bims-mepmim 2024-12-22 papers

bims-mepmim

Biomed News

on Metabolites in pathological microenvironments and immunometabolism

Issue of 2024–12–22
twenty-one papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism

Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD.
Guardians of the cell: mitochondria as a rheostat for cellular NAD+ levels.
Regulation of lipid storage and inflammation in the liver by CEACAM1.
Selenoprotein O Promotes Melanoma Metastasis and Regulates Mitochondrial Complex II Activity.
Interplay between Netrin-1 and Norrin controls arteriovenous zonation of blood-retina barrier integrity.
SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts.
Microenvironmental G protein-coupled estrogen receptor-mediated glutamine metabolic coupling between cancer-associated fibroblasts and triple-negative breast cancer cells governs tumour progression.
Cytosolic S100A8/A9 promotes Ca2+ supply at LFA-1 adhesion clusters during neutrophil recruitment.
Type I IFN induces long-chain acyl-CoA synthetase 1 to generate a phosphatidic acid reservoir for lipotoxic saturated fatty acids.
Identification of antigen-presenting cell-T cell interactions driving immune responses to food.
Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography.
Muscle spindle macrophages regulate motor coordination.
Epigenetic suppression of creatine kinase B in adipocytes links endoplasmic reticulum stress to obesity-associated inflammation.
P-cadherin mechanoactivates tumor-mesothelium metabolic coupling to promote ovarian cancer metastasis.
Heme promotes venetoclax resistance in multiple myeloma through MEK-ERK signaling and purine biosynthesis.
ACSL4-mediated H3K9 and H3K27 hyperacetylation upregulates SNAIL to drive TNBC metastasis.
Distinct Tissue-Dependent Composition and Gene Expression of Human Fetal Innate Lymphoid Cells.
Phase Partitioning of the Neutrophil Oxidative Burst is Coordinated by Accessory Pathways of Glucose Metabolism and Mitochondrial Activity.
Mitochondrial unfolded protein response-dependent β-catenin signaling promotes neuroendocrine prostate cancer.
Imaging of tumor-associated macrophage dynamics during immunotherapy using a CD163-specific nanobody-based immunotracer.
Distinct release properties of glutamate/GABA co-transmission serve as a frequency-dependent filtering of supramammillary inputs.

Nat Metab. 2024 Dec;6(12): 2319-2337

Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD.

Lena E Høyland, Magali R VanLinden, Marc Niere, Øyvind Strømland, Suraj Sharma, Jörn Dietze, Ingvill Tolås, Eva Lucena, Ersilia Bifulco, Lars J Sverkeli, Camila Cimadamore-Werthein, Hanan Ashrafi, Kjellfrid F Haukanes, Barbara van der Hoeven, Christian Dölle, Cédric Davidsen, Ina K N Pettersen, Karl J Tronstad, Svein A Mjøs, Faisal Hayat, Mikhail V Makarov, Marie E Migaud, Ines Heiland, Mathias Ziegler.

The coenzyme NAD+ is consumed by signalling enzymes, including poly-ADP-ribosyltransferases (PARPs) and sirtuins. Ageing is associated with a decrease in cellular NAD+ levels, but how cells cope with persistently decreased NAD+ concentrations is unclear. Here, we show that subcellular NAD+ pools are interconnected, with mitochondria acting as a rheostat to maintain NAD+ levels upon excessive consumption. To evoke chronic, compartment-specific overconsumption of NAD+, we engineered cell lines stably expressing PARP activity in mitochondria, the cytosol, endoplasmic reticulum or peroxisomes, resulting in a decline of cellular NAD+ concentrations by up to 50%. Isotope-tracer flux measurements and mathematical modelling show that the lowered NAD+ concentration kinetically restricts NAD+ consumption to maintain a balance with the NAD+ biosynthesis rate, which remains unchanged. Chronic NAD+ deficiency is well tolerated unless mitochondria are directly targeted. Mitochondria maintain NAD+ by import through SLC25A51 and reversibly cleave NAD+ to nicotinamide mononucleotide and ATP when NMNAT3 is present. Thus, these organelles can maintain an additional, virtual NAD+ pool. Our results are consistent with a well-tolerated ageing-related NAD+ decline as long as the vulnerable mitochondrial pool is not directly affected.

DOI: https://doi.org/10.1038/s42255-024-01174-w
Nat Metab. 2024 Dec;6(12): 2215-2217

Guardians of the cell: mitochondria as a rheostat for cellular NAD+ levels.

