bims-cagime 2025-12-28 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2025–12–28
twenty-one papers selected by
Kıvanç Görgülü, Technical University of Munich

Microautophagy mediated by lysosomal membrane proteins: insights from LAMP2B-dependent microlipophagy.
TMEM Doorway Mediated Metastasis in Pancreatic Ductal Adenocarcinoma by Tie2 Signaling.
Novel Acinar Metaplastic States Uncovered in Exocrine Pancreas Disease.
A window trial in metastatic pancreatic ductal adenocarcinoma reveals resistance mechanisms to targeting the KRAS-MEK pathway.
Lymph node microenvironment rewires ferroptosis redox defenses.
NAC controls nascent chain fate through tunnel sensing and chaperone action.
Simultaneous targeting of KRAS and CDK4 synergistically induces durable growth arrest in pancreatic cancer cells.
Mitochondrial VHL rewires cell metabolism in hypoxia.
Depletion of Fibrinogen Suppresses Growth of Primary Tumors and Metastasis of Pancreatic Ductal Adenocarcinoma.
Emergence of high-metastatic potentials and prediction of recurrence and metastasis.
Mechanosensitive dynamics of lysosomes along microtubules regulate leader cell emergence during collective cell migration.
RamanOmics Decodes Spatial Vibrational-Molecular Architecture and Rewiring in Aging and Repair.
Lysosomal swelling triggers LRRK2 activity.
MAPK/p38-ULK1-PI4KB signaling defines a non-canonical autophagy mechanism in KRAS-Mutant tumors.
Mapping cellular targets of covalent cancer drugs in the entire mammalian body.
A gut-to-brain pathway that limits protein intake.
Hepatic adaptation to chronic metabolic stress primes tumorigenesis.
Targeting myeloid cell polarization to prevent GBM recurrence.
Society for Immunotherapy of Cancer: Standards for Reporting of Multiplex Immunohistochemistry/Immunofluorescence Assays (STORMI).
A Phase Ib/II trial of XL888 (HSP90 inhibitor) and pembrolizumab in metastatic pancreatic cancer with translational immune profiling.
Transsulfuration metabolism is essential for ferroptosis resistance in quiescent endothelial cells.

Autophagy. 2025 Dec 24.

Microautophagy mediated by lysosomal membrane proteins: insights from LAMP2B-dependent microlipophagy.

Ryohei Sakai, Tomohiro Kabuta.

  Microautophagy involves the direct uptake of cytoplasmic materials by lysosomes, but its regulation, including substrate specificity, has remained largely unclear in mammalian cells. Microlipophagy, a form of lipid droplet microautophagy, has been suggested in mammalian cells, yet the molecular basis that links lysosomes to lipid droplets and supports their uptake has not been elucidated. In our recent study, we showed that the lysosomal membrane protein LAMP2B mediates this process via its cytoplasmic region, which can bind phosphatidic acid, a lipid present on lipid droplets. We also found that this pathway depends on the ESCRT machinery and proceeds independently of macroautophagy. In this commentary, we summarize these findings and describe how LAMP2B affects lipid droplet degradation in cells. We describe that LAMP2B overexpression protects mice from high-fat-diet-induced obesity and related disorders. We also outline a model of microautophagy and microautophagy-like processes in which LAMP2 isoforms use their cytoplasmic regions to recognize distinct cargos.

Keywords:  Autophagy; LAMP2; LAMP2B; lipid droplet; microautophagy; microlipophagy

DOI:  https://doi.org/10.1080/15548627.2025.2609920
bioRxiv. 2025 Dec 09. pii: 2025.12.05.692608. [Epub ahead of print]

TMEM Doorway Mediated Metastasis in Pancreatic Ductal Adenocarcinoma by Tie2 Signaling.

Erika Pereira Zambalde, Lina A Ariyan, Francisco Puerta-Martinez, Yu Quin Zhu, Priyanka Patil, Nicole C Panarelli, Jiufeng Li, Yookyung Jung, Christian Adkisson, Jakeb Petersen, Dianne Cox, Hava Gil-Henn, Robert Eddy, Ben Z Stanger, David Entenberg, Maja H Oktay, John S Condeelis, John C McAuliffe.

Pancreatic ductal adenocarcinoma (PDAC) is almost invariably fatal due to early hematogenous dissemination that occurs before the primary tumor is clinically detectable, yet the cellular mechanism of tumor cell intravasation has remained unknown. Using multiphoton intravital imaging in autochthonous and orthotopic PDAC models, we demonstrate that intravasation occurs at Tumor Microenvironment of Metastasis (TMEM) doorways-tri-cellular structures comprising a MENA-expressing tumor cell, a Tie2⁺ macrophage, and an endothelial cell in direct contact. These structures are abundant in human PDAC, enriched for Tie2⁺ macrophages, and markedly reduced after neoadjuvant chemotherapy. Selective pharmacologic inhibition of Tie2 with rebastinib decreases TMEM-associated transient vascular openings, suppresses circulating and hepatic disseminated tumor cells, and-when combined with perioperative FOLFIRINOX after curative-intent resection-improves median survival in murine PDAC. These findings establish TMEM doorways as a common, druggable mechanism of intravasation across epithelial cancers and identify Tie2⁺ macrophages as a therapeutic target to prevent metastatic seeding in PDAC, a disease with no anti-metastatic therapies. TMEM doorway-mediated intravasation in PDAC supports its role as a common gateway for hematogenous metastasis in carcinoma.

