2604716123

Adaptive mechanochemical mechanisms of the nucleus during confined cell migration.

Wenying Luo, Xindong Chen, Bo Li, Xi-Qiao Feng.

  Cell migration through spatially confined microenvironments occurs in many biological processes such as embryonic development, immune surveillance, and cancer metastasis. A major bottleneck during such migration is the nucleus, which acts not only as a rigid mechanical obstacle but also as a crucial mechanosensor that modulates downstream signaling pathways. However, it remains poorly understood how nuclear deformation and mechanosensation together regulate cell migration through confined spaces. Here, we propose a three-dimensional (3D) mechanochemical model of confined nuclear translocation that integrates nuclear deformation with deformation-induced calcium signaling and subsequent regulation of cytoskeletal contractility. We show that cells undergo adaptive nuclear deformation, including nuclear envelope elongation and 3D buckling, to efficiently navigate confinements of varying sizes. There exists a biphasic relation between nuclear velocity and confinement size, arising from the interplay between nuclear deformability and mechanosensitive feedback. We demonstrate that local nuclear envelope rupture can occur under large deformation, enabling nuclear translocation through extreme confinements, as observed in prior experiments. Furthermore, we elucidate the critical roles of chromatin organization in nuclear translocation. This work reveals key mechanochemical mechanisms driving confined cell migration and provides a theoretical framework for studying nuclear dynamics across physiological and pathological contexts.

Keywords:  confined cell migration; mechanochemical model; mechanotransduction; nuclear dynamics

DOI:  https://doi.org/10.1073/pnas.2604716123
Cell. 2026 06 25. pii: S0092-8674(26)00638-0. [Epub ahead of print]189(13): 3845-3846

A new sense for electrical fields.

Michael Riedl, Michael Sixt.

Most cells polarize and migrate in response to electrical fields. In this issue of Cell, Belliveau et al. identify TMEM154/Galvanin, a receptor that serves as a cellular antenna to sense electrical gradients and guide migration toward the cathode.

DOI: https://doi.org/10.1016/j.cell.2026.05.038
Nature. 2026 Jul;655(8121): 45-46

Cancer cells adopt unprecedented strategies to produce a molecule that protects them from iron-dependent death.

Amaia Zabala-Letona, Arkaitz Carracedo.



Keywords:  Biochemistry; Cancer; Cell biology

DOI:  https://doi.org/10.1038/d41586-026-01802-3
Cell Press Blue. 2026 May 18. pii: 100008. [Epub ahead of print]1(2):

Quantitative 3D histology reveals localized immune remodeling during early pancreatic cancer progression.

Ashley L Kiemen, Valentina Matos, Cristina Almagro-Pérez, André Forjaz, Alicia M Braxton Hickman, Lucie Dequiedt, Jeeun Parksong, Courtney D Cannon, Xuan Yuan, Sarah M Shin, Jaanvi Mahesh Babu, Elizabeth D Thompson, Toby C Cornish, Won Jin Ho, Laura D Wood, Pei-Hsun Wu, Arrate Muñoz Barrutia, Ralph H Hruban, Denis Wirtz.

Pancreatic cancer features a dense, immune-excluded stroma whose origins remain unclear. In this work, we extended CODA, a cellular-resolution three-dimensional (3D) histology pipeline, to map inflammation around more than 1,000 pancreatic precancers in large human pancreas specimens. Bulk analyses reproduce prior associations between overall inflammation and precancer burden, fibrosis, and acinar dropout, implicating ductal obstruction and stromal remodeling in early immune changes. Crucially, 3D mapping reveals that inflammation around individual precancers is highly heterogeneous, with immune hotspots and cold spots interchanging over tens of microns. Hotspots are found around regions of higher-grade dysplasia and ductal obstruction and are enriched for regulatory T cells and macrophages, indicating focal emergence of immunosuppression at the precancer stage. Integration with spatially resolved DNA sequencing implicated mutation in inflammation. These results position 3D mapping as a framework to identify rare sites of active microenvironmental priming and highlight focal immunosuppressive niches as candidate sites for early interception.