Fiona M Fitzpatrick, Nora Kory.

DOI: https://doi.org/10.1038/s42255-024-01160-2
Eur J Clin Invest. 2024 Dec;54 Suppl 2 e14338

Regulation of lipid storage and inflammation in the liver by CEACAM1.

Sonia M Najjar, John E Shively.

  This review focuses on a special aspect of hepatic lipid storage and inflammation that occurs during nutritional excess in obesity. Mounting evidence supports that prolonged excess fatty acid (FA) uptake in the liver is strongly associated with hepatic lipid storage and inflammation and that the two processes are closely linked by a homeostatic mechanism. There is also strong evidence that bacterial lipids may enter the gut by a common mechanism with lipid absorption and that there is a set point to determine when their uptake triggers an inflammatory response in the liver. In fact, the progression from high uptake of FAs in the liver resulting in Metabolic dysfunction-associated steatotic liver disease (MASLD) to the development of the more serious Metabolic dysfunction-associated steatohepatitis (MASH) depends on the degree of inflammation and its progression from an acute to a chronic state. Thus, MASLD/MASH implicates both excess fatty acids and progressive inflammation in the aetiology of liver disease. We start the discussion by introduction of CD36, a major player in FA and lipopolysaccharide (LPS) uptake in the duodenum, liver and adipose tissue. We will then introduce CEACAM1, a major player in the regulation of hepatic de novo lipogenesis and the inflammatory response in the liver, and its dual association with CD36 in enterocytes and hepatocytes. We conclude that CEACAM1 and CD36 together regulate lipid droplet formation and inflammation in the liver.

Keywords:  CD36; CEACAM1; LPS; fatty liver disease; inflammation

DOI:  https://doi.org/10.1111/eci.14338
Cancer Res. 2024 Dec 19.

Selenoprotein O Promotes Melanoma Metastasis and Regulates Mitochondrial Complex II Activity.

Luiza Martins Nascentes Melo, Marie Sabatier, Vijayashree Ramesh, Krystina J Szylo, Cameron S Fraser, Alexandra Pon, Evann C Mitchell, Kelly A Servage, Gabriele Allies, Isa V Westedt, Feyza Cansiz, Jonathan Krystkiewicz, Andrea Kutritz, Dirk Schadendorf, Sean J Morrison, Jessalyn M Ubellacker, Anju Sreelatha, Alpaslan Tasdogan.

Evolutionarily conserved selenoprotein O (SELENOO) catalyzes a post-translational protein modification known as AMPylation that is essential for the oxidative stress response in bacteria and yeast. Given that oxidative stress experienced in the blood limits survival of metastasizing melanoma cells, SELENOO might be able to impact metastatic potential. However, further work is needed to elucidate the substrates and functional relevance of the mammalian homologue of SELENOO. Here, we revealed that SELENOO promotes cancer metastasis and identified substrates of SELENOO in mammalian mitochondria. In patients with melanoma, high SELENOO expression was correlated with metastasis and poor overall survival. In a murine model of spontaneous melanoma metastasis, SELENOO deficiency significantly reduced metastasis to distant visceral organs, which could be rescued by treatment with the antioxidant N-acetylcysteine. Mechanistically, SELENOO AMPylated multiple mitochondrial substrates, including succinate dehydrogenase subunit A, one of the four key subunits of mitochondrial complex II. Consistently, SELENOO-deficient cells featured increased mitochondrial complex II activity. Together, these findings demonstrate that SELENOO deficiency limits melanoma metastasis by modulating mitochondrial function and oxidative stress.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2194
Proc Natl Acad Sci U S A. 2024 Dec 24. 121(52): e2408674121

Interplay between Netrin-1 and Norrin controls arteriovenous zonation of blood-retina barrier integrity.

Jessica Furtado, Luiz Henrique Geraldo, Felipe Saceanu Leser, Bartlomiej Bartkowiak, Mathilde Poulet, Hyojin Park, Mark Robinson, Laurence Pibouin-Fragner, Anne Eichmann, Kevin Boyé.

