bims-camemi 2025-01-05 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2025–01–05
37 papers selected by
Christian Frezza, Universität zu Köln

The human zinc-binding cysteine proteome.
mTOR Signaling Regulates Multiple Metabolic Pathways in Human Lung Fibroblasts After TGF-β and in Pulmonary Fibrosis.
Enterocyte-like differentiation defines metabolic gene signatures of CMS3 colorectal cancers and provides therapeutic vulnerability.
A thermodynamic bottleneck in the TCA cycle contributes to acetate overflow in Staphylococcus aureus.
Aspartate signalling drives lung metastasis via alternative translation.
AMPK-regulated glycerol excretion maintains metabolic crosstalk between reductive and energetic stress.
Somatic mtDNA mutation burden shapes metabolic plasticity in leukemogenesis.
TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling.
Reduced ATP turnover during hibernation in relaxed skeletal muscle.
Pantothenate kinase 4 controls skeletal muscle substrate metabolism.
Mammalian SLC39A13 promotes ER/Golgi iron transport and iron homeostasis in multiple compartments.
Remodelling of the immune landscape by IFNγ counteracts IFNγ-dependent tumour escape in mouse tumour models.
Basic Science and Pathogenesis.
Basic Science and Pathogenesis.
Nuclear speckles regulate functional programs in cancer.
The de novo synthesis of GABA and its gene regulatory function control hepatocellular carcinoma metastasis.
The T cell receptor sequence influences the likelihood of T cell memory formation.
FBP1 controls liver cancer evolution from senescent MASH hepatocytes.
An ultra-conserved poison exon in the Tra2b gene encoding a splicing activator is essential for male fertility and meiotic cell division.
A stromal inflammasome Ras safeguard against Myc-driven lymphomagenesis.
Paradoxical link between senescent cell state and liver cancer resolved.
Histone mark age of human tissues and cell types.
Sensory quiescence induces a cell-non-autonomous integrated stress response curbed by condensate formation of the ATF4 and XRP1 effectors.
Lipids guide T cell antitumor immunity by shaping their metabolic and functional fitness.
Z-Nucleic Acid Sensing and Activation of ZBP1 in Cellular Physiology and Disease Pathogenesis.
Identification of a selective pyruvate dehydrogenase kinase 1 (PDHK1) chemical probe by virtual screening.
Mitochondrial-cytochrome c oxidase II promotes glutaminolysis to sustain tumor cell survival upon glucose deprivation.
DLK-dependent axonal mitochondrial fission drives degeneration after axotomy.
Gliomagenesis mimics an injury response orchestrated by neural crest-like cells.
Endocrine-targeting therapies shift the breast microbiome to reduce estrogen receptor-α breast cancer risk.
Modern biology of extrachromosomal DNA: A decade-long voyage of discovery.
On the causal connection in lifespan correlations and the possible existence of a 'number of life' at molecular level.
Mechanical regulation of macrophage metabolism by allograft inflammatory factor 1 leads to adverse remodeling after cardiac injury.
Cell-autonomous adaptation: an overlooked avenue of adaptation in human evolution.
Engineering immunity using metabolically active polymeric nanoparticles.
IMPDH2 dephosphorylation under FGFR signaling promotes S-phase progression and tumor growth.
Persistence and/or Senescence: Not So Lasting at Last?

Cell. 2024 Dec 26. pii: S0092-8674(24)01341-2. [Epub ahead of print]

The human zinc-binding cysteine proteome.

Nils Burger, Melanie J Mittenbühler, Haopeng Xiao, Sanghee Shin, Shelley M Wei, Erik K Henze, Sebastian Schindler, Sepideh Mehravar, David M Wood, Jonathan J Petrocelli, Yizhi Sun, Hans-Georg Sprenger, Pedro Latorre-Muro, Amanda L Smythers, Luiz H M Bozi, Narek Darabedian, Yingde Zhu, Hyuk-Soo Seo, Sirano Dhe-Paganon, Jianwei Che, Edward T Chouchani.

  Zinc is an essential micronutrient that regulates a wide range of physiological processes, most often through zinc binding to protein cysteine residues. Despite being critical for modulation of protein function, the cysteine sites in the majority of the human proteome that are subject to zinc binding remain undefined. Here, we develop ZnCPT, a deep and quantitative mapping of the zinc-binding cysteine proteome. We define 6,173 zinc-binding cysteines, uncovering protein families across major domains of biology that are subject to constitutive or inducible zinc binding. ZnCPT enables systematic discovery of zinc-regulated structural, enzymatic, and allosteric functional domains. On this basis, we identify 52 cancer genetic dependencies subject to zinc binding and nominate malignancies sensitive to zinc-induced cytotoxicity. We discover a mechanism of zinc regulation over glutathione reductase (GSR), which drives cell death in GSR-dependent lung cancers. We provide ZnCPT as a resource for understanding mechanisms of zinc regulation of protein function.

Keywords:  GSR; cancer; cysteine proteomics; glutathione reductase; zinc; zinc-binding proteome

DOI:  https://doi.org/10.1016/j.cell.2024.11.025
Am J Physiol Lung Cell Mol Physiol. 2025 Jan 02.

mTOR Signaling Regulates Multiple Metabolic Pathways in Human Lung Fibroblasts After TGF-β and in Pulmonary Fibrosis.

Kun Woo D Shin, M Volkan Atalay, Rengul Cetin-Atalay, Erin M O'Leary, Mariel E Glass, Jennifer C Houpy Szafran, Parker S Woods, Angelo Y Meliton, Obada R Shamaa, Yufeng Tian, Gökhan M Mutlu, Robert B Hamanaka.

  Idiopathic pulmonary fibrosis is a fatal disease characterized by the TGF-β-dependent activation of lung fibroblasts, leading to excessive deposition of collagen proteins and progressive replacement of healthy lung with scar tissue. We and others have shown that TGF-β-mediated activation of the Mechanistic Target of Rapamycin Complex 1 (mTORC1) and downstream upregulation of Activating Transcription Factor 4 (ATF4) promote metabolic reprogramming in lung fibroblasts characterized by upregulation of the de novo synthesis of glycine, the most abundant amino acid found in collagen protein. Whether mTOR and ATF4 regulate other metabolic pathways in lung fibroblasts has not been explored. Here, we used RNA sequencing to determine how both ATF4 and mTOR regulate gene expression in human lung fibroblasts following TGF-β. We found that ATF4 primarily regulates enzymes and transporters involved in amino acid homeostasis as well as aminoacyl-tRNA synthetases. mTOR inhibition resulted not only in the loss of ATF4 target gene expression, but also in the reduced expression of glycolytic enzymes and mitochondrial electron transport chain subunits. Analysis of TGF-β-induced changes in cellular metabolite levels confirmed that ATF4 regulates amino acid homeostasis in lung fibroblasts while mTOR also regulates glycolytic and TCA cycle metabolites. We further analyzed publicly available single-cell RNA-seq data sets and found increased expression of ATF4 and mTOR-regulated genes in pathologic fibroblast populations from the lungs of IPF patients. Our results provide insight into the mechanisms of metabolic reprogramming in lung fibroblasts and highlight novel ATF4 and mTOR-dependent pathways that may be targeted to inhibit fibrotic processes.

Keywords:  ATF4; Fibrosis; Metabolism; mTOR

DOI:  https://doi.org/10.1152/ajplung.00189.2024
Nat Commun. 2025 Jan 02. 16(1): 264

Enterocyte-like differentiation defines metabolic gene signatures of CMS3 colorectal cancers and provides therapeutic vulnerability.

Arezo Torang, Aleksandar B Kirov, Veerle Lammers, Kate Cameron, Valérie M Wouters, Rene F Jackstadt, Tamsin R M Lannagan, Joan H de Jong, Jan Koster, Owen Sansom, Jan Paul Medema.