DOI: https://doi.org/10.1016/j.cpblue.2026.100008
Adv Sci (Weinh). 2026 Jun 23. e76075

Endobody: Genetically Encodable Nanobody-CPP Chimeras for Degradation of Membrane and Extracellular Proteins.

Chengjian Zhou, Huiping He, Simin Xia, Xi Chen.

  Membrane protein degraders (MPDs) like LYTACs are emerging tools for targeting disease-relevant membrane proteins, but their reliance on specific endocytic receptors limits their applicability across diverse cell types. Here, we present a structurally concise and genetically encodable class of degraders, nanobody-cell-penetrating peptide (CPP) chimeras, termed endobodies. We demonstrated that a genetically fused CPP is sufficient to mediate the internalization and subsequent degradation of membrane or extracellular proteins recognized by the nanobody. Using this platform, we achieved targeted degradation of membrane proteins including EGFR, PD-L1, and HER2 in cancer cells. Importantly, the undruggable serum HE4, an ovarian cancer marker which could not be addressed by small-molecule degraders, was also effectively depleted. Additionally, we first showcased the possibility to simultaneously degrade both extracellular and membrane proteins using a bispecific endobody. To further eliminate endosomal escapees, we engineered a panel of enhanced endobodies incorporating an additional proteasome-targeting domain (PTD), resulting in more robust degradation. Notably, EGFR depletion by an enhanced endobody suppressed lung cancer cell proliferation and tumor growth in vivo. Collectively, endobody is an innovative class of MPDs, offering promising therapeutic potential.

Keywords:  cell‐penetrating peptide (CPP); epidermal growth factor receptor (EGFR); human epididymis protein 4 (HE4); nanobody; targeted protein degradation

DOI:  https://doi.org/10.1002/advs.76075
Dis Model Mech. 2026 06 01. pii: dmm052807. [Epub ahead of print]19(6):

A modeller's guide for biomedical discovery.

Philip Greulich.

Mathematical and computational modelling can do far more than reproduce experimental data or make predictions. When used with intent, models become instruments of discovery: they translate qualitative biological ideas into quantitative, testable hypotheses; they connect microscopic questions to macroscopic data; and, crucially, they help falsify plausible but incorrect mechanistic narratives. This Perspective explores how modelling achieves these goals. I begin by outlining why classical experimental strategies and conventional statistics sometimes fall short of addressing the mechanisms we care about. I then present a model-centred workflow for scientific discovery, using clonal lineage tracing as a running example. The second half focuses on a phenomenon that both limits and empowers model inference - universality - and explains how to turn it from a curse into an opportunity. I conclude with a concise, practical guide that distils these ideas into steps for day-to-day biomedical research.

DOI: https://doi.org/10.1242/dmm.052807
Science. 2026 Jun 25. 392(6805): eaed3823

Iron-catalyzed active lipid peroxides drive ultrafast collective cell death in blooming algae.

Yinjie Zhu, Xiaoxiong Wang, Yifan Tong, Chengzhen Jia, Huansheng Cao, Hongying Hu, Yi Tao.

Harmful algal blooms, the most severe ecological hazards worldwide, terminate abruptly within a few days. In this work, we identified that iron-catalyzed active lipid peroxides predominantly trigger individual cell ferroptosis and drive the population collapse of blooming cyanobacteria. We reveal the chronological sequence of labile iron burst, oxidative stress, lipid peroxidation, and cell death during a Microcystis bloom demise event. Dead cells exhibit a nonrandom spatial distribution within colonies. Intensifying lipid peroxidation catalyzed by cellular labile iron generates truncated phospholipids with shortened fatty acyl chains bearing alkyl groups. These active lipid peroxides destabilize plasma membranes and induce nanoscale membrane pore formation, resulting in individual cell ferroptosis and lysis. Oxidized lipids are also released from ferroptotic cells, propagating lipid peroxidation to neighboring cells, thereby spreading death throughout the population.

DOI: https://doi.org/10.1126/science.aed3823
Aging (Albany NY). 2026 Jun 22. 18(1): 719-732

The multifaceted inducers of cellular senescence.

Hilah Gal, Valery Krizhanovsky.