  The integrity of the blood-retina barrier (BRB) is crucial for phototransduction and vision, by tightly restricting transport of molecules between the blood and surrounding neuronal cells. Breakdown of the BRB leads to the development of retinal diseases. Here, we show that Netrin-1/Unc5b and Norrin/Lrp5 signaling establish a zonated endothelial cell gene expression program that controls BRB integrity. Using single-cell RNA sequencing (scRNA-seq) of postnatal BRB-competent mouse retina endothelial cells (ECs), we identify >100 BRB genes encoding Wnt signaling components, tight junction proteins, and ion and nutrient transporters. We find that BRB gene expression is zonated across arteries, capillaries, and veins and regulated by opposing gradients of the Netrin-1 receptor Unc5b and Lrp5-β-catenin signaling between retinal arterioles and venules. Mice deficient for Ntn1 or Unc5b display more BRB leakage at the arterial end of the vasculature, while Lrp5 loss of function causes predominantly venular BRB leakage. ScRNA-seq of Ntn1 and Unc5b mutant ECs reveals down-regulated β-catenin signaling and BRB gene expression that is rescued by Ctnnb1 overactivation, along with BRB integrity. Mechanistically, we demonstrate that Netrin-1 and Norrin additively enhance β-catenin transcriptional activity and Lrp5 phosphorylation via the Discs large homologue 1 (Dlg1) scaffolding protein, and endothelial Lrp5-Unc5b function converges in protection of capillary BRB integrity. These findings explain how arteriovenous zonation is established and maintained in the BRB and reveal that BRB gene expression is regulated at the level of endothelial subtypes.

Keywords:  Netrin-1-Unc5b; WNT-b-catenin; blood brain barrier; blood retina barrier; single cell sequencing

DOI:  https://doi.org/10.1073/pnas.2408674121
J Clin Invest. 2024 Dec 16. pii: e176708. [Epub ahead of print]134(24):

SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts.

Leigh Goedeke, Yina Ma, Rafael C Gaspar, Ali Nasiri, Jieun Lee, Dongyan Zhang, Katrine Douglas Galsgaard, Xiaoyue Hu, Jiasheng Zhang, Nicole Guerrera, Xiruo Li, Traci LaMoia, Brandon T Hubbard, Sofie Haedersdal, Xiaohong Wu, John Stack, Sylvie Dufour, Gina Marie Butrico, Mario Kahn, Rachel J Perry, Gary W Cline, Lawrence H Young, Gerald I Shulman.

  Previous studies highlight the potential for sodium-glucose cotransporter type 2 (SGLT2) inhibitors (SGLT2i) to exert cardioprotective effects in heart failure by increasing plasma ketones and shifting myocardial fuel utilization toward ketone oxidation. However, SGLT2i have multiple in vivo effects and the differential impact of SGLT2i treatment and ketone supplementation on cardiac metabolism remains unclear. Here, using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology combined with infusions of [13C6]glucose or [13C4]βOHB, we demonstrate that acute SGLT2 inhibition with dapagliflozin shifts relative rates of myocardial mitochondrial metabolism toward ketone oxidation, decreasing pyruvate oxidation with little effect on fatty acid oxidation in awake rats. Shifts in myocardial ketone oxidation persisted when plasma glucose levels were maintained. In contrast, acute βOHB infusion similarly augmented ketone oxidation, but markedly reduced fatty acid oxidation and did not alter glucose uptake or pyruvate oxidation. After inducing heart failure, dapagliflozin increased relative rates of ketone and fatty acid oxidation, but decreased pyruvate oxidation. Dapagliflozin increased mitochondrial redox and reduced myocardial oxidative stress in heart failure, which was associated with improvements in left ventricular ejection fraction after 3 weeks of treatment. Thus, SGLT2i have pleiotropic effects on systemic and heart metabolism, which are distinct from ketone supplementation and may contribute to the long-term cardioprotective benefits of SGLT2i.

Keywords:  Cardiology; Glucose metabolism; Intermediary metabolism; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/JCI176708
Clin Transl Med. 2024 Dec;14(12): e70131

Microenvironmental G protein-coupled estrogen receptor-mediated glutamine metabolic coupling between cancer-associated fibroblasts and triple-negative breast cancer cells governs tumour progression.

Chongwu He, Meixi Peng, Xiaoqiang Zeng, Hanzhi Dong, Zhengkui Sun, Jiawei Xu, Manran Liu, Liyan Liu, Yanxiao Huang, Zhiqiang Peng, Yu-An Qiu, Chunling Jiang, Bin Xu, Tenghua Yu.