Colorectal cancer (CRC) is stratified into four consensus molecular subtypes (CMS1-4). CMS3 represents the metabolic subtype, but its wiring remains largely undefined. To identify the underlying tumorigenesis of CMS3, organoids derived from 16 genetically engineered mouse models are analyzed. Upon in vitro Cre-recombinase activation, transformation is established and transcriptional profiling reveals that distinct CMSs (CMS2-4) are modeled with different organoids. CMS3-like, metabolic signature-positive, organoids are induced by KRAS mutations. Interestingly, metabolic signatures are subsequently shown to result from enterocyte-like differentiation both in organoids and human cancers. Further analysis reveals carbamoyl-phosphate synthase 1 (CPS1) and sucrase-isomaltase (SI) as signature proteins. More importantly, CPS1 is crucial for de novo pyrimidine synthesis in CMS3 and its inhibition targets proliferation and stemness, facilitating enterocyte-like differentiation, while CMS2 and CMS4 models are not affected. Our data point to an enterocyte-like differentiation of CMS3 CRCs and reveal a selective vulnerability of this subtype through CPS1 inhibition.

DOI: https://doi.org/10.1038/s41467-024-55574-3
mSphere. 2024 Dec 31. e0088324

A thermodynamic bottleneck in the TCA cycle contributes to acetate overflow in Staphylococcus aureus.

Nabia Shahreen, Jongsam Ahn, Adil Alsiyabi, Niaz Bahar Chowdhury, Dhananjay Shinde, Sujata S Chaudhari, Kenneth W Bayles, Vinai C Thomas, Rajib Saha.

  During aerobic growth, S. aureus relies on acetate overflow metabolism, a process where glucose is incompletely oxidized to acetate, for its bioenergetic needs. Acetate is not immediately captured as a carbon source and is excreted as waste by cells. The underlying factors governing acetate overflow in S. aureus have not been identified. Here, we show that acetate overflow is favored due to a thermodynamic bottleneck in the TCA cycle specifically involving the oxidation of succinate to fumarate by succinate dehydrogenase. This bottleneck reduces flux through the TCA cycle, making it more efficient for S. aureus to generate ATP via acetate overflow metabolism. Additionally, the protein allocation cost of maintaining ATP flux through the restricted TCA cycle is greater than that of acetate overflow metabolism. Finally, we show that the TCA cycle bottleneck provides S. aureus the flexibility to redirect carbon toward maintaining redox balance through lactate overflow when oxygen becomes limiting, albeit at the expense of ATP production through acetate overflow. Overall, our findings suggest that overflow metabolism offers S. aureus distinct bioenergetic advantages over a thermodynamically constrained TCA cycle, potentially supporting its commensal-pathogenic lifestyle.

Keywords:  acetate overflow; membrane crowding; overflow metabolism; redox imbalance; thermodynamic bottleneck

DOI:  https://doi.org/10.1128/msphere.00883-24
Nature. 2025 Jan 01.

Aspartate signalling drives lung metastasis via alternative translation.

Ginevra Doglioni, Juan Fernández-García, Sebastian Igelmann, Patricia Altea-Manzano, Arnaud Blomme, Rita La Rovere, Xiao-Zheng Liu, Yawen Liu, Tine Tricot, Max Nobis, Ning An, Marine Leclercq, Sarah El Kharraz, Panagiotis Karras, Yu-Heng Hsieh, Fiorella A Solari, Luiza Martins Nascentes Melo, Gabrielle Allies, Annalisa Scopelliti, Matteo Rossi, Ines Vermeire, Dorien Broekaert, Ana Margarida Ferreira Campos, Patrick Neven, Marion Maetens, Karen Van Baelen, H Furkan Alkan, Mélanie Planque, Giuseppe Floris, Albert Sickmann, Alpaslan Tasdogan, Jean-Christophe Marine, Colinda L G J Scheele, Christine Desmedt, Geert Bultynck, Pierre Close, Sarah-Maria Fendt.

Lung metastases occur in up to 54% of patients with metastatic tumours1,2. Contributing factors to this high frequency include the physical properties of the pulmonary system and a less oxidative environment that may favour the survival of cancer cells3. Moreover, secreted factors from primary tumours alter immune cells and the extracellular matrix of the lung, creating a permissive pre-metastatic environment primed for the arriving cancer cells4,5. Nutrients are also primed during pre-metastatic niche formation6. Yet, whether and how nutrients available in organs in which tumours metastasize confer cancer cells with aggressive traits is mostly undefined. Here we found that pulmonary aspartate triggers a cellular signalling cascade in disseminated cancer cells, resulting in a translational programme that boosts aggressiveness of lung metastases. Specifically, we observe that patients and mice with breast cancer have high concentrations of aspartate in their lung interstitial fluid. This extracellular aspartate activates the ionotropic N-methyl-D-aspartate receptor in cancer cells, which promotes CREB-dependent expression of deoxyhypusine hydroxylase (DOHH). DOHH is essential for hypusination, a post-translational modification that is required for the activity of the non-classical translation initiation factor eIF5A. In turn, a translational programme with TGFβ signalling as a central hub promotes collagen synthesis in lung-disseminated breast cancer cells. We detected key proteins of this mechanism in lung metastases from patients with breast cancer. In summary, we found that aspartate, a classical biosynthesis metabolite, functions in the lung environment as an extracellular signalling molecule to promote aggressiveness of metastases.

DOI: https://doi.org/10.1038/s41586-024-08335-7
Nat Cell Biol. 2025 Jan 02.

AMPK-regulated glycerol excretion maintains metabolic crosstalk between reductive and energetic stress.

Xuewei Zhai, Ronghui Yang, Qiaoyun Chu, Zihao Guo, Pengjiao Hou, Xuexue Li, Changsen Bai, Ziwen Lu, Luxin Qiao, Yanxia Fu, Jing Niu, Binghui Li.

Glucose metabolism has been studied extensively, but the role of glucose-derived excretory glycerol remains unclear. Here we show that hypoxia induces NADH accumulation to promote glycerol excretion and this pathway consumes NADH continuously, thus attenuating its accumulation and reductive stress. Aldolase B accounts for glycerol biosynthesis by forming a complex with glycerol 3-phosphate dehydrogenases GPD1 and GPD1L. Blocking GPD1, GPD1L or glycerol 3-phosphate phosphatase exacerbates reductive stress and suppresses cell proliferation under hypoxia and tumour growth in vivo. Overexpression of these enzymes increases glycerol excretion but still reduces cell viability under hypoxia and tumour proliferation due to energy stress. AMPK inactivates aldolase B to mitigate glycerol synthesis that dissipates ATP, alleviating NADH accumulation-induced energy crisis. Therefore, glycerol biosynthesis/excretion regulates the trade-off between reductive stress and energy stress. Moreover, this mode of regulation seems to be prevalent in reductive stress-driven transformations, enhancing our understanding of the metabolic complexity and guiding tumour treatment.

DOI: https://doi.org/10.1038/s41556-024-01549-x
Sci Adv. 2025 Jan 03. 11(1): eads8489

Somatic mtDNA mutation burden shapes metabolic plasticity in leukemogenesis.

Xiujie Li-Harms, Jingjun Lu, Yu Fukuda, John Lynch, Aditya Sheth, Gautam Pareek, Marcin M Kaminski, Hailey S Ross, Christopher W Wright, Amber L Smith, Huiyun Wu, Yong-Dong Wang, Marc Valentine, Geoffrey Neale, Peter Vogel, Stanley Pounds, John D Schuetz, Min Ni, Mondira Kundu.