  Cellular senescence is a stable form of cell-cycle arrest induced by diverse intrinsic and extrinsic stimuli. While senescence contributes to tumor suppression, wound repair, and placental and embryonic development, the chronic accumulation of senescent cells promotes tissue dysfunction, chronic inflammation, tumorigenesis, and age-related diseases. This review provides a comprehensive overview of the major inducers of cellular senescence, including DNA damage, oxidative and mitochondrial stress, telomere attrition, oncogene activation, cell-cell fusion, senescence-induced senescence and developmental stimuli, and summarizes the molecular mechanisms through which they trigger the senescence program. Although these stimuli differ widely, many converge to core effector pathways, resulting in a stable growth arrest. Understanding the varied stimuli and their underlying mechanisms of senescence induction is crucial for revealing the heterogeneity of senescent cells and developing interventions that modulate senescence during aging and disease.

Keywords:  aging; cell senescence

DOI:  https://doi.org/10.18632/aging.206391
Mol Biol Cell. 2026 Jun 24. mbcE26010059

Csf1 facilitates adaptive membrane lipid remodeling linked to ER-plasma membrane contact sites.

Fumiyoshi Abe, Tetsuo Mioka, Yusuke Suzuki, Akane Ogasawara, Daisuke Mochizuki, Saki Imura, Yusuke Kato, Ayana Toda, Sana Nikaido, Takahiro Mochizuki.

Membrane lipid composition must be dynamically adjusted to preserve bilayer physical properties, yet the cellular mechanisms that support bulk lipid remodeling under physical stress remain incompletely understood. Here, we identify Csf1 as a regulator of membrane lipid remodeling functionally associated with endoplasmic reticulum-plasma membrane (ER-PM) contact sites in Saccharomyces cerevisiae, with features consistent with bridge-like lipid transfer proteins. Using high hydrostatic pressure as a defined physical perturbation that constrains membrane packing, we reveal a requirement for Csf1-dependent lipid remodeling linked to ER-PM contact sites that is masked under standard growth conditions. Quantitative lipidomic and membrane biophysical analyses show that, under hydrostatic compression, loss of Csf1 disrupts coordinated lipid remodeling, leading to reduced phospholipid unsaturation, increased membrane rigidity, and destabilization of PM permeases. We further show that Csf1 cooperates with Osh6/7 to sustain lipid flux and bilayer re-equilibration linked to ER-PM contact sites under conditions permissive for Osh6/7 activity. These findings identify Csf1 as a stress-dependent lipid-remodeling factor that enables adaptive membrane remodeling and preserves membrane protein stability under conditions of constrained membrane flexibility.

DOI: https://doi.org/10.1091/mbc.E26-01-0059
Trends Cancer. 2026 Jun 24. pii: S2405-8033(26)00133-0. [Epub ahead of print]

An immunological panacea for cancer-related cachexia.

Jingyu Xue, Tianyi Lu, Kailin Yang, Alexander Birbrair, Shengtao Zhou.

  Cancer cachexia, responsible for up to 30% of cancer deaths, has transitioned conceptually from a mere nutritional deficit into a highly coordinated, multi-organ immunometabolic network that systematically dismantles host homeostasis. This review synthesizes the paradigm-shifting discoveries that position the immune system as the central conductor of tissue wasting. We delineate how redundant inflammatory cascades, neuro-immune circuits, and local cellular plasticity converge to drive muscle and adipose catabolism. Furthermore, we dissect the metabolic competition for nutrients between tumor cells and host immunity, which accelerates structural degradation. Finally, we highlight how single-cell multiomics, spatial transcriptomics, and artificial intelligence are redefining clinical stratification, shifting the therapeutic horizon toward individualized, multi-node immunometabolic interventions, thereby providing a theoretical framework for the management of cachectic wasting syndrome.

Keywords:  cachexia; cytokines; immune cells; immune metabolism

DOI:  https://doi.org/10.1016/j.trecan.2026.06.005
Proc Natl Acad Sci U S A. 2026 Jun 30. 123(26): e2530579123

Protein-enhanced small molecule disruptors of ordered membrane domains.