   BACKGROUND: Triple-negative breast cancer (TNBC) is a particularly aggressive type of breast cancer, known for its lack of effective treatments and unfavorable prognosis. The G protein-coupled estrogen receptor (GPER), a novel estrogen receptor, is linked to increased malignancy in various cancers. However, its involvement in the metabolic regulation of cancer-associated fibroblasts (CAFs), a key component in the tumour microenvironment, remains largely unexplored. This study investigates how GPER influences the metabolic interaction between CAFs and TNBC cells, aiming to identify potential therapeutic targets.
METHODS: The co-culture system is performed to examine the interaction between CAFs and TNBC cells, with a focus on GPER-mediated glutamine production and release by CAFs and its subsequent uptake and utilization by TNBC cells. The definite roles of microenvironmental GPER/cAMP/PKA/CREB signalling in regulating the expression of glutamine synthetase (GLUL) and lactate dehydrogenase B (LDHB) are further investigated.
RESULTS: Our findings reveal that estrogen-activated GPER in CAFs significantly upregulates the expression of GLUL and LDHB, leading to increased glutamine production. This glutamine is then secreted into the extracellular matrix and absorbed by TNBC cells, enhancing their viability, motility, and chemoresistance both in vitro and in vivo. TNBC cells further metabolize the glutamine through the glutamine transporter (ASCT2) and glutaminase (GLS1) axes, which, in turn, promote mitochondrial activity and tumour progression.
CONCLUSIONS: The study identifies GPER as a critical mediator of metabolic coupling between CAFs and TNBC cells, primarily through glutamine metabolism. Targeting the estrogen/GPER/glutamine signalling axis in CAFs offers a promising therapeutic strategy to inhibit TNBC progression and improve patient outcomes. This novel insight into the tumour microenvironment highlights the potential of metabolic interventions in treating TNBC.
KEY POINTS: Estrogen-activated GPER in CAFs enhances GLUL and LDHB expression via the cAMP/PKA/CREB signalling, facilitating glutamine production and utilization. Microenvironmental GPER-induced glutamine serves as a crucial mediator of metabolic coupling between CAFs and TNBC cells, boosting tumour progression by enhancing mitochondrial function. Targeting the glutamine metabolic coupling triggered by estrogen/GPER/GLUL signalling in CAFs is a promising therapeutic strategy for TNBC treatment.

Keywords:  CAFs; GPER; TNBC; glutamine metabolism; tumour progression

DOI:  https://doi.org/10.1002/ctm2.70131
Elife. 2024 Dec 19. pii: RP96810. [Epub ahead of print]13

Cytosolic S100A8/A9 promotes Ca2+ supply at LFA-1 adhesion clusters during neutrophil recruitment.

Matteo Napoli, Roland Immler, Ina Rohwedder, Valerio Lupperger, Johannes Pfabe, Mariano Gonzalez Pisfil, Anna Yevtushenko, Thomas Vogl, Johannes Roth, Melanie Salvermoser, Steffen Dietzel, Marjan Slak Rupnik, Carsten Marr, Barbara Walzog, Markus Sperandio, Monika Pruenster.

  S100A8/A9 is an endogenous alarmin secreted by myeloid cells during many acute and chronic inflammatory disorders. Despite increasing evidence of the proinflammatory effects of extracellular S100A8/A9, little is known about its intracellular function. Here, we show that cytosolic S100A8/A9 is indispensable for neutrophil post-arrest modifications during outside-in signaling under flow conditions in vitro and neutrophil recruitment in vivo, independent of its extracellular functions. Mechanistically, genetic deletion of S100A9 in mice caused dysregulated Ca2+ signatures in activated neutrophils resulting in reduced Ca2+ availability at the formed LFA-1/F-actin clusters with defective β2 integrin outside-in signaling during post-arrest modifications. Consequently, we observed impaired cytoskeletal rearrangement, cell polarization, and spreading, as well as cell protrusion formation in S100a9-/- compared to wildtype (WT) neutrophils, making S100a9-/- cells more susceptible to detach under flow, thereby preventing efficient neutrophil recruitment and extravasation into inflamed tissue.

Keywords:  LFA-1 integrin clustering; acute inflammation; calcium signaling; immunology; inflammation; intracellular S100A8/A9; intracellular signaling; mouse; neutrophil recruitment

DOI:  https://doi.org/10.7554/eLife.96810
J Lipid Res. 2024 Dec 13. pii: S0022-2275(24)00235-9. [Epub ahead of print] 100730

Type I IFN induces long-chain acyl-CoA synthetase 1 to generate a phosphatidic acid reservoir for lipotoxic saturated fatty acids.