The role of somatic mitochondrial DNA (mtDNA) mutations in leukemogenesis remains poorly characterized. To determine the impact of somatic mtDNA mutations on this process, we assessed the leukemogenic potential of hematopoietic progenitor cells (HPCs) from mtDNA mutator mice (Polg D257A) with or without NMyc overexpression. We observed a higher incidence of spontaneous leukemogenesis in recipients transplanted with heterozygous Polg HPCs and a lower incidence of NMyc-driven leukemia in those with homozygous Polg HPCs compared to controls. Although mtDNA mutations in heterozygous and homozygous HPCs caused similar baseline impairments in mitochondrial function, only heterozygous HPCs responded to and supported altered metabolic demands associated with NMyc overexpression. Homozygous HPCs showed altered glucose utilization with pyruvate dehydrogenase inhibition due to increased phosphorylation, exacerbated by NMyc overexpression. The impaired growth of NMyc-expressing homozygous HPCs was partially rescued by inhibiting pyruvate dehydrogenase kinase, highlighting a relationship between mtDNA mutation burden and metabolic plasticity in leukemogenesis.

DOI: https://doi.org/10.1126/sciadv.ads8489
Nat Cell Biol. 2024 Dec 30.

TRACERx analysis identifies a role for FAT1 in regulating chromosomal instability and whole-genome doubling via Hippo signalling.

TRACERx Consortium

Chromosomal instability (CIN) is common in solid tumours and fuels evolutionary adaptation and poor prognosis by increasing intratumour heterogeneity. Systematic characterization of driver events in the TRACERx non-small-cell lung cancer (NSCLC) cohort identified that genetic alterations in six genes, including FAT1, result in homologous recombination (HR) repair deficiencies and CIN. Using orthogonal genetic and experimental approaches, we demonstrate that FAT1 alterations are positively selected before genome doubling and associated with HR deficiency. FAT1 ablation causes persistent replication stress, an elevated mitotic failure rate, nuclear deformation and elevated structural CIN, including chromosome translocations and radial chromosomes. FAT1 loss contributes to whole-genome doubling (a form of numerical CIN) through the dysregulation of YAP1. Co-depletion of YAP1 partially rescues numerical CIN caused by FAT1 loss but does not relieve HR deficiencies, nor structural CIN. Importantly, overexpression of constitutively active YAP15SA is sufficient to induce numerical CIN. Taken together, we show that FAT1 loss in NSCLC attenuates HR and exacerbates CIN through two distinct downstream mechanisms, leading to increased tumour heterogeneity.

DOI: https://doi.org/10.1038/s41556-024-01558-w
Nat Commun. 2025 Jan 02. 16(1): 80

Reduced ATP turnover during hibernation in relaxed skeletal muscle.

Cosimo De Napoli, Luisa Schmidt, Mauro Montesel, Laura Cussonneau, Samuele Sanniti, Lorenzo Marcucci, Elena Germinario, Jonas Kindberg, Alina Lynn Evans, Guillemette Gauquelin-Koch, Marco Narici, Fabrice Bertile, Etienne Lefai, Marcus Krüger, Leonardo Nogara, Bert Blaauw.

Hibernating brown bears, due to a drastic reduction in metabolic rate, show only moderate muscle wasting. Here, we evaluate if ATPase activity of resting skeletal muscle myosin can contribute to this energy sparing. By analyzing single muscle fibers taken from the same bears, either during hibernation or in summer, we find that fibers from hibernating bears have a mild decline in force production and a significant reduction in ATPase activity. Single fiber proteomics, western blotting, and immunohistochemical analyses reveal major remodeling of the mitochondrial proteome during hibernation. Furthermore, using bioinformatical approaches and western blotting we find that phosphorylated myosin light chain, a known stimulator of basal myosin ATPase activity, is decreased in hibernating and disused muscles. These results suggest that skeletal muscle limits energy loss by reducing myosin ATPase activity, indicating a possible role for myosin ATPase activity modulation in multiple muscle wasting conditions.

DOI: https://doi.org/10.1038/s41467-024-55565-4
Nat Commun. 2025 Jan 02. 16(1): 345

Pantothenate kinase 4 controls skeletal muscle substrate metabolism.

Adriana Miranda-Cervantes, Andreas M Fritzen, Steffen H Raun, Ondřej Hodek, Lisbeth L V Møller, Kornelia Johann, Luisa Deisen, Paul Gregorevic, Anders Gudiksen, Anna Artati, Jerzy Adamski, Nicoline R Andersen, Casper M Sigvardsen, Christian S Carl, Christian T Voldstedlund, Rasmus Kjøbsted, Stefanie M Hauck, Peter Schjerling, Thomas E Jensen, Alberto Cebrian-Serrano, Markus Jähnert, Pascal Gottmann, Ingo Burtscher, Heiko Lickert, Henriette Pilegaard, Annette Schürmann, Matthias H Tschöp, Thomas Moritz, Timo D Müller, Lykke Sylow, Bente Kiens, Erik A Richter, Maximilian Kleinert.

Metabolic flexibility in skeletal muscle is essential for maintaining healthy glucose and lipid metabolism, and its dysfunction is closely linked to metabolic diseases. Exercise enhances metabolic flexibility, making it an important tool for discovering mechanisms that promote metabolic health. Here we show that pantothenate kinase 4 (PanK4) is a new conserved exercise target with high abundance in muscle. Muscle-specific deletion of PanK4 impairs fatty acid oxidation which is related to higher intramuscular acetyl-CoA and malonyl-CoA levels. Elevated acetyl-CoA levels persist regardless of feeding state and are associated with whole-body glucose intolerance, reduced insulin-stimulated glucose uptake in glycolytic muscle, and impaired glucose uptake during exercise. Conversely, increasing PanK4 levels in glycolytic muscle lowers acetyl-CoA and enhances glucose uptake. Our findings highlight PanK4 as an important regulator of acetyl-CoA levels, playing a key role in both muscle lipid and glucose metabolism.

DOI: https://doi.org/10.1038/s41467-024-55036-w
Nat Commun. 2024 Dec 30. 15(1): 10838

Mammalian SLC39A13 promotes ER/Golgi iron transport and iron homeostasis in multiple compartments.

Huihui Li, Yanmei Cui, Yule Hu, Mengran Zhao, Kuanyu Li, Xiaoyun Pang, Fei Sun, Bing Zhou.

Iron is a potent biochemical, and accurate homeostatic control is orchestrated by a network of interacting players at multiple levels. Although our understanding of organismal iron homeostasis has advanced, intracellular iron homeostasis is poorly understood, including coordination between organelles and iron export into the ER/Golgi. Here, we show that SLC39A13 (ZIP13), previously identified as a zinc transporter, promotes intracellular iron transport and reduces intracellular iron levels. ZIP13 loss causes an iron deficiency in the ER/Golgi and other intracellular compartments, such as lysosomes and mitochondria, as well as elevating iron in the cytosol. ZIP13 overexpression has the opposite effect, increasing iron in organellar compartments. We suggest that ZIP13 gatekeeps an iron trafficking route that shunts iron from the cytosol to the ER/Golgi hub. Zip13-knockout male mice have iron deposition in several tissues. These data demonstrate that mammalian ZIP13 is crucial for iron homeostasis and suggest a potential iron transport function.

DOI: https://doi.org/10.1038/s41467-024-55149-2
Nat Commun. 2025 Jan 02. 16(1): 2

Remodelling of the immune landscape by IFNγ counteracts IFNγ-dependent tumour escape in mouse tumour models.

Vivian W C Lau, Gracie J Mead, Zofia Varyova, Julie M Mazet, Anagha Krishnan, Edward W Roberts, Gennaro Prota, Uzi Gileadi, Kim S Midwood, Vincenzo Cerundolo, Audrey Gérard.