Katherine M Stefanski, Geoffrey C Li, Dustin D Luu, Kelvin K Fosu, Eduardo Guadarrama, James M Hutchison, Nilabh Saksena, Yelyzaveta Zuy, Alexander J Fisch, Thomas P Hasaka, Joshua A Bauer, Alfred L George, Anne K Kenworthy, Wade D Van Horn, Charles R Sanders.

  Membrane order and fluidity influence many biological processes. However, tools to manipulate membranes under physiological conditions have been limited. In the process of high-throughput screening for molecules that shift the phase partitioning between ordered and disordered membrane phases of the tetraspan membrane protein peripheral myelin protein 22 (PMP22), we identified two chemically similar compounds, VU0615562 and VU0619195, that shift PMP22 toward the disordered phase and destabilize the "lipid raft"-like ordered phase. Follow-up experiments showed that this latter activity is, counterintuitively, enhanced by the presence of PMP22, which normally stabilizes the ordered phase. Biophysical studies indicate that these compounds reduce raft stability through a mechanism that involves both direct interactions with proteins and the disruption of lipid packing. We further observed that acute treatment of live cells with VU0619195 modulated membrane fluidity and TRPM8 channel function while both compounds altered KCNQ1 channel activity, providing examples of practical applications for these compounds. These protein-enhanced raft modulators reveal distinct lipid and protein-based forces that destabilize membrane order and may be useful as pharmacological tools for manipulating and probing the biological roles of ordered membrane domains in cells.

Keywords:  GPMVs; high-throughput screen; lipid raft; membrane fluidity; small molecule

DOI:  https://doi.org/10.1073/pnas.2530579123
Cancer Treat Rev. 2026 Jun 24. pii: S0305-7372(26)00088-5. [Epub ahead of print]148 103174

Beyond body surface area: CT-derived body composition as a predictor of chemotherapy toxicity and survival in pancreatic ductal adenocarcinoma: a systematic review.

Beatriz Chacón-Ovejero, Vilma Pacheco-Barcia, Magda Palka-Kotlowska, Sara Custodio-Cabello, Raul Guerra-Hernandez, Paula Jimenez-Fonseca, Andrés Muñoz-Martin, Jorge Francisco Gómez-Cerezo, Luis Cabezón-Gutiérrez.

   BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterised by a high prevalence of severe muscle wasting (sarcopenia) and fatty muscle infiltration (myosteatosis), yet chemotherapy dosing still relies on body surface area (BSA), a metric that does not reflect individual patients' lean body mass (LBM) or muscle quality. A growing body of evidence from oncology meta-analyses demonstrates that low skeletal muscle mass (sarcopenia) independently predicts chemotherapy toxicity across multiple cancer types, and that myosteatosis is associated with significantly increased mortality risk. We performed a systematic review to determine whether CT-based body composition metrics better predict chemotherapy toxicity and survival outcomes in PDAC than conventional BSA-based dosing.
METHODS: We searched PubMed and EMBASE (up to 10 April 2026) according to PRISMA 2020 guidelines. Of 340 identified records, a total of 16 were included after screening and eligibility assessment: 14 primary studies/abstracts (10 retrospective cohorts, 1 prospective study, 3 conference abstracts); 2 prior systematic reviews were appraised qualitatively for contextual background. Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS) for cohort studies and AMSTAR-2 for systematic reviews. Conference abstracts were assessed qualitatively; their inclusion and associated limitations are transparently acknowledged. Data were extracted on severe (grade ≥ 3) toxicities graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), dose-limiting toxicities (DLT), treatment modifications, and overall survival. Body composition measures assessed included skeletal muscle index (SMI) and skeletal muscle density (SMD) (surrogates for muscle quantity and quality, respectively), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and longitudinal changes in these parameters.
RESULTS: Muscle quality (low SMD/myosteatosis) was as predictive of severe toxicity as muscle mass (SMI) in multiple studies, and when low SMI and SMD co-occurred, patients had significantly higher odds of grade ≥ 3 toxicity (odds ratio ∼ 1.7 in the largest cohort of 636 patients). Patients receiving high chemotherapy doses relative to LBM (e.g. >5.8 mg of nab-paclitaxel per kg LBM) were significantly more likely to experience DLT (p = 0.028), whereas standard BSA-normalised dosing did not discriminate risk. Early skeletal muscle loss (≥7.9% SMI decline within 2 months of FOLFIRINOX) was linked to a fourfold higher risk of mortality (HR 4.02; 95% CI 1.54-10.5). Overall, CT-derived body composition measures consistently outperformed BSA for toxicity and outcome prediction, although evidence remains largely retrospective and heterogeneous. Automated CT body composition analysis was demonstrated to be feasible, supporting integration into routine PDAC care.
CONCLUSIONS: CT-derived body composition metrics, particularly LBM-normalised dosing parameters and serial skeletal muscle measurements, appear to provide a more patient-tailored, physiologically relevant approach to chemotherapy dosing in PDAC than exclusive reliance on BSA. Given the predominantly retrospective evidence base and limited prospective validation to date, these findings should be interpreted as hypothesis-generating rather than practice-changing. Prospective trials of LBM-adapted dosing protocols are needed to validate their impact on toxicity and survival.