DOI: https://doi.org/10.64898/2025.12.05.692608
Cell Mol Gastroenterol Hepatol. 2025 Dec 24. pii: S2352-345X(25)00259-0. [Epub ahead of print] 101717

Novel Acinar Metaplastic States Uncovered in Exocrine Pancreas Disease.

Katherine J Aney, Woo-Jeong Jeong, Pal Koak, Anders W Ohman, Canh Hiep Nguyen, Brian M Wolpin, Jonathan A Nowak, Sahar Nissim.

   BACKGROUND & AIMS: In response to injury, pancreatic acinar cells undergo acinar-to-ductal metaplasia (ADM), marked by loss of acinar identity and acquisition of ductal features. While ADM can resolve to support tissue repair, it may also persist and serve as a precursor to pancreatic cancer. Whether diverse pancreatic stressors drive a shared or context-specific ADM program remains unclear. We sought to comprehensively define metaplastic responses to clinically relevant exocrine pancreas diseases known to increase cancer risk.
METHODS: We profiled ADM and the surrounding microenvironment across mouse models of exocrine disease-including acute, recurrent, and chronic pancreatitis, as well as in the setting of oncogenic Kras-capturing over 300,000 single cells. To enable high-quality transcriptomic profiling in enzyme-rich tissue, we leveraged FixNCut, a method that preserves RNA integrity in the exocrine pancreas. Findings were validated in human pancreas tissue using CosMx spatial transcriptomics.
RESULTS: We identify a conserved acinar response across disease contexts that gives rise to previously unrecognized distinct metaplastic states, including a "gateway" ADM population that precedes more advanced metaplastic states marked by complete loss of acinar identity. In pancreatic intraepithelial neoplasia (PanIN) precancerous lesions, we detect classical-like and basal-like states, suggesting that pancreatic cancer subtypes are specified much earlier than previously appreciated. In Kras-mutant tissue, we identify a second wave of inflammation and the emergence of an immunosuppressive niche, coinciding with PanIN formation CONCLUSIONS: Our findings define a conserved program of acinar plasticity across exocrine pancreas diseases. We further link unresolved ADM to immune remodeling during precursor lesion formation and observe the emergence of pancreatic cancer subtypes in early PanIN lesions.

Keywords:  Acinar-to-ductal metaplasia; PanIN; Pancreas Single-Cell RNA-Sequencing; Pancreatic Cancer Initiation; Pancreatitis

DOI:  https://doi.org/10.1016/j.jcmgh.2025.101717
bioRxiv. 2025 Dec 15. pii: 2025.12.12.693851. [Epub ahead of print]

A window trial in metastatic pancreatic ductal adenocarcinoma reveals resistance mechanisms to targeting the KRAS-MEK pathway.

Motoyuki Tsuda, Dove Keith, Colin J Daniel, Carl Pelz, Katie E Blise, Tugba Y Ozmen, Furkan Ozmen, Kevin Hawthone, Jennifer R Eng, Xi Li, Xiaoyan Wang, Hayley Zimny, Shamilene Sivagnanam, Konjit Betre, Nell Kirchberger, Benson Chong, Jinho Lee, Aubry Matter, Alexander Smith, Ethan S Agritelley, Trent Waugh, Ashwin Sannecy, Kimberly Alarcon, Isaac Youm, Sara Protzek, Julian Egger, Isabel A English, Min Yang, Vidhi M Shah, Jason M Link, Allison L Creason, Patrick J Worth, Shaun M Goodyear, Koei Chin, John L Muschler, Christopher G Suciu, Christopher L Corless, Sha Cao, Laura Soucek, Adel Kardosh, Lisa M Coussens, Jonathan R Brody, Charles D Lopez, Gordon B Mills, Rosalie C Sears.

Copy number alterations of KRAS, mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC), and MYC occur in 30-40% of PDAC. Here we demonstrate that KRAS and MYC are frequently co-gained and accompanied with worse prognosis in PDAC. In a Window-of-Opportunity clinical trial for metastatic PDAC, serial biopsies and deep multi-omics analyses were utilized to explore resistance mechanisms to MEK inhibition, as a surrogate for KRAS inhibition. Tumors from four of 14 patients showed Ki-67/CA19-9-based biomarker response (BR). Non-BR tumors were enriched for KRAS / MYC co-gain and KRAS G12D variant. A transcriptomic signature of BR tumors was inversely correlated with KRAS G12D / MYC co-gain in a large PDAC dataset and predictive for KRAS inhibitor response in multiple models. Finally, co-targeting KRAS and MYC was synergistic in KRAS G12D / MYC co-gain PDAC. Together, this study provides insight into KRAS inhibitor resistance and supports MYC as an important target to improve patient outcomes in this deadly disease.