Loss of IFNγ-sensitivity by tumours is thought to be a mechanism enabling evasion, but recent studies suggest that IFNγ-resistant tumours can be sensitised for immunotherapy, yet the underlying mechanism remains unclear. Here, we show that IFNγ receptor-deficient B16-F10 mouse melanoma tumours are controlled as efficiently as WT tumours despite their lower MHC class I expression. Mechanistically, IFNγ receptor deletion in B16-F10 tumours increases IFNγ availability, triggering a remodelling of the immune landscape characterised by inflammatory monocyte infiltration and the generation of 'mono-macs'. This altered myeloid compartment synergises with an increase in antigen-specific CD8+ T cells to promote anti-tumour immunity against IFNγ receptor-deficient tumours, with such an immune crosstalk observed around blood vessels. Importantly, analysis of transcriptomic datasets suggests that similar immune remodelling occurs in human tumours carrying mutations in the IFNγ pathway. Our work thus serves mechanistic insight for the crosstalk between tumour IFNγ resistance and anti-tumour immunity, and implicates this regulation for future cancer therapy.

DOI: https://doi.org/10.1038/s41467-024-54791-0
Alzheimers Dement. 2024 Dec;20 Suppl 1 e085457

Basic Science and Pathogenesis.

Weichen Zhou, Kalpita R Karan, Wenjin Gu, Hans-Ulrich Klein, Gabriel Sturm, Philip L De Jager, David A Bennett, Michio Hirano, Martin Picard, Ryan E Mills.

BACKGROUND: The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in non-human species and recently demonstrated to occur in rare instances from one human generation to the next.
METHOD: Here we investigated numtogenesis dynamics in humans in two ways. First, we quantified Numts in 1,187 post-mortem brain and blood samples from different individuals. Second, we tested the dynamic transfer of Numts using a repeated-measures whole genome sequencing design in a human fibroblast model that recapitulates several molecular hallmarks of aging.
RESULT: In the ROSMAP dataset, compared to circulating immune cells (n = 389), post-mitotic brain tissue (n = 798) contained more Numts, consistent with their potential somatic accumulation. Within brain samples we observed a 5.5-fold enrichment of somatic Numt insertions in the dorsolateral prefrontal cortex compared to cerebellum samples, suggesting that brain Numts arose spontaneously during development or across the lifespan. Moreover, more brain Numts was linked to earlier mortality. The brains of individuals with no cognitive impairment who died at younger ages carried approximately 2 more Numts per decade of life lost than those who lived longer. In the lifespan model, the longitudinal experiments revealed a gradual accumulation of one Numt every ∼13 days. Numtogenesis was independent of large-scale genomic instability and unlikely driven cell clonality. Targeted pharmacological perturbations including chronic glucocorticoid signaling or impairing mitochondrial oxidative phosphorylation (OxPhos) only modestly increased the rate of numtogenesis, whereas patient-derived SURF1-mutant cells exhibiting mtDNA instability accumulated Numts 4.7-fold faster than healthy donors.
CONCLUSION: Combined, our data document spontaneous numtogenesis in human cells and demonstrate an association between brain cortical somatic Numts and human lifespan. These findings open the possibility that mito-nuclear horizontal gene transfer among human post-mitotic tissues produces functionally-relevant human Numts over timescales shorter than previously assumed.

DOI: https://doi.org/10.1002/alz.085457
Alzheimers Dement. 2024 Dec;20 Suppl 1 e084464

Basic Science and Pathogenesis.

Daniel Barnett, Till S Zimmer, Caroline Booraem, Fernando Palaguachi, Samantha M Meadows, Haopeng Xiao, Edward T Chouchani, Anna G Orr, Adam L Orr.

BACKGROUND: Mitochondrial reactive oxygen species (mROS), such as superoxide and hydrogen peroxide (H2O2), are implicated in aging-associated neurological disorders, including Alzheimer's Disease and frontotemporal dementia. Mitochondrial complex III of the respiratory chain has the highest capacity for mROS production and generates mROS toward the cytosol, poising it to regulate intracellular signaling and disease mechanisms. However, the exact triggers of complex III-derived ROS (CIII-ROS), its downstream molecular targets, and its functional roles in dementia-related pathogenesis remain unclear.
METHOD: Here, we investigated the drivers and consequences of CIII-ROS production in primary mouse astrocytes and mouse models of dementia-linked proteinopathy using site-selective mROS suppressors and genetic approaches together with live-cell imaging of sub-compartmental H2O2 dynamics, stoichiometric redox proteomics, and transcriptomics.
RESULT: We found that specific disease-related factors transiently increase astrocytic CIII-ROS levels, and this effect is dependent on a mitochondrial sodium-calcium exchanger. CIII-ROS oxidized specific cysteines on astrocytic proteins associated with disease, amplified STAT3 phosphorylation and nuclear translocation, and promoted gene expression changes linked to STAT3 and related neuroimmune pathways. Inhibition of other sites of ROS production, including mitochondrial complex I and NADPH oxidase, had no effects on mROS responses or STAT3 signaling, demonstrating the specificity of CIII-ROS induction and its context-dependent modulation of STAT3 activities. Blockade of CIII-ROS in transgenic mouse models of dementia with a site-selective and brain-penetrant suppressor reduced astrocytic alterations, neuropathology, and premature mortality.
CONCLUSION: Our data suggest that dementia-associated factors induce site-specific mROS production and that CIII-ROS promote precise post-translational redox modifications and amplify STAT3-linked signaling and changes in gene expression. Together, our findings reveal CIII-ROS as an important node of mitochondrial-nuclear communication in pathogenic conditions, whereby mROS transients are converted into long-lasting changes in gene transcription and cell function. CIII-ROS and redox signaling offer new therapeutic opportunities for aging-associated neurological disorders.

DOI: https://doi.org/10.1002/alz.084464
Nat Cell Biol. 2025 Jan 02.

Nuclear speckles regulate functional programs in cancer.

Katherine A Alexander, Ruofan Yu, Nicolas Skuli, Nathan J Coffey, Son Nguyen, Christine L Faunce, Hua Huang, Ian P Dardani, Austin L Good, Joan Lim, Catherine Y Li, Nicholas Biddle, Eric F Joyce, Arjun Raj, Daniel Lee, Brian Keith, M Celeste Simon, Shelley L Berger.

Nuclear speckles are dynamic nuclear bodies characterized by high concentrations of factors involved in RNA production. Although the contents of speckles suggest multifaceted roles in gene regulation, their biological functions are unclear. Here we investigate speckle variation in human cancer, finding two main signatures. One speckle signature was similar to healthy adjacent tissues, whereas the other was dissimilar, and considered an aberrant cancer speckle state. Aberrant speckles show altered positioning within the nucleus, higher levels of the TREX RNA export complex and correlate with poorer patient outcomes in clear cell renal cell carcinoma (ccRCC), a cancer typified by hyperactivation of the HIF-2α transcription factor. We demonstrate that HIF-2α promotes physical association of certain target genes with speckles depending on HIF-2α protein speckle-targeting motifs, defined in this study. We identify homologous speckle-targeting motifs within many transcription factors, suggesting that DNA-speckle targeting may be a general gene regulatory mechanism. Integrating functional, genomic and imaging studies, we show that HIF-2α gene regulatory programs are impacted by speckle state and by abrogation of HIF-2α-driven speckle targeting. These findings suggest that, in ccRCC, a key biological function of nuclear speckles is to modulate expression of select HIF-2α-regulated target genes that, in turn, influence patient outcomes. Beyond ccRCC, tumour speckle states broadly correlate with altered functional pathways and expression of speckle-associated gene neighbourhoods, exposing a general link between nuclear speckles and gene expression dysregulation in human cancer.

DOI: https://doi.org/10.1038/s41556-024-01570-0
Dev Cell. 2024 Dec 25. pii: S1534-5807(24)00729-9. [Epub ahead of print]

The de novo synthesis of GABA and its gene regulatory function control hepatocellular carcinoma metastasis.

Li Li, Youli Kang, Running Cheng, Fangming Liu, Fujia Wu, Zizhao Liu, Junjie Kou, Zhenxi Zhang, Wei Li, Haitao Zhao, Xiaojing He, Wenjing Du.