Keywords:  Body composition; Body surface area; Chemotherapy toxicity; Computed tomography; Dose optimization; Lean body mass; Myosteatosis; Pancreatic cancer; Sarcopenia

DOI:  https://doi.org/10.1016/j.ctrv.2026.103174
FEBS J. 2026 Jun 21.

Physiological media and oxygen levels modulate cancer hallmarks in cultured breast cancer cells.

Jacob E Wiebe, Ricardo Alva, Fereshteh Moradi, Sarah Alderman, Ping Liang, Jeffrey A Stuart.

  The concepts of physioxia and physiological media for mammalian cell culture have gained attention over the past several years. Although the effects of oxygen tension or nutrient composition have been examined individually, their combined, large-scale impacts on cancer cell biology remain poorly understood. Here, we integrated transcriptomic, proteomic, and functional analyses to assess how oxygen levels (18% vs. 5% O2) and medium composition (DMEM vs. Plasmax) influence human breast cancer (MCF7) cells. We found that culturing MCF7 cells in physioxia (5% O2) and Plasmax medium induces a transcriptional profile that more closely resembles breast tumors in vivo. Moreover, changes in transcript and protein abundance were significantly associated with cellular growth, motility, and metabolism. At the functional level, oxygen level and culture medium affected proliferation, migration, glucose consumption, and metabolic activity in MCF7 cells. We conclude that both oxygen levels and medium composition in culture modulate hallmark cancer phenotypes, underscoring the importance of mimicking physiological microenvironments when studying biological mechanisms and therapeutic approaches in cancer.

Keywords:  cancer cells; cell culture; culture media; oxygen; physiological cell culture; proteomics; transcriptomics

DOI:  https://doi.org/10.1111/febs.70629
Cell. 2026 Jun 22. pii: S0092-8674(26)00636-7. [Epub ahead of print]

Cuproptosis-immunity crosstalk informs strategy to overcome immunotherapy resistance.

Guang Lei, Zhengze Lu, Zhihao Xu, Chen Braun, David Huo, Jian Gao, Lin Tan, Ting Hong, Shengrong Wu, Mingchuang Sun, Xi Zhao, Qidong Li, Xiong Chen, Yuelong Yan, Hyemin Lee, Chao Mao, Li Zhuang, Li-Ting Ku, Nahum Puebla, Hampartsoum Barsoumian, Jun Yao, Lingzhi Hong, Jianjun Zhang, Hai Tran, Jiun-Kae Jack Lee, Don Gibbons, Ara Vaporciyan, John Heymach, Chunru Lin, Eyal Gottlieb, Mingjian James You, James W Welsh, Steven H Lin, Xingxing Zang, Ziyi Li, Boyi Gan.