DOI: https://doi.org/10.64898/2025.12.12.693851
Trends Mol Med. 2025 Dec 23. pii: S1471-4914(25)00292-8. [Epub ahead of print]

Lymph node microenvironment rewires ferroptosis redox defenses.

Jillian Stark, Jia-Shu Yang, Victor W Hsu, Whitney S Henry.

  Palma et al. show that melanoma cells adapt to oxidative stress imposed by the lymphatic niche by shifting their dependency from glutathione peroxidase 4 (GPX4) to ferroptosis suppressor protein 1 (FSP1), to protect from ferroptosis. This highlights the importance of the microenvironment in shaping ferroptosis defenses and supports FSP1 as a targetable vulnerability for lymph node metastases.

Keywords:  FSP1; GPX4; ferroptosis; hypoxia; lymph node; melanoma; oxidative stress; tumor microenvironment

DOI:  https://doi.org/10.1016/j.molmed.2025.12.005
Nature. 2025 Dec 22.

NAC controls nascent chain fate through tunnel sensing and chaperone action.

Jae Ho Lee, Laurenz Rabl, Martin Gamerdinger, Vaishali Goyal, Katrin Michaela Khakzar, Natalia Moreira Barbosa, Juliana Abramovich, Fabian Morales-Polanco, Ann-Kathrin Köhler, Ekaterina Samatova, Marina V Rodnina, Elke Deuerling, Judith Frydman.

The nascent polypeptide-associated complex (NAC) is a conserved ribosome-bound factor with essential yet incompletely understood roles in protein biogenesis1. Here, we show that NAC is a multifaceted regulator that coordinates translation elongation, cotranslational folding, and organelle targeting through distinct interactions with nascent polypeptides both inside and outside the ribosome exit tunnel. Using NAC-selective ribosome profiling in C. elegans, we identify thousands of sequence-specific NAC binding events across the nascent proteome, revealing broad cotranslational engagement with hydrophobic and helical motifs in cytosolic, nuclear, ER, and mitochondrial proteins. Unexpectedly, we discover an intra-tunnel sensing mode, where NAC engages ribosomes with extremely short nascent polypeptides inside the exit tunnel in a sequence-specific manner. Moreover, initial NAC interactions induce an early elongation slowdown that tunes ribosome flux and prevent ribosome collisions, linking NAC's chaperone activity to kinetic control of translation. We propose NAC action protects aggregation-prone intermediates by shielding amphipathic helices, thus promoting cytonuclear folding. NAC also supports mitochondrial membrane protein biogenesis and ER targeting by early recognition of signal sequences and transmembrane domain. Our findings establish NAC as an early-acting, multifaceted orchestrator of cotranslational proteostasis, with distinct mechanisms of action on nascent chains depending on their sequence features and subcellular destinations.

DOI: https://doi.org/10.1038/s41586-025-10058-2
Cell Death Dis. 2025 Dec 23.

Simultaneous targeting of KRAS and CDK4 synergistically induces durable growth arrest in pancreatic cancer cells.

Maj-Britt Paulsohn, Klara Henrike Frahnert, Denise Schlösser, Joana Oschwald, Waltraut Kopp, Xin Fang, Carolin Schneider, Constanza Tapia Contreras, Adi Danieli-Mackay, Fabian Ludewig, Martina Bleyer, Gabriela Salinas, Günter Schneider, Elisabeth Hessmann, Matthias Dobbelstein.

Mutant Ras oncoproteins, particularly KRAS, are among the most prevalent drivers of cancer. Small-molecule KRAS inhibitors have emerged as promising cancer therapeutics, yet resistance development remains a major hurdle. To overcome this challenge, we explored rational combination strategies aimed at enhancing therapeutic efficacy and durability. We show that the KRAS-G12C inhibitor Sotorasib synergizes with the CDK4/6 inhibitor Palbociclib to eliminate pancreatic ductal adenocarcinoma (PDAC) cells and organoids harboring KRAS-G12C mutations. This synergy was especially pronounced following drug washout, indicating a durable cellular response. Similar synergistic effects were observed in non-small-cell lung cancer (NSCLC) cells. Additionally, the KRAS-G12D inhibitor MRTX1133 cooperated with Palbociclib to suppress growth of KRAS-G12D-mutant PDAC cells. Mechanistically, the combinations induced sustained cell cycle arrest, marked by reduced RB phosphorylation, decreased E2F1 expression, and increased levels of CDKN1B/p27. Deletion of CDKN1B largely reversed the growth-inhibitory effect, highlighting its essential role in mediating the observed synergy. In an orthotopic, immunocompetent mouse model of PDAC, MRTX1133 significantly reduced tumor growth and extended survival; however, despite its ability to suppress RB phosphorylation, Palbociclib failed to enhance these effects. Single-cell RNA sequencing suggested that Palbociclib treatment induces tumor vascularization, perhaps contributing to the lack of drug synergy observed in vivo. In summary, our findings demonstrate the therapeutic potential of enhancing cell cycle restriction point activation in KRAS inhibitor-based therapies, while emphasizing the importance of placing combination therapies into a suitable context.

DOI: https://doi.org/10.1038/s41419-025-08362-w
Cell Metab. 2025 Dec 22. pii: S1550-4131(25)00527-3. [Epub ahead of print]

Mitochondrial VHL rewires cell metabolism in hypoxia.