  The neurotransmitter gamma-aminobutyric acid (GABA) has been thought to be involved in the development of some types of cancer. Yet, the de novo synthesis of GABA and how it functions in hepatocellular carcinoma (HCC) remain unclear. Here, we report that SLC6A12 acts as a transporter of GABA, and that aldehyde dehydrogenase 9 family member A1 (ALDH9A1), not glutamate decarboxylase 1 (GAD1), generates GABA in human HCC. Interestingly, SLC6A12 and ALDH9A1 are upregulated during lung metastases of HCC, and depletion of either of them leads to impaired HCC metastasis. Mechanistically, GABA directly binds and stabilizes β-catenin, resulting in activated Wnt/β-catenin signaling, and thereby enhancing HCC metastasis. Reciprocally, β-catenin transcriptionally upregulates SLC6A12 to import more GABA to stabilize β-catenin. Thus, our findings identify ALDH9A1 as the major GABA synthetase in HCC, demonstrate a positive-feedback regulatory mechanism for sustaining Wnt/β-catenin signaling, and reveal a role for β-catenin in sensing GABA, which contributes to HCC metastasis.

Keywords:  ALDH9A1; GABA; HCC metastasis; metabolite sensing; β-catenin stabilization

DOI:  https://doi.org/10.1016/j.devcel.2024.12.007
Cell Rep. 2024 Dec 27. pii: S2211-1247(24)01449-9. [Epub ahead of print]44(1): 115098

The T cell receptor sequence influences the likelihood of T cell memory formation.

Kaitlyn A Lagattuta, Ayano C Kohlgruber, Nouran S Abdelfattah, Aparna Nathan, Laurie Rumker, Michael E Birnbaum, Stephen J Elledge, Soumya Raychaudhuri.

  The amino acid sequence of the T cell receptor (TCR) varies between T cells of an individual's immune system. Particular TCR residues nearly guarantee mucosal-associated invariant T (MAIT) and natural killer T (NKT) cell transcriptional fates. To define how the TCR sequence affects T cell fates, we analyze the paired αβTCR sequence and transcriptome of 961,531 single cells. We find that hydrophobic complementarity-determining region (CDR)3 residues promote regulatory T cell fates in both the CD8 and CD4 lineages. Most strikingly, we find a set of TCR sequence features that promote the T cell transition from naive to memory. We quantify the extent of these features through our TCR scoring function "TCR-mem." Using TCR transduction experiments, we demonstrate that increased TCR-mem promotes T cell activation, even among T cells that recognize the same antigen. Our results reveal a common set of TCR sequence features that enable T cell activation and immunological memory.

Keywords:  CP: Immunology; T-cells; TCR; activation; immunology; memory; transcriptomics

DOI:  https://doi.org/10.1016/j.celrep.2024.115098
Nature. 2025 Jan 01.

FBP1 controls liver cancer evolution from senescent MASH hepatocytes.

Liver Cancer Collaborative

Hepatocellular carcinoma (HCC) originates from differentiated hepatocytes undergoing compensatory proliferation in livers damaged by viruses or metabolic-dysfunction-associated steatohepatitis (MASH)1. While increasing HCC risk2, MASH triggers p53-dependent hepatocyte senescence3, which we found to parallel hypernutrition-induced DNA breaks. How this tumour-suppressive response is bypassed to license oncogenic mutagenesis and enable HCC evolution was previously unclear. Here we identified the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) as a p53 target that is elevated in senescent-like MASH hepatocytes but suppressed through promoter hypermethylation and proteasomal degradation in most human HCCs. FBP1 first declines in metabolically stressed premalignant disease-associated hepatocytes and HCC progenitor cells4,5, paralleling the protumorigenic activation of AKT and NRF2. By accelerating FBP1 and p53 degradation, AKT and NRF2 enhance the proliferation and metabolic activity of previously senescent HCC progenitors. The senescence-reversing and proliferation-supportive NRF2-FBP1-AKT-p53 metabolic switch, operative in mice and humans, also enhances the accumulation of DNA-damage-induced somatic mutations needed for MASH-to-HCC progression.

DOI: https://doi.org/10.1038/s41586-024-08317-9
EMBO J. 2025 Jan 02.

An ultra-conserved poison exon in the Tra2b gene encoding a splicing activator is essential for male fertility and meiotic cell division.

Caroline Dalgliesh, Saad Aldalaqan, Christian Atallah, Andrew Best, Emma Scott, Ingrid Ehrmann, George Merces, Joel Mannion, Barbora Badurova, Raveen Sandher, Ylva Illing, Brunhilde Wirth, Sara Wells, Gemma Codner, Lydia Teboul, Graham R Smith, Ann Hedley, Mary Herbert, Dirk G de Rooij, Colin Miles, Louise N Reynard, David J Elliott.

  The cellular concentrations of splicing factors (SFs) are critical for controlling alternative splicing. Most serine and arginine-enriched (SR) protein SFs regulate their own concentration via a homeostatic feedback mechanism that involves regulation of inclusion of non-coding 'poison exons' (PEs) that target transcripts for nonsense-mediated decay. The importance of SR protein PE splicing during animal development is largely unknown despite PE ultra-conservation across animal genomes. To address this, we used mouse genetics to disrupt an ultra-conserved PE in the Tra2b gene encoding the SR protein Tra2β. Focussing on germ cell development, we found that Tra2b PE deletion causes azoospermia due to catastrophic cell death during meiotic prophase. Failure to proceed through meiosis was associated with increased Tra2b expression sufficient to drive aberrant Tra2β protein hyper-responsive splice patterns. Although critical for meiotic prophase, Tra2b PE deletion spared earlier mitotically active germ cells, even though these still required Tra2b gene function. Our data indicate that PE splicing control prevents the accumulation of toxic levels of Tra2β protein that are incompatible with meiotic prophase. This unexpected connection with male fertility helps explain Tra2b PE ultra-conservation and indicates the importance of evaluating PE function in animal models.

Keywords:  Alternative Splicing; Fertility; Poison Exon; Spermatogenesis; Ultraconserved Genome Sequence

DOI:  https://doi.org/10.1038/s44318-024-00344-6
Nat Immunol. 2025 Jan;26(1): 53-67

A stromal inflammasome Ras safeguard against Myc-driven lymphomagenesis.

Andrew Kent, Kristel Joy Yee Mon, Zachary Hutchins, Gregory Putzel, Dmitry Zhigarev, Alexander Grier, Baosen Jia, Roderik M Kortlever, Gaetan Barbet, Gerard I Evan, J Magarian Blander.

The inflammasome plays multifaceted roles in cancer, but less is known about its function during premalignancy upon initial cell transformation. We report a homeostatic function of the inflammasome in suppressing malignant transformation through Ras inhibition. We identified increased hematopoietic stem cell (HSC) proliferation within the bone marrow of inflammasome-deficient mice. HSCs within an inflammasome-deficient stroma expressed a Ras signature associated with increased Ras pathway- and cancer-related transcripts and heightened levels of cytokine, chemokine and growth factor receptors. Stromal inflammasome deficiency established a poised Ras-dependent mitogenic state within HSCs, which fueled progeny B cell lymphomagenesis upon Myc deregulation in a spontaneous model of B cell lymphoma, and shortened its premalignant stage leading to faster onset of malignancy. Thus, the stromal inflammasome preserves tissue balance by restraining Ras to disrupt the most common oncogenic Myc-Ras cooperation and establish a natural defense against transition to malignancy. These findings should inform preventative therapies against hematological malignancies.

DOI: https://doi.org/10.1038/s41590-024-02028-z
Nature. 2025 Jan 01.

Paradoxical link between senescent cell state and liver cancer resolved.



Keywords:  Cancer; Cell biology

DOI:  https://doi.org/10.1038/d41586-024-04137-z
Sci Adv. 2025 Jan 03. 11(1): eadk9373

Histone mark age of human tissues and cell types.

Lucas Paulo de Lima Camillo, Muhammad Haider Asif, Steve Horvath, Erica Larschan, Ritambhara Singh.