  Cuproptosis is a recently identified form of copper-dependent cell death that depends on ferredoxin 1 (FDX1)-mediated protein lipoylation. Here, we reveal that CD8+ T cell-mediated antitumor immunity enhances tumor cell susceptibility to cuproptosis, leading to a more potent tumor-suppressive effect of cuproptosis inducers in immunocompetent hosts compared with immunodeficient ones. Mechanistically, cuproptotic tumor cells act as a form of immunogenic cell death, releasing damage-associated molecular patterns that activate dendritic cells and enhance antitumor immunity. Reciprocally, CD8+ T cell-derived interferon (IFN)-γ enhances FDX1 transcription in tumor cells by activating the signal transducer and activator of transcription 1 (STAT1)-IFN regulatory factor-1 (IRF1) signaling axis, resulting in heightened tumor cell sensitivity to cuproptosis. Consequently, combining a cuproptosis inducer with anti-programmed cell death ligand 1 (PD-L1) therapy amplifies tumoral cuproptosis and demonstrates efficacy in overcoming PD-L1 therapy resistance across multiple preclinical models. Our findings unveil a previously unrecognized connection between antitumor immunity and cuproptosis and highlight a potential therapeutic approach to counteract tumor immunotherapy resistance by targeting this unique cell death pathway.

Keywords:  CD8(+) T cell; FDX1; cuproptosis; immunogenic cell death; immunotherapy resistance

DOI:  https://doi.org/10.1016/j.cell.2026.05.036
Bioengineering (Basel). 2026 Jun 11. pii: 678. [Epub ahead of print]13(6):

A Micro-Quantitative and FFPE-Compatible Workflow for Immunohistochemistry-Guided Spatial Proteomic Analysis of Cellular Subpopulations Within the Tumor Microenvironment.

Junya Peng, Lu Ping, Ruikang Dun, Lulu Liu, Yihong Shi, Ruizhe He, Qing Zhong, Yang Chen, Wenmin Tian, Yupei Zhao.

  Understanding the spatial proteomic landscape of human tumors is essential for dissecting cellular heterogeneity and microenvironmental interactions in cancer biology. Traditional bulk proteomic approaches, however, obscure spatial information and average out signals from distinct cell populations. Here, we present a detailed and reproducible micro-quantitative protocol for spatially resolved proteomic analysis of specific cellular subpopulations isolated from immunohistochemistry (IHC)-labeled formalin-fixed paraffin-embedded (FFPE) tissue sections using laser microdissection (LMD). By combining IHC staining to visually define phenotypically distinct cells within preserved tissue architecture and precise LMD capture, approximately 6000 target cells can be isolated per sample for downstream proteomic quantification. Despite the ultra-low input, optimized lysis and digestion steps ensure consistent peptide recovery and highly reproducible label-free LC-MS/MS data across replicates. Integrating immunohistochemistry staining-guided spatial sampling with ultrasensitive quantitative proteomics, this workflow enables reliable cell-type-specific profiling directly within human tumor tissues. The protocol bridges histopathology and proteomics, offering a practical framework for translational research exploring spatial protein signatures and tumor microenvironmental heterogeneity.

Keywords:  FFPE tissue; immunohistochemistry; laser microdissection; tumor microenvironment

DOI:  https://doi.org/10.3390/bioengineering13060678
Life Metab. 2026 Aug;5(4): loag012

CLPTM1L modulates membrane lipid rafts to promote tumor EGFR signaling.

Dejian Pang, Xuan Yang, Xinyao Li, Zixuan Xue, Xincan Hou, Kemu Xiao, Yun Yang, Guanlin Wang, Tong-Jin Zhao, Junfeng Bi.

  The plasma membrane dynamically organizes into specialized lipid domains to sustain cell proliferative signaling, yet the regu-latory mechanisms driving this process, especially during tumor progression, remain poorly understood. Here, we uncover cleft lip and palate transmembrane protein 1-like protein (CLPTM1L), an endoplasmic reticulum-localized lipid scramblase, as a critical regulator of membrane raft formation and the epidermal growth factor receptor (EGFR)-mediated proliferative signaling in cancer. High CLPTM1L expression was significantly associated with poor patient survival in glioblastoma (GBM), the most aggressive brain cancer. Depletion of CLPTM1L disrupts cellular lipid homeostasis and results in a substantial loss of membrane raft components, including glycosphingolipids and glycosylphosphatidylinositol (GPI)-anchored proteins. The cell-surface level of EGFR, which colocalizes with raft marker GM1, is markedly reduced upon CLPTM1L loss. We show that CLPTM1L-mediated raft remodeling promotes EGFR signaling and drives cell proliferation in both cancer and non-cancer cells. In GBM mouse models, CLPTM1L depletion inhibits EGFR signaling and profoundly impairs orthotopic tumor growth. Our work establishes CLPTM1L as a key regulator of membrane raft domain formation and highlights its critical role in cancer proliferative signaling.