Guobang Li, Wenfeng Pan, Long Wu, Zhiliang Cai, Haoming Chen, Xingui Wu, Tiantian Yu, Kun Liao, Hui Zhang, Xingqiao Wen, Bo Li.

  Under normoxia, von Hippel-Lindau (VHL) protein targets the oxygen-induced, hydroxylated α subunits of hypoxia-inducible factors (HIFs) for degradation to orchestrate mammalian oxygen sensing. However, whether VHL plays non-canonical roles in hypoxia, when protein hydroxylation is attenuated, remains elusive. Here, we show that most cytosolic VHL is degraded under chronic hypoxia, with the remaining VHL pool primarily translocating to the mitochondria. Mitochondrial VHL binds and inhibits 3-methylcrotonyl-coenzyme A carboxylase subunit 2 (MCCC2), an essential subunit of the leucine catabolic machinery. Accumulated leucine allosterically activates glutamate dehydrogenase to promote glutaminolysis, generating sufficient lipids and nucleotides to support hypoxic cell growth. Furthermore, SRC-mediated VHL phosphorylation and protein arginine methyltransferase 5 (PRMT5)-mediated MCCC2 methylation synergistically regulate the VHL-MCCC2 interaction and concomitant metabolic changes, which are recapitulated in animal models of ischemic injury and functionally associated with VHL mutations in cancer. Our study highlights VHL as a bona fide regulator of hypoxic metabolism within mitochondria, rather than a solely "standby adaptor" for HIFs under hypoxia.

Keywords:  VHL; hypoxia; leucine; metabolism; mitochondria

DOI:  https://doi.org/10.1016/j.cmet.2025.11.013
Gastroenterology. 2025 Dec 23. pii: S0016-5085(25)06025-1. [Epub ahead of print]

Depletion of Fibrinogen Suppresses Growth of Primary Tumors and Metastasis of Pancreatic Ductal Adenocarcinoma.

Nayela N Chowdhury, Dana K Mitchell, Kadri Kangro, Kierra Eldridge, Sara Abrahams, Francesca Ferraresso, Lih J Juang, Silpa Gampala, Kylee Brewster, Alexey Revenko, Christian Kastrup, Paul R Territo, D Wade Clapp, Jia Wang, Jorge A Belgodere, Omer Saeed, Sae Rome Choi, Bumsoo Han, Alisa S Wolberg, Sha Cao, Chi Zhang, Matthew J Flick, Melissa L Fishel.

   BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive, highly metastatic disease that provokes dysregulation of the coagulation system. Patients exhibit significantly elevated circulating levels of blood clotting protein fibrin(ogen). Extravascular fibrin deposits contribute to the complex tumor microenvironment in PDAC.
METHODS: We depleted fibrinogen in 3 PDAC patient-derived xenograft models using technology platforms that are currently being tested clinically (antisense oligonucleotide or lipid nanoparticles containing small interfering RNAs) and monitored tumor growth and metastasis. Proteomics and spatial transcriptomics were used to interrogate the mechanisms behind the in vivo work.
RESULTS: The role of fibrin on tumor progression was evaluated in vitro and in vivo and reduction of fibrin led to decreased tumor cell proliferation in vitro and significantly suppressed primary orthotopic tumor growth. Fibrin depletion provoked a significant shift in extracellular matrix-associated proteins and serine protease inhibitors, suggesting a decrease in the activity of serine proteases known to be responsible for extracellular matrix remodeling and metastatic dissemination. Spatial transcriptomics revealed that tumors from fibrinogen-depleted mice exhibit significantly increased presence of stromal components, including tumor-restraining cancer-associated fibroblasts. Congruently, fibrinogen knockdown in a metastatic orthotopic model markedly impaired spontaneous metastasis to the liver. However, fibrinogen knockdown did not affect liver colonization in an intrasplenic injection model, which recapitulates the late stages of metastasis.
CONCLUSIONS: These data suggest that fibrin(ogen) reprograms the primary tumor microenvironment to support growth and promote early, but not late, metastatic steps. Our findings support prospective evaluation of a novel clinical approach involving the integration of fibrin(ogen)-targeting or depleting agents into chemotherapy regimens to control the spread of pancreatic cancer.

Keywords:  Extracellular Matrix; Fibrinogen; Metastasis; PDX Models; Pancreatic Cancer; Tumor Microenvironment

DOI:  https://doi.org/10.1053/j.gastro.2025.09.024
Cell Rep. 2025 Dec 23. pii: S2211-1247(25)01606-7. [Epub ahead of print]45(1): 116834

Emergence of high-metastatic potentials and prediction of recurrence and metastasis.

Aravind Srinivasan, Arwen Conod, Yann Tapponnier, Marianna Silvano, Luca Dall'Olio, Céline Delucinge-Vivier, Isabel Borges-Grazina, Ariel Ruiz I Altaba.