Aging is a complex and multifaceted process involving many epigenetic alterations. One key area of interest in aging research is the role of histone modifications, which can dynamically regulate gene expression. Here, we conducted a pan-tissue analysis of the dynamics of seven key histone modifications during human aging. Our histone-specific age prediction models showed surprisingly accurate performance, proving resilient to experimental and artificial noise. Simulation experiments for comparison with DNA methylation age predictors revealed competitive performance. Moreover, gene set enrichment analysis uncovered several critical developmental pathways for age prediction. Different from DNA methylation age predictors, genes known to be involved in aging biology are among the most important ones for the models. Last, we developed a pan-tissue pan-histone age predictor, suggesting that age-related epigenetic information is degenerated across the epigenome. This research highlights the power of histone marks as input for creating robust age predictors and opens avenues for understanding the role of epigenetic changes during aging.

DOI: https://doi.org/10.1126/sciadv.adk9373
Nat Commun. 2025 Jan 02. 16(1): 252

Sensory quiescence induces a cell-non-autonomous integrated stress response curbed by condensate formation of the ATF4 and XRP1 effectors.

Shashank Shekhar, Charles Tracy, Peter V Lidsky, Raul Andino, Katherine J Wert, Helmut Krämer.

Sensory disabilities have been identified as significant risk factors for dementia but underlying molecular mechanisms are unknown. In different Drosophila models with loss of sensory input, we observe non-autonomous induction of the integrated stress response (ISR) deep in the brain, as indicated by eIF2αS50 phosphorylation-dependent elevated levels of the ISR effectors ATF4 and XRP1. Unlike during canonical ISR, however, the ATF4 and XRP1 transcription factors are enriched in cytosolic granules that are positive for RNA and the stress granule markers Caprin, FMR1, and p62, and are reversible upon restoration of vision for blind flies. Cytosolic restraint of the ATF4 and XRP1 transcription factors dampens expression of their downstream targets including genes of cell death pathways activated during chronic cellular stress and thus constitutes a chronic stress protective response (CSPR). Cytosolic granules containing both p62 and ATF4 are also evident in the thalamus and hippocampus of mouse models of congenital or degenerative blindness. These data indicate a conserved link between loss of sensory input and curbed stress responses critical for protein quality control in the brain.

DOI: https://doi.org/10.1038/s41467-024-55576-1
Trends Endocrinol Metab. 2024 Dec 31. pii: S1043-2760(24)00321-7. [Epub ahead of print]

Lipids guide T cell antitumor immunity by shaping their metabolic and functional fitness.

Letizia Rumiano, Teresa Manzo.

  Lipids are metabolic messengers essential for energy production, membrane structure, and signal transduction. Beyond their recognized role, lipids have emerged as metabolic rheostats of T cell responses, with distinct species differentially modulating CD8+ T cell (CTL) fate and function. Indeed, lipids can influence T cell signaling by altering their membrane composition; in addition, they can affect the differentiation path of T cells through cellular metabolism. This Review discusses the ability of lipids to shape T cell phenotypes and functions. Based on this link between lipid metabolism, metabolic fitness and immunosurveillance, we suggest that lipid could be rationally integrated in the context of immunotherapies to fine-tune fitness and function of adoptive T cell therapy (ACT) products.

Keywords:  CD8 T cells; antitumor immunity; immunotherapy; lipids; metabolism

DOI:  https://doi.org/10.1016/j.tem.2024.11.014
Immunol Rev. 2025 Jan;329(1): e13437

Z-Nucleic Acid Sensing and Activation of ZBP1 in Cellular Physiology and Disease Pathogenesis.

Sanchita Mishra, Ayushi Amin Dey, Sannula Kesavardhana.

  Z-nucleic acid binding protein 1 (ZBP1) is an innate immune sensor recognizing nucleic acids in Z-conformation. Upon Z-nucleic acid sensing, ZBP1 triggers innate immune activation, inflammation, and programmed cell death during viral infections, mice development, and inflammation-associated diseases. The Zα domains of ZBP1 sense Z-nucleic acids and promote RIP-homotypic interaction motif (RHIM)-dependent signaling complex assembly to mount cell death and inflammation. The studies on ZBP1 spurred an understanding of the role of Z-form RNA and DNA in cellular and physiological functions. In particular, short viral genomic segments, endogenous retroviral elements, and 3'UTR regions are likely sources of Z-RNAs that orchestrate ZBP1 functions. Recent seminal studies identify an intriguing association of ZBP1 with adenosine deaminase acting on RNA-1 (ADAR1), and cyclic GMP-AMP synthase (cGAS) in regulating aberrant nucleic acid sensing, chronic inflammation, and cancer. Thus, ZBP1 is an attractive target to aid the development of specific therapeutic regimes for disease biology. Here, we discuss the role of ZBP1 in Z-RNA sensing, activation of programmed cell death, and inflammation. Also, we discuss how ZBP1 coordinates intracellular perturbations in homeostasis, and Z-nucleic acid formation to regulate chronic diseases and cancer.

Keywords:  ADAR1; ZBP1; Z‐RNA sensing; cGAS; cancer; cell death; inflammation

DOI:  https://doi.org/10.1111/imr.13437
Eur J Med Chem. 2024 Dec 26. pii: S0223-5234(24)01092-4. [Epub ahead of print]284 117210

Identification of a selective pyruvate dehydrogenase kinase 1 (PDHK1) chemical probe by virtual screening.

Mason A Baber, Mya D Gough, Larisa Yeomans, Kyle Giesler, Kendall Muzzarelli, Chih-Jung Chen, Zahra Assar, Peter L Toogood.

  PDHK1 is a non-canonical Ser/Thr kinase that negatively regulates the pyruvate dehydrogenase complex (PDC), restricting entry of acetyl-CoA into the tricarboxylic acid (TCA) cycle and downregulating oxidative phosphorylation. In many glycolytic tumors, PDHK1 is overexpressed to suppress activity of the PDC and cause a shift in metabolism toward an increased reliance on glycolysis (the Warburg effect). Genetic studies have shown that knockdown or knockout of PDHK1 reverts this phenotype and inhibits tumor growth in vitro and in vivo, but chemical tools to pharmacologically validate and build upon these data are lacking. We used AtomNet®, a deep convolutional neural network bioactivity predictor, to identify compound 7 as a potential inhibitor of PDHK1. During the process of hit validation, the active species was determined to be isomeric compound 10. Structure-activity studies based on 10 identified 17 as a low μM inhibitor of PDHK1 (IC50 = 1.5 ± 0.3 μM) that is selective against the other PDHK isoforms in both biochemical and cell-based assays. In A549 epithelial lung carcinoma cells, compound 17 inhibits phosphorylation of PDC E1α Ser232, a site that is specifically phosphorylated only by PDHK1, while minimally suppressing phosphorylation of Ser293, a site that is phosphorylated by all four PDHK isoforms. Altogether, these data identify 17 as a selective PDHK1 chemical probe useful for biochemical and cell-based studies.

Keywords:  PDHK; Pyruvate metabolism; Virtual screening

DOI:  https://doi.org/10.1016/j.ejmech.2024.117210
Nat Commun. 2025 Jan 02. 16(1): 212

Mitochondrial-cytochrome c oxidase II promotes glutaminolysis to sustain tumor cell survival upon glucose deprivation.

Yong Yi, Guoqiang Wang, Wenhua Zhang, Shuhan Yu, Junjie Fei, Tingting An, Jianqiao Yi, Fengtian Li, Ting Huang, Jian Yang, Mengmeng Niu, Yang Wang, Chuan Xu, Zhi-Xiong Jim Xiao.