Keywords:  CLPTM1L; GPI-anchored proteins; RTK signaling; glioblastoma; lipid rafts; membrane lipid remodeling

DOI:  https://doi.org/10.1093/lifemeta/loag012
bioRxiv. 2026 Jun 11. pii: 2026.06.10.731409. [Epub ahead of print]

A membrane homeostatic response to lipid overload coordinates fatty acid metabolism.

Xiaojun Xiang, Yohannes A Ambaw, Ozlem Tok, Sheng Hui, Wei-Chun Tang, Arda Mizrak, Qingyue Zhang, Luke Cohen-Abeles, Robert V Farese, Tobias C Walther.

Excess fatty acids can disrupt membrane and organelle function. Cells buffer fatty acid toxicity by synthesizing and storing triglycerides (TGs) in lipid droplets, but their capacity for TG storage is limited. Here, using hepatocytes with impaired TG synthesis, we identified adaptive pathways that restore homeostasis during lipid overload. One arm of the response is transcriptional activation of peroxisome proliferator-activated receptors to promote fatty acid oxidation. The other suppresses sterol regulatory element-binding protein 1 (SREBP1)-mediated lipogenesis, reducing fatty acid synthesis and desaturation. Mechanistically, SREBP1 cleavage-activation occurs with changes in membrane fluidity: impaired TG synthesis increased membrane fluidity and suppressed SREBP1 activation, whereas saturated fatty acids exerted opposite effects. These findings reveal feedback regulation that maintains fatty acid homeostasis by coordinating their synthesis and oxidation. They also support a model in which ER membrane fluidity regulates SREBP1 activity to maintain membrane lipid homeostasis, a finding with broad implications for physiology and disease.
Highlights: Impaired triglyceride synthesis induces feedback regulation of fatty acid metabolism to restore fatty acid homeostasis.Homeostasis is restored via peroxisome proliferator-activated receptor transcriptional activity to enhance fatty acid oxidation.Reduced lipogenesis occurs by suppression of sterol regulatory element-binding protein 1 (SREBP1)-mediated fatty acid synthesis and desaturation.Changes in ER membrane fluidity regulate SREBP1 activity to maintain membrane lipid homeostasis.

DOI: https://doi.org/10.64898/2026.06.10.731409
Nat Struct Mol Biol. 2026 Jun 25.

Surveying the roles of NINJ1 in plasma membrane rupture.

Ishan Deshpande, Nobuhiko Kayagaki.

DOI: https://doi.org/10.1038/s41594-026-01834-3
J Biol Eng. 2026 Jun 23.

Ex vivo assay for organ-specific cancer cell invasion.

François Tyckaert, Paul Frieso Göddertz, Maria Reichhold, Bettina Sarg, Klaus Faserl, Pere Patón González, Felix Eichin, Andreas Villunger, Steffen Ormanns, Stefan Redl, Julia Hofmann, Theresa Hautz, Francesco Baschieri.