  What makes a cancer highly metastatic is not known. Here, we inquire on the metastatic potential (MP) of tumor cells, which reflects their probability to emigrate from the primary tumor to new sites to form secondary cancers. We determine the transcriptomic landscapes of single-cell-derived clones in hybrid EMT space and define metastatic potential gradient genes (MPGGs) that linearly track MP strength. Perturbation of selected MPGGs and linked processes reveals a dynamic cellular and molecular framework of what we define as "cell-state ensembles" underlying the emergence of high MPs. To test if MPGGs predict cancer recurrence, we build the MangroveGS machine-learning model with "gene signature ensembles": MangroveGSMPGGs robustly predicts patient tumor recurrence and metastases, outperforms all other signatures and staging systems tested, and can be extended to multiple cancer types of epithelial nature. Our findings uncover an unsuspected shared strategy for the onset of metastases that underlies clinical outcome.

Keywords:  CP: cancer; cancer; cell states; disease recurrence; ensemble; gradient; metastasis; metastatic potential; plasticity; prediction; risk

DOI:  https://doi.org/10.1016/j.celrep.2025.116834
Nat Commun. 2025 Dec 21.

Mechanosensitive dynamics of lysosomes along microtubules regulate leader cell emergence during collective cell migration.

Rituraj Marwaha, Diya Manoj, Simran Rawal, Purnati Khuntia, Sanak Banerjee, Praver Gupta, Basil Thurakkal, Manish Jaiswal, Tamal Das.

Collective cell migration during embryonic development, wound healing, and cancer metastasis requires the emergence of leader cells at the migration front. Despite their physiological relevance, the full mechanisms underlying the emergence of leader cells remain elusive. Here we report that leader cells display a peripheral accumulation of lysosomes in diverse model systems for wound healing, including cultured epithelial monolayer, mouse embryonic skin, and Drosophila embryos. This accumulation involves cellular contractile forces driving lysosomal transport along microtubules towards the leading edge. Indeed, we control leader cell emergence by manipulating lysosomal movement on microtubules. We further find that peripheral lysosomes associate with Rac1 molecules at the leading periphery, regulating local Rac1-activity, triggering actin polymerization and promoting lamellipodium formation. Taken together, we demonstrate that beyond their catabolic role, lysosomes act as an intracellular platform that links mechanical and biochemical signals to control the emergence of leader cells.

DOI: https://doi.org/10.1038/s41467-025-67645-0
bioRxiv. 2025 Dec 08. pii: 2025.12.04.692337. [Epub ahead of print]

RamanOmics Decodes Spatial Vibrational-Molecular Architecture and Rewiring in Aging and Repair.

Ke Zhang, Xingjian Chen, Francesco Monticolo, Salvatore Sorrentino, Haochun Huang, Claire Callahan, Yueqing Qiao, Judy Zhou, Sonia Brodowska, Styliani Sapantzi, Jianhuan Qi, Yinghan Wu, Thai Nam Son Dang, Francesca Viggiani, Chia-Kang Ho, Yanxin Xu, Koseki J Kobayashi-Kirschvink, Thang Mung, Hemali Phatnani, Zhixun Dou, Jeon Woong Kang, Peter T C So, Jian Shu.

Aging and tissue repair involve multilayered and spatially heterogeneous remodeling across transcriptional, biochemical, and cellular dimensions, yet prevailing definitions rely on isolated molecular markers that obscure how biochemical and transcriptional states co-evolve in tissues. Here we present RamanOmics, a multimodal framework that integrates single-nucleus RNA sequencing (snRNA-seq), spatial transcriptomics, and label-free Raman imaging to map the spatial vibrational-biochemical and molecular architecture of aging and senescence directly in intact tissues. Applied to mouse lung and skin, RamanOmics generates spatially resolved biochemical-molecular maps revealing tissue-specific programs: lung senescent cells are enriched for extracellular matrix (ECM) remodeling and TGF-β signaling ( Serpine1, Dab2, Igfbp7 ), whereas skin senescence is dominated by keratinization and barrier homeostasis modules ( Krt10, Lor, Sbsn ). Across tissues, we identify a conserved branched-chain fatty-acid-linked biochemical profile and Raman signature (1131-1135 cm⁻¹) that robustly marks p21 ⁺ senescent cells. To unify these layers, we develop a machine learning derived "multimodal barcode" that quantitatively integrates biochemical and transcriptional features, enabling non-destructive identification of senescence in situ . In a wound-healing model, RamanOmics further reveals coordinated reactivation of barrier-repair programs in senescent cells, marked by upregulation of Krt10 , Lor , Sbsn , Sfn , and Dmkn together with matching increases in lipid-associated Raman signatures, confirming biological generalizability beyond steady-state aging. By directly integrating gene programs to spatial vibrational-biochemical states, RamanOmics provides a general framework and resource for scalable, multimodal profiling of cellular states.

DOI: https://doi.org/10.64898/2025.12.04.692337
bioRxiv. 2025 Dec 12. pii: 2025.12.09.693280. [Epub ahead of print]

Lysosomal swelling triggers LRRK2 activity.

Tuyana Malankhanova, Zhiyong Liu, Samuel Strader, Weiping Wang, Kiwoon Sung, Zhong Li, Shawn M Ferguson, Andrew B West.