Glucose deprivation, a hallmark of the tumor microenvironment, compels tumor cells to seek alternative energy sources for survival and growth. Here, we show that glucose deprivation upregulates the expression of mitochondrial-cytochrome c oxidase II (MT-CO2), a subunit essential for the respiratory chain complex IV, in facilitating glutaminolysis and sustaining tumor cell survival. Mechanistically, glucose deprivation activates Ras signaling to enhance MT-CO2 transcription and inhibits IGF2BP3, an RNA-binding protein, to stabilize MT-CO2 mRNA. Elevated MT-CO2 increases flavin adenosine dinucleotide (FAD) levels in activating lysine-specific demethylase 1 (LSD1) to epigenetically upregulate JUN transcription, consequently promoting glutaminase-1 (GLS1) and glutaminolysis for tumor cell survival. Furthermore, MT-CO2 is indispensable for oncogenic Ras-induced glutaminolysis and tumor growth, and elevated expression of MT-CO2 is associated with poor prognosis in lung cancer patients. Together, these findings reveal a role for MT-CO2 in adapting to metabolic stress and highlight MT-CO2 as a putative therapeutic target for Ras-driven cancers.

DOI: https://doi.org/10.1038/s41467-024-55768-9
Nat Commun. 2024 Dec 30. 15(1): 10806

DLK-dependent axonal mitochondrial fission drives degeneration after axotomy.

Jorge Gómez-Deza, Matthew Nebiyou, Mor R Alkaslasi, Francisco M Nadal-Nicolás, Preethi Somasundaram, Anastasia L Slavutsky, Wei Li, Michael E Ward, Trent A Watkins, Claire E Le Pichon.

Currently there are no effective treatments for an array of neurodegenerative disorders to a large part because cell-based models fail to recapitulate disease. Here we develop a reproducible human iPSC-based model where laser axotomy causes retrograde axon degeneration leading to neuronal cell death. Time-lapse confocal imaging revealed that damage triggers an apoptotic wave of mitochondrial fission proceeding from the site of injury to the soma. We demonstrate that this apoptotic wave is locally initiated in the axon by dual leucine zipper kinase (DLK). We find that mitochondrial fission and resultant cell death are entirely dependent on phosphorylation of dynamin related protein 1 (DRP1) downstream of DLK, revealing a mechanism by which DLK can drive apoptosis. Importantly, we show that CRISPR mediated Drp1 depletion protects mouse retinal ganglion neurons from degeneration after optic nerve crush. Our results provide a platform for studying degeneration of human neurons, pinpoint key early events in damage related neural death and provide potential focus for therapeutic intervention.

DOI: https://doi.org/10.1038/s41467-024-54982-9
Nature. 2025 Jan 01.

Gliomagenesis mimics an injury response orchestrated by neural crest-like cells.

Akram A Hamed, Kui Hua, Quang M Trinh, Benjamin D Simons, John C Marioni, Lincoln D Stein, Peter B Dirks.

Glioblastoma is an incurable brain malignancy. By the time of clinical diagnosis, these tumours exhibit a degree of genetic and cellular heterogeneity that provides few clues to the mechanisms that initiate and drive gliomagenesis1,2. Here, to explore the early steps in gliomagenesis, we utilized conditional gene deletion and lineage tracing in tumour mouse models, coupled with serial magnetic resonance imaging, to initiate and then closely track tumour formation. We isolated labelled and unlabelled cells at multiple stages-before the first visible abnormality, at the time of the first visible lesion, and then through the stages of tumour growth-and subjected cells of each stage to single-cell profiling. We identify a malignant cell state with a neural crest-like gene expression signature that is highly abundant in the early stages, but relatively diminished in the late stage of tumour growth. Genomic analysis based on the presence of copy number alterations suggests that these neural crest-like states exist as part of a heterogeneous clonal hierarchy that evolves with tumour growth. By exploring the injury response in wounded normal mouse brains, we identify cells with a similar signature that emerge following injury and then disappear over time, suggesting that activation of an injury response program occurs during tumorigenesis. Indeed, our experiments reveal a non-malignant injury-like microenvironment that is initiated in the brain following oncogene activation in cerebral precursor cells. Collectively, our findings provide insight into the early stages of glioblastoma, identifying a unique cell state and an injury response program tied to early tumour formation. These findings have implications for glioblastoma therapies and raise new possibilities for early diagnosis and prevention of disease.

DOI: https://doi.org/10.1038/s41586-024-08356-2
Cell Rep Med. 2024 Dec 26. pii: S2666-3791(24)00651-7. [Epub ahead of print] 101880

Endocrine-targeting therapies shift the breast microbiome to reduce estrogen receptor-α breast cancer risk.

Alana A Arnone, Yu-Ting Tsai, J Mark Cline, Adam S Wilson, Brian Westwood, Meghan E Seger, Akiko Chiba, Marissa Howard-McNatt, Edward A Levine, Alexandra Thomas, David R Soto-Pantoja, Katherine L Cook.

  Studies indicate that breast tissue has a distinct modifiable microbiome population. We demonstrate that endocrine-targeting therapies, such as tamoxifen, reshape the non-cancerous breast microbiome to influence tissue metabolism and reduce tumorigenesis. Using 16S sequencing, we found that tamoxifen alters β-diversity and increases Firmicutes abundance, including Lactobacillus spp., in mammary glands (MGs) of mice and non-human primates. Immunohistochemistry showed that lipoteichoic acid (LTA)-positive bacteria were elevated in tamoxifen-treated breast tissue. In B6.MMTV-PyMT mice, intra-nipple probiotic bacteria injections reduced tumorigenesis, altered metabolic gene expression, and decreased tumor proliferation. Probiotic-conditioned media selectively reduced viability in estrogen receptor-positive (ER+) breast cancer cells and altered mitochondrial metabolism in non-cancerous epithelial cells. Human tumor samples revealed that LTA-positive bacteria negatively correlated with Ki67, suggesting that endocrine therapies influence tumor-associated microbiota to regulate proliferation. Our data indicate that endocrine-targeting therapies modify the breast microbiome, corresponding with a shift in tissue metabolism to potentially reduce ER+ breast cancer risk.

Keywords:  Lactobacillus; MMTV-PyMT mice; Streptococcus; aromatase inhibitors; breast cancer; diet; estrogen receptor; faslodex; glycolysis; metabolism; microbiome; prevention; tamoxifen

DOI:  https://doi.org/10.1016/j.xcrm.2024.101880
Cell Res. 2025 Jan 03.

Modern biology of extrachromosomal DNA: A decade-long voyage of discovery.

Qing-Lin Yang, Yipeng Xie, Kailiang Qiao, Jun Yi Stanley Lim, Sihan Wu.

Genomic instability is a hallmark of cancer and is a major driving force of tumorigenesis. A key manifestation of genomic instability is the formation of extrachromosomal DNAs (ecDNAs) - acentric, circular DNA molecules ranging from 50 kb to 5 Mb in size, distinct from chromosomes. Ontological studies have revealed that ecDNA serves as a carrier of oncogenes, immunoregulatory genes, and enhancers, capable of driving elevated transcription of its cargo genes and cancer heterogeneity, leading to rapid tumor evolution and therapy resistance. Although ecDNA was documented over half a century ago, the past decade has witnessed a surge in breakthrough discoveries about its biological functions. Here, we systematically review the modern biology of ecDNA uncovered over the last ten years, focusing on how discoveries during this pioneering stage have illuminated our understanding of ecDNA-driven transcription, heterogeneity, and cancer progression. Furthermore, we discuss ongoing efforts to target ecDNA as a novel approach to cancer therapy. This burgeoning field is entering a new phase, poised to reshape our knowledge of cancer biology and therapeutic strategies.

DOI: https://doi.org/10.1038/s41422-024-01054-8
Sci Rep. 2024 Dec 30. 14(1): 31707

On the causal connection in lifespan correlations and the possible existence of a 'number of life' at molecular level.

Andrés Escala.