   BACKGROUND: Metastasis is the leading cause of cancer-related mortality, yet experimental models often fail to recapitulate the tissue-specific microenvironments shaping metastatic dissemination. While in vivo systems provide physiological relevance, they remain challenging for mechanistic studies. Conversely, conventional in vitro assays lack the organ-specific extracellular matrix (ECM) that regulates invasive behavior. Accessible models that balance biological relevance with experimental feasibility are thus needed.
RESULTS: We developed an ex vivo invasion platform based on mild detergent decellularization of mouse organs followed by vibratome slicing. This approach generates optically transparent lung, liver, and intestine ECM scaffolds that preserve native matrix architecture, mechanical properties, and retain biochemical hallmarks of their tissues of origin. Organ-derived matrices were integrated into standard microfluidic channels and analyzed using conventional fluorescence microscopy to enable quantitative assessment of cancer cell invasion. Benchmarking with breast cancer cell lines of defined invasive capacity, we could demonstrate the robustness and biological relevance of the system. Non-invasive MCF7 cells failed to infiltrate any scaffold. In turn, highly invasive MDA-MB-231 cells successfully invaded permissive soils (lung/liver) but were unable to colonize the non-permissive soil (intestine). Our platform enabled quantitative assessment of invasion rates, and revealed organ-specific transcriptional programs associated with invasive adaptation by RNA-seq.
CONCLUSIONS: The ex vivo organ-derived ECM framework presented here provides a scalable, cost-effective, and experimentally accessible system to study ECM-driven determinants of metastatic invasion. Preserving tissue-specific matrix cues while reducing reliance on animal models, it enables interrogation of ECM-driven metastasis mechanisms and therapeutic evaluation.

Keywords:  Cancer; Extracellular matrix; Invasion; Metastasis; Tissue decellularization

DOI:  https://doi.org/10.1186/s13036-026-00719-9
Clin Cancer Res. 2026 Jun 25.

Biomarker analysis from patients with metastatic PDAC treated with TGFβ antibody, NIS793, plus abraxane+gemcitabine vs. abraxane+gemcitabine alone in a phase II, open label, randomized study.

Marc Pelletier, Jie Yang, Mukta Joshi, Angelo Grauel, Cara Abecunas, Maria Athina Altzerinakou, Zheng Zhou, Xiaoping Zhu, Kirk Clark, Li Li, Li-Yuan Bai, Michele Milella, Teresa Macarulla Mercade, Wai Meng David Tai, Bruno Bockorny, Peter Grell, Shivan Sivakumar, Mark Ka Wong, Cheng Ean Chee, Thomas Aparicio, Gerald Prager, Geraldine Bostel, Brigitte Schiessl, Heiko Maacke, Glenn Dranoff, Alice Shaw, Claire Fabre, Jennifer Mataraza, Shiva Malek, Viviana Cremasco.

BACKGROUND: Transforming Growth Factor Beta (TGFβ) plays a dual role in cancer, acting as a tumor suppressor early in disease but promoting progression and immune evasion when dysregulated. In pancreatic ductal adenocarcinoma (PDAC), TGFβ-driven desmoplasia fosters chemoresistance and immunosuppression, limiting therapeutic efficacy. NIS793, a fully human monoclonal antibody targeting TGFβ, demonstrated anti-fibrotic and immunomodulatory activity in preclinical models and early-phase trials.
METHODS: We conducted a randomized, open-label, phase II study in treatment-naïve metastatic PDAC patients to evaluate NIS793 ± spartalizumab (anti-PD-1) combined with nab-paclitaxel/gemcitabine (ABRA/GEM) versus ABRA/GEM alone. Primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), safety, pharmacokinetics, and biomarker analyses. Exploratory assessments included paired tumor RNA sequencing, cfDNA profiling, and plasma proteomics.
RESULTS: NIS793 demonstrated target engagement and suppression of TGFβ signaling, confirmed by transcriptomic and proteomic analyses. Stromal remodeling was evident, with significant downregulation of CAF markers (ACTA2, FAP) and collagen-related signatures. Despite proof-of-mechanism, clinical efficacy was not observed: median PFS and OS were comparable or numerically worse in NIS793 arm versus control (HR for OS in NIS793+ABRA/GEM vs ABRA/GEM: 1.32; 95% CI: 0.84-2.07). Safety profile was manageable, with no unexpected toxicities. Biomarker data revealed increased expression of neutrophil-related genes post-treatment, suggesting potential induction of tumor-promoting inflammation.
CONCLUSIONS: NIS793 effectively inhibited TGFβ signaling and led to stroma remodeling but failed to improve outcomes in metastatic PDAC. These findings highlight the complexity of TGFβ biology and caution against its blockade in combination with chemotherapy for PDAC. Future strategies should consider context-dependent effects of TGFβ inhibition(NCT04390763).

DOI: https://doi.org/10.1158/1078-0432.CCR-26-0805