LRRK2 is implicated in lysosomal functions, but the physiological upstream cues that engage endogenous LRRK2 activity are incompletely defined. Here we show that lysosomal swelling serves as a selective and reversible trigger for LRRK2-mediated Rab phosphorylation, without requiring membrane damage. Acute inhibition of PIKfyve, but not the general disruption of phosphoinositide signaling, induces the robust accumulation of phosphorylated Rabs across endolysosomal membranes. Rescue of swelling through pharmacological restoration of lysosomal ionic imbalances from PIKfyve inhibition suppresses LRRK2 activation without restoring lysosomal function. Mechanical lysosomal swelling from indigestible osmolyte uptake causes a dose-dependent increase in LRRK2-mediated Rab phosphorylation on both swollen and non-swollen lysosomes. Together, these findings identify LRRK2 as a sensor of lysosomal volume and mechanical stress, not specifically membrane damage or PIKfyve inhibition. As lysosomal swelling is a shared pathological feature across LRRK2 -linked diseases, these results reframe LRRK2 as part of an endolysosomal surveillance system responsive to lysosomal distension.

DOI: https://doi.org/10.64898/2025.12.09.693280
Autophagy. 2025 Dec;21(12): 2535-2536

MAPK/p38-ULK1-PI4KB signaling defines a non-canonical autophagy mechanism in KRAS-Mutant tumors.

Xin Wen, Daniel J Klionsky.

  Although KRAS-driven tumors exhibit elevated macroautophagy/autophagy, the extent to which this process diverges from canonical regulatory pathways has not been well characterized. In a recent study published in Cell Research, Wang et al. unveil a novel form of non-canonical autophagy driven by oncogenic RAS mutations, which they termed RAS-induced non-canonical autophagy via ATG8ylation (RINCAA). This pathway operates through a unique MAPK/p38-ULK1-PI4KB axis, diverging significantly from canonical starvation-induced autophagy. The research not only elucidates a new regulatory mechanism but also identifies a potential, highly specific therapeutic target for RAS-mutant cancers.Abbreviations: PI4KB, phosphatidylinositol 4-kinase beta; PtdIns4P, phosphatidylinositol-4-phosphate; RINCAA, RAS-induced non-canonical autophagy via Atg8ylation; ULK1, unc-51 like autophagy activating kinase 1; WIPI2, WD repeat domain phosphoinositide-interacting protein 2.

Keywords:  Autophagy; RAS; RINCAA; oncogene; p38-ULK1-PI4KB axis

DOI:  https://doi.org/10.1080/15548627.2025.2555048
Cell. 2025 Dec 22. pii: S0092-8674(25)01365-0. [Epub ahead of print]

Mapping cellular targets of covalent cancer drugs in the entire mammalian body.

Zhengyuan Pang, Verina H Leung, Cailynn C Wang, Ahmadreza Attarpour, Anthony Rinaldi, Hanbing Shen, Maria Dolores Moya-Garzon, Logan H Sigua, Claire Rammel, Alexandra Selke, Christopher Glynn, Melaina Yender, Senhan Xu, Javid J Moslehi, Peng Wu, Jonathan Z Long, Maged Goubran, Benjamin F Cravatt, Li Ye.

  As our understanding of biological systems reaches single-cell and high spatial resolutions, it becomes imperative that pharmacological approaches match this precision to understand drug actions. This need is particularly urgent for the targeted covalent inhibitors that are currently re-entering the stage for cancer treatments. By leveraging the unique kinetics of click reactions, we developed volumetric clearing-assisted tissue click chemistry (vCATCH) to enable deep and homogeneous click labeling across the three-dimensional (3D) mammalian body. With simple and passive incubation steps, vCATCH offers cellular-resolution drug imaging in the entire adult mouse. We combined vCATCH with hydrogel-based reinforcement of three-dimensional imaging solvent-cleared organs (HYBRiD) imaging and virtual reality to visualize and quantify in vivo targets of two clinical cancer drugs, afatinib and ibrutinib, which recapitulated their known pharmacological distribution and revealed previously unreported tissue and cell-type engagement potentially linked to off-target effects. vCATCH provides a body-wide, unbiased platform to map covalent drug engagements at unprecedented scale and precision.

Keywords:  drug targets; targeted covalent inhibitors; tissue clearing; whole-body imaging

DOI:  https://doi.org/10.1016/j.cell.2025.11.030
Cell. 2025 Dec 24. pii: S0092-8674(25)01363-7. [Epub ahead of print]188(26): 7333-7334

A gut-to-brain pathway that limits protein intake.

Marito Hayashi.

In this issue of Cell, Jaschke and Luchsinger et al. uncover a gut-to-brain signaling mechanism that dynamically shapes protein intake. During recovery from extreme fasting, ammonia derived from the metabolism of specific dietary amino acids is detected by Trpa1-expressing intestinal epithelial cells, leading to the activation of a protein aversion pathway.

DOI: https://doi.org/10.1016/j.cell.2025.11.028
Cell. 2025 Dec 22. pii: S0092-8674(25)01366-2. [Epub ahead of print]

Hepatic adaptation to chronic metabolic stress primes tumorigenesis.