Multiple physiological traits correlates with lifespan, being unclear both the causal connection among them and with the process of ageing. In this paper, we show that six traits (such as metabolic rate, mass, heart rate, etc) acting at the system level, are all related to lifespan thru the existence of an approximately constant number of respiration cycles in a lifespan ([Formula: see text]), therefore, we find that those relationships are not independently related to ageing. In addition, we study if the approximately constant [Formula: see text] is possibly linked with the end-of-lifespan somatic mutation burden, another number recently found to be approximately constant (Cagan, Nature 604:517-524, 2022). We find that the dataset of mammals studied is consistent with a direct proportionality between the somatic mutation rate and the respiration frequency, being a tentative link between both invariant numbers.

DOI: https://doi.org/10.1038/s41598-024-82671-6
Nat Cardiovasc Res. 2025 Jan 02.

Mechanical regulation of macrophage metabolism by allograft inflammatory factor 1 leads to adverse remodeling after cardiac injury.

Matthew DeBerge, Kristofor Glinton, Connor Lantz, Zhi-Dong Ge, David P Sullivan, Swapna Patil, Bo Ryung Lee, Minori I Thorp, Adam Mullick, Steve Yeh, Shuling Han, Anja M van der Laan, Hans W M Niessen, Xunrong Luo, Nicholas E S Sibinga, Edward B Thorp.

Myocardial infarction (MI) mobilizes macrophages, the central protagonists of tissue repair in the infarcted heart. Although necessary for repair, macrophages also contribute to adverse remodeling and progression to heart failure. In this context, specific targeting of inflammatory macrophage activation may attenuate maladaptive responses and enhance cardiac repair. Allograft inflammatory factor 1 (AIF1) is a macrophage-specific protein expressed in a variety of inflammatory settings, but its function after MI is unknown. Here we identify a maladaptive role for macrophage AIF1 after MI in mice. Mechanistic studies show that AIF1 increases actin remodeling in macrophages to promote reactive oxygen species-dependent activation of hypoxia-inducible factor (HIF)-1α. This directs a switch to glycolytic metabolism to fuel macrophage-mediated inflammation, adverse ventricular remodeling and progression to heart failure. Targeted knockdown of Aif1 using antisense oligonucleotides improved cardiac repair, supporting further exploration of macrophage AIF1 as a therapeutic target after MI.

DOI: https://doi.org/10.1038/s44161-024-00585-y
Trends Genet. 2024 Dec 27. pii: S0168-9525(24)00260-9. [Epub ahead of print]

Cell-autonomous adaptation: an overlooked avenue of adaptation in human evolution.

Ruthie Golomb, Orna Dahan, Dvir Dahary, Yitzhak Pilpel.

  Adaptation to environmental conditions occurs over diverse evolutionary timescales. In multi-cellular organisms, adaptive traits are often studied in tissues/organs relevant to the environmental challenge. We argue for the importance of an underappreciated layer of evolutionary adaptation manifesting at the cellular level. Cell-autonomous adaptations (CAAs) are inherited traits that boost organismal fitness by enhancing individual cell function. For instance, the cell-autonomous enhancement of mitochondrial oxygen utilization in hypoxic environments differs from an optimized erythropoiesis response, which involves multiple tissues. We explore the breadth of CAAs across challenges and highlight their counterparts in unicellular organisms. Applying these insights, we mine selection signals in Andean highlanders, revealing novel candidate CAAs. The conservation of CAAs across species may reveal valuable insights into multi-cellular evolution.

Keywords:  adaptation; cell-autonomous; high altitudes; human evolution

DOI:  https://doi.org/10.1016/j.tig.2024.10.009
Trends Biotechnol. 2024 Dec 27. pii: S0167-7799(24)00345-7. [Epub ahead of print]

Engineering immunity using metabolically active polymeric nanoparticles.

Kate V Griffin, Michael N Saunders, Costas A Lyssiotis, Lonnie D Shea.

  Immune system functions play crucial roles in both health and disease, and these functions are regulated by their metabolic programming. The field of immune engineering has emerged to develop therapeutic strategies, including polymeric nanoparticles (NPs), that can direct immune cell phenotype and function by directing immunometabolic changes. Precise control of bioenergetic processes may offer the opportunity to prevent undesired immune activity and improve disease-specific outcomes. In this review we discuss the role that polymeric NPs can play in shaping immunometabolism and subsequent immune system activity through particle-mediated delivery of metabolically active agents as either structural components or cargo.

Keywords:  immunoengineering; immunometabolism; metabolic reprogramming; polymeric nanoparticle

DOI:  https://doi.org/10.1016/j.tibtech.2024.11.016
Cell Rep. 2024 Dec 30. pii: S2211-1247(24)01467-0. [Epub ahead of print]44(1): 115116

IMPDH2 dephosphorylation under FGFR signaling promotes S-phase progression and tumor growth.

Bei Zhou, Qin Zhao, Guofang Hou, Jing He, Nannan Sha, Ke Zheng, Hongyu Peng, Wang Wang, Yue Zhou, Tao Chen, Yuhui Jiang.

  Inosine monophosphate dehydrogenase 2 (IMPDH2) is highly expressed in human cancers; however, its physiological relevance under growth signaling remains to be investigated. Here, we show that IMPDH2 serine 122 is phosphorylated by CDK1, and this modification attenuates the catalytic activity of IMPDH2 for IMP oxidation and simultaneously represses its allosteric modulation by purine nucleotides. Fibroblast growth factor receptor (FGFR) signaling activation triggers IMPDH2-Ser122 dephosphorylation mediated by protein phosphatase 2A (PP2A), which is dependent on FGFR3-mediated PPP2R1A-Tyr261 phosphorylation leading to PPP2CA-PPP2R1A-IMPDH2 interactions. In turn, Ser122 dephosphorylation positively modulates IMPDH2 activity and contributes to guanine nucleotide synthesis and purine homeostasis, thereby facilitating S-phase completion and cell proliferation. Accordingly, IMPDH2 dephosphorylation is implicated in FGFR activation-enhanced tumorigenesis, and the low level of IMPDH2-Ser122 phosphorylation predicts the poor prognosis of patients with colorectal cancer. These findings illustrate a regulatory mechanism of purine nucleotide production under FGFR signaling, in which the oncogenic effect of reinforced IMPDH2 activity is underscored.

Keywords:  CDK1; CP: Cancer; FGFR; PP2A; S-phase progression; allosteric regulation; phosphorylation; purine homeostasis; tumor cell growth.; ◼◼◼IMPDH2

DOI:  https://doi.org/10.1016/j.celrep.2024.115116
Cancer Res. 2025 Jan 02. 85(1): 7-9

Persistence and/or Senescence: Not So Lasting at Last?

Clemens A Schmitt.

Therapy-exposed surviving cancer cells may have encountered profound epigenetic remodeling that renders these drug-tolerant persisters candidate drivers of particularly aggressive relapses. Typically presenting as slow-to-nongrowing cells, persisters are senescent or senescence-like cells. In this issue of Cancer Research, Ramponi and colleagues study mTOR/PI3K inhibitor-induced embryonic diapause-like arrest (DLA) as a model of persistence in lung cancer and melanoma cells and compare this persister condition with therapy-induced senescence in the same cells. The DLA phenotype recapitulated some but not all features attributed to senescent cells, lacking, for instance, an inflammatory secretome otherwise known as the senescence-associated secretory phenotype. A CRISPR dropout screen pointed to methyl group-providing one-carbon metabolism and further to H4K20me3-mediated repression of senescence-associated secretory phenotype-related IFN response genes selectively in DLA-like persister cells. Conversely, inhibition of H4K20-active KMT5B/C methyltransferases derepressed inflammatory programs and was toxic in DLA cells. These findings not only suggest exploitable vulnerabilities of DLA-like persister cells but also unveil general technical and conceptual challenges of cultured multipassage cell line-based persister studies. Collectively, the approach chosen and insights obtained will stimulate a productive scientific debate on senescence-like features and their reversibility across drug-tolerant persister cells. See related article by Ramponi et al., p. 32.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-3744