Constantine N Tzouanas, Jessica E S Shay, Marc S Sherman, Adam J Rubin, Benjamin E Mead, Tyler T Dao, Junyan Tao, Brandon M Lehrich, George Eng, Jeffrey Patterson-Fortin, Titus Butzlaff, Miyeko D Mana, Kellie E Kolb, Chad Walesky, Brian J Pepe-Mooney, Colton J Smith, Sanjay M Prakadan, Michelle L Ramseier, Yuzhou Evelyn Tong, Julia Joung, Fangtao Chi, Thomas McMahon-Skates, Carolyn L Winston, Woo-Jeong Jeong, Katherine J Aney, Ethan Chen, Sahar Nissim, Feng Zhang, Vikram Deshpande, Satdarshan P Monga, Georg M Lauer, Wolfram Goessling, Ömer H Yilmaz, Alex K Shalek.

  During chronic stress, cells must support both tissue function and their own survival. Hepatocytes perform metabolic, synthetic, and detoxification roles, but chronic nutrient imbalances can induce hepatocyte death and precipitate metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH). Despite prior work identifying stress-induced drivers of hepatocyte death, chronic stress' functional impact on surviving cells remains unclear. Through cross-species longitudinal single-cell multi-omics, we show that ongoing stress drives prognostic developmental and cancer-associated programs in non-transformed hepatocytes while reducing their mature functional identity. Creating integrative computational methods, we identify and then experimentally validate master regulators perturbing hepatocyte functional balance, increasing proliferation under stress, and directly priming future tumorigenesis. Through geographic regression on human tissue microarray spatial transcriptomics, we uncover spatially structured multicellular communities and signaling interactions shaping stress responses. Our work reveals how cells' early solutions to chronic stress can prime future tumorigenesis and outcomes, unifying diverse modes of cellular dysfunction around core actionable mechanisms.

Keywords:  chronic stress response; computational methods development; epigenetic priming; genetic perturbation; liver; metabolism; single-cell genomics; tissue memory

DOI:  https://doi.org/10.1016/j.cell.2025.11.031
Mol Ther. 2025 Dec 19. pii: S1525-0016(25)01042-1. [Epub ahead of print]

Targeting myeloid cell polarization to prevent GBM recurrence.

Christopher Garris, Gavin P Dunn, Ralph Weissleder.

DOI: https://doi.org/10.1016/j.ymthe.2025.12.019
J Immunother Cancer. 2025 Dec 21. pii: e012280. [Epub ahead of print]13(12):

Society for Immunotherapy of Cancer: Standards for Reporting of Multiplex Immunohistochemistry/Immunofluorescence Assays (STORMI).

Sam Sater, Carlo B Bifulco, Jaime Rodriguez-Canales, Joe Yeong, Guray Akturk, Michael Angelo, Carmen Ballesteros-Merino, Peter Bankhead, Subham Basu, Jorge M Blando, Saska Brajkovic, Marco Cassano, Benjamin J Chen, Ahmet F Coskun, Tricia R Cottrell, Carlos E De Andrea, Robin H Edwards, Colt Egelston, Logan L Engle, Marc S Ernstoff, Rong Fan, Michael Feldman, Bernard A Fox, Jerome Galon, Robyn Gartrell, Sacha Gnjatic, Benjamin F Green, James L Gulley, Anne Hellebust, Stephen Hewitt, Travis J Hollmann, Lucas A Horn, William J Howat, Clifford C Hoyt, Shawn M Jensen, Arutha Kulasinghe, Wiem Lassoued, Steven Lott, James Mansfield, Sebastian Marwitz, George Netto, David B Page, Edwin Parra, David L Rimm, Scott J Rodig, Roberto Salgado, Denis Schapiro, Kurt A Schalper, Joel C Sunshine, Michael J Surace, Alexander S Szalay, Magdalena Thurin, Jose C Villasboas, Keith Wharton, Ignacio I Wistuba, Jennifer H Yearley, Yinyin Yuan, Geroge Zaki, James Ziai, Janis M Taube.

  Multiplex immunofluorescence and immunohistochemistry (mIF/IHC) are increasingly employed antibody-based technologies that use tissue sparingly and facilitate the detection of co-localized or neighboring biomarkers. Specifically, these platforms enable spatial analyses of the tumor microenvironment as well as extended applications, for example, describing normal tissue anatomy, autoimmunity, infectious diseases, etc. mIF/IHC has greatly enhanced biomarker discovery efforts, and a growing number of studies suggest superiority to traditional IHC. Standardization of staining approaches, reporting of image analysis strategies and resultant data is critical for facilitating cross-study comparisons, validation, deployment, and generalization of findings. To address this challenge, The Society for Immunotherapy of Cancer (SITC) previously published two articles providing best practice guidelines for mIF/IHC staining, image analysis, and data sharing. Here, SITC convened stakeholders to develop the third article in the series, a consensus checklist for scientific reporting of mIF/IHC data to support and complement the best practice guidelines. The checklist includes critical components of mIF/IHC applications to be defined within publications such as detailed descriptions of analytical validation; image acquisition, selection, and registration methods; and cell clustering and spatial analysis strategies, amongst others. Such information will help with data reproducibility and comparison across studies towards future drug and assay development.

Keywords:  Biomarker; Immunotherapy; Pathology; Tumor microenvironment - TME

DOI:  https://doi.org/10.1136/jitc-2025-012280
Cancer Lett. 2025 Dec 23. pii: S0304-3835(25)00805-5. [Epub ahead of print] 218233

A Phase Ib/II trial of XL888 (HSP90 inhibitor) and pembrolizumab in metastatic pancreatic cancer with translational immune profiling.

Natalie K Horvat, Maria Diab, Maggie J Phillips, Ashley Veal-McCook, Erin E Grundy, Olatunji B Alese, Emily Greene, Olumide Gbolahan, Kathleen Coleman, Deon Doxie, Cameron J Herting, Jacklyn Hammons, Zaid Mahdi, Jeffrey M Switchenko, Chrystal M Paulos, Bassel F El-Rayes, Gregory B Lesinski.

  Pancreatic adenocarcinoma is marked by high mortality and limited treatment options. In mice, HSP90 inhibition limits cancer-associated fibroblasts activation and enhances T cell infiltration, sensitizing tumors to PD-1 blockade. We hypothesized that co-administration of pembrolizumab (anti-PD-1) with XL888 (an HSP90 inhibitor) would be safe and induce measurable immunological changes in the PDAC tumor microenvironment that could influence clinical outcome. We report results from an expansion cohort of patients with advanced PDAC (n=16), who were enrolled in a single-center, open-label, nonrandomized, dose-escalation study. Patients received one cycle of either pembrolizumab (200 mg) alone or in combination with XL888 (90 mg, orally twice per week) over a 21-day cycle, followed by crossover to combination therapy. Peripheral blood and image guided liver biopsies were collected on Day 1 before treatment (C1D1) and Day 15 on-treatment (C1D15) for correlative studies. The cxombination regimen was well-tolerated with no unexpected adverse events. No objective responses were observed; two patients (13.3%) achieved stable disease, while the remaining 13 (86.7%) experienced disease progression. Median progression-free survival was 2.0 months, and median overall survival was 4.4 months. Treatment was associated with increased circulating Th1-associated cytokines and chemokines. Peripheral blood mononuclear cell (PBMC) analysis revealed elevated terminal effector CD8+ T cells and CD4+ regulatory T cells in the combination arm compared to pembrolizumab alone. Paired liver biopsies revealed no significant changes across treatment groups. While the combination of XL888 and pembrolizumab was safe and induced systemic immune modulation, limited clinical efficacy was observed and did not impact the PDAC TME.

Keywords:  HSP90 inhibition; PDAC; XL888; checkpoint inhibition; immunotherapy resistance; liver metastasis; tumor microenvironment

DOI:  https://doi.org/10.1016/j.canlet.2025.218233
Cell Death Dis. 2025 Dec 20.

Transsulfuration metabolism is essential for ferroptosis resistance in quiescent endothelial cells.

Roxana Elena Oberkersch, Jacopo Lidonnici, Sebastiano Andreuzza, Eleonora Zambon, Gabriele Imperato, Silvia Pedretti, Nico Mitro, Massimo Mattia Santoro.

Angiogenesis, the formation of new blood vessels from pre-existing ones, is a crucial process involved in both physiological and pathological contexts. During angiogenesis, quiescent endothelial cells (QECs) forming the vascular bed begin to proliferate and switch their metabolism to support anabolic and energetic needs in response to growth factors and hypoxic conditions. Recent research has demonstrated that ferroptosis, an iron-dependent form of cell death mediated by lipid peroxidation, can affect angiogenesis. Cysteine, a thiol-containing amino acid, is crucial for the synthesis of sulfur-containing biomolecules that control ferroptosis. Glutathione (GSH), a reducing tripeptide containing a cysteine residue, serves as a cofactor for the enzyme glutathione peroxidase 4 (GPX4) to donate electrons to peroxides of polyunsaturated fatty acyl phospholipids. Cysteine can be acquired from its extracellular oxidized form, cystine, via the glutamate-cystine antiporter (system xCT) or synthesized de novo via the transsulfuration pathway (TSP). However, whether proliferating ECs (PECs) and QECs differentially modulate the cysteine/GSH/GPX4 axis to protect themselves from ferroptosis is still unknown. Our findings revealed that PECs primarily utilize extracellular cystine to synthesize GSH, which is essential for avoiding ferroptosis. In contrast, QECs exhibit a resilient response to cystine starvation by activating the TSP. Interestingly, chronic and severe hypoxia induces ferroptosis resistance in PECs exposed to cystine limitation, mimicking the metabolic profile of QECs. Molecularly, QECs exhibit high NRF2 expression necessary to support TSP under cystine limitation and protect QECs from ferroptosis. In vivo experiments confirm the susceptibility of ECs to cell death by xCT inhibition in a retinal model of sprouting angiogenesis. These findings highlight differential regulation of cysteine metabolism in PECs and QECs and suggest that the cysteine/GSH/GPX4 axis could be a potential therapeutic target for diseases involving angiogenesis.

DOI: https://doi.org/10.1038/s41419-025-08333-1