Shelley Barnhart, Masami Shimizu-Albergine, Eyal Kedar, Vishal Kothari, Baohai Shao, Melissa Krueger, Cheng-Chieh Hsu, Jingjing Tang, Jenny E Kanter, Farah Kramer, Danijel Djukovic, Vadim Pascua, Yueh-Ming Loo, Lucrezia Colonna, Sadie J Van den Bogaerde, Jie An, Michael Gale, Karen Reue, Edward A Fisher, Sina A Gharib, Keith B Elkon, Karin E Bornfeldt.

  Long-chain acyl-CoA synthetase 1 (ACSL1) catalyzes the conversion of long-chain fatty acids to acyl-CoAs. ACSL1 is required for β-oxidation in tissues that rely on fatty acids as fuel, but no consensus exists on why ACSL1 is induced by inflammatory mediators in immune cells. We used a comprehensive and unbiased approach to investigate the role of ACSL1 induction by interferon type I (IFN-I) in myeloid cells in vitro and in a mouse model of IFN-I overproduction. Our results show that IFN-I induces ACSL1 in macrophages via its interferon-α/β receptor, and consequently that expression of ACSL1 is increased in myeloid cells from individuals with systemic lupus erythematosus (SLE), an autoimmune condition characterized by increased IFN production. Taking advantage of a myeloid cell-targeted ACSL1-deficient mouse model and a series of lipidomics, proteomics, metabolomics and functional analyses, we show that IFN-I leverages induction of ACSL1 to increase accumulation of fully saturated phosphatidic acid species in macrophages. Conversely, ACSL1 induction is not needed for IFN-I's ability to induce the prototypical IFN-stimulated protein signature or to suppress proliferation or macrophage metabolism. Loss of ACSL1 in IFN-I stimulated myeloid cells enhances apoptosis and secondary necrosis in vitro, especially in the presence of increased saturated fatty acid load, and in a mouse model of atherosclerosis associated with IFN overproduction, resulting in larger lesion necrotic cores. We propose that ACSL1 induction is a mechanism used by IFN-I to increase phosphatidic acid saturation while protecting the cells from saturated fatty acid-induced cell death.

Keywords:  Bis[monoacylglycerol]phosphates; Enzymology/Enzyme mechanisms; Glycerophospholipids; Inflammation; Lipotoxicity; Macrophage; Phospholipids/Phosphatidic acid

DOI:  https://doi.org/10.1016/j.jlr.2024.100730
Science. 2024 Dec 19. eado5088

Identification of antigen-presenting cell-T cell interactions driving immune responses to food.

Maria C C Canesso, Tiago B R Castro, Sandra Nakandakari-Higa, Ainsley Lockhart, Julia Luehr, Juliana Bortolatto, Roham Parsa, Daria Esterházy, Mengze Lyu, Tian-Tian Liu, Kenneth M Murphy, Gregory F Sonnenberg, Bernardo S Reis, Gabriel D Victora, Daniel Mucida.

The intestinal immune system must concomitantly tolerate food and commensals and protect against pathogens. Antigen-presenting cells (APCs) orchestrate these immune responses by presenting luminal antigens to CD4+ T cells and inducing their differentiation into regulatory (pTreg) or inflammatory (Th) subsets. We used a proximity labeling method (LIPSTIC) to identify APCs that presented dietary antigens under tolerizing and inflammatory conditions and understand cellular mechanisms by which tolerance to food is induced and can be disrupted by infection. Helminth infections disrupted tolerance induction proportionally to the reduction in the ratio between tolerogenic APCs, including migratory dendritic cells (cDC1s) and Rorγt+ APCs, and inflammatory APCs, that were primarily cDC2s. These inflammatory cDC2s expanded by helminth infection did not present dietary antigens, thus avoiding diet-specific Th2 responses.

DOI: https://doi.org/10.1126/science.ado5088
Nat Commun. 2024 Dec 17. 15(1): 10484

Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography.

Hannah E Greenwood, Abigail R Barber, Richard S Edwards, Will E Tyrrell, Madeleine E George, Sofia N Dos Santos, Friedrich Baark, Muhammet Tanc, Eman Khalil, Aimee Falzone, Nathan P Ward, Janine M DeBlasi, Laura Torrente, Pritin N Soni, David R Pearce, George Firth, Lydia M Smith, Oskar Vilhelmsson Timmermand, Ariana Huebner, Charles Swanton, Robert E Hynds, Gina M DeNicola, Timothy H Witney.

Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. Currently, there is no means to non-invasively identify NRF2 activation in living subjects. Here, we show that positron emission tomography imaging with the system xc- radiotracer, [18F]FSPG, provides a sensitive and specific marker of NRF2 activation in orthotopic, patient-derived, and genetically engineered mouse models of NSCLC. We found a NRF2-related gene expression signature in a large cohort of NSCLC patients, suggesting an opportunity to preselect patients prior to [18F]FSPG imaging. Furthermore, we reveal that system xc- is a metabolic vulnerability that can be therapeutically targeted with an antibody-drug conjugate for sustained tumour growth suppression. Overall, our results establish [18F]FSPG as a predictive marker of therapy resistance in NSCLC and provide the basis for the clinical evaluation of both imaging and therapeutic agents that target this important antioxidant pathway.

DOI: https://doi.org/10.1038/s41467-024-54852-4
Nat Rev Immunol. 2024 Dec 16.

Muscle spindle macrophages regulate motor coordination.

Kirsty Minton.

DOI: https://doi.org/10.1038/s41577-024-01125-2
Mol Metab. 2024 Dec 13. pii: S2212-8778(24)00213-8. [Epub ahead of print] 102082

Epigenetic suppression of creatine kinase B in adipocytes links endoplasmic reticulum stress to obesity-associated inflammation.

Gianluca Renzi, Ivan Vlassakev, Mattias Hansen, Romane Higos, Simon Lecoutre, Merve Elmastas, Ondrej Hodek, Thomas Moritz, Lynn M Alaeddine, Scott Frendo-Cumbo, Ingrid Dahlman, Alastair Kerr, Salwan Maqdasy, Niklas Mejhert, Mikael Rydén.

  In white adipose tissue, disturbed creatine metabolism through reduced creatine kinase B (CKB) transcription contributes to obesity-related inflammation. However, the mechanisms regulating CKB expression in human white adipocytes remain unclear. By screening conditions perturbed in obesity, we identified endoplasmic reticulum (ER) stress as a key suppressor of CKB transcription across multiple cell types. Through follow-up studies, we found that ER stress through the IRE1-XBP1s pathway, promotes CKB promoter methylation via the methyltransferase DNMT3A. This epigenetic change represses CKB transcription, shifting metabolism towards glycolysis and increasing the production of the pro-inflammatory chemokine CCL2. We validated our findings in vivo, demonstrating that individuals living with obesity show an inverse relationship between CKB expression and promoter methylation in white adipocytes, along with elevated CCL2 secretion. Overall, our study uncovers a regulatory axis where ER stress drives inflammation in obesity by reducing CKB abundance, and consequently altering the bioenergetic state of the cell.

Keywords:  Chromatin remodeling; Creatine pathway; Glycolysis; Immunometabolism; Tunicamycin

DOI:  https://doi.org/10.1016/j.molmet.2024.102082
Cell Rep. 2024 Dec 18. pii: S2211-1247(24)01447-5. [Epub ahead of print]44(1): 115096

P-cadherin mechanoactivates tumor-mesothelium metabolic coupling to promote ovarian cancer metastasis.

Jing Ma, Sally Kit Yan To, Katie Sze Wai Fung, Kun Wang, Jiangwen Zhang, Alfonso Hing Wan Ngan, Susan Yung, Tak Mao Chan, Carmen Chak Lui Wong, Philip Pun Ching Ip, Ling Peng, Hong-Yan Guo, Chi Bun Chan, Alice Sze Tsai Wong.

  Cancer adhesion to the mesothelium is critical for peritoneal metastasis, but how metastatic cells adapt to the biomechanical microenvironment remains unclear. Our study demonstrates that highly metastatic (HM), but not non-metastatic, ovarian cancer cells selectively activate the peritoneal mesothelium. HM cells exert a stronger adhesive force on mesothelial cells via P-cadherin, an adhesion molecule abundant in late-stage tumors. Mechanical activation of P-cadherin enhances lipogenic gene expression and lipid content in HM cells through SREBP1. P-cadherin also induces glycolysis in the interacting mesothelium without affecting lipogenic activity, with the resulting lactate serving as a substrate for lipogenesis in HM cells. Nanodelivery of small interfering RNA (siRNA) targeting P-cadherin or MCT1/4 transporters significantly suppresses metastasis in mice. Moreover, increased fatty acid synthase levels in metastatic patient samples correlate with high P-cadherin expression, supporting enhanced de novo lipogenesis in the metastatic niche. This study reveals P-cadherin-mediated mechano-metabolic coupling as a promising target to restrain metastasis.

Keywords:  CP: Cancer; CP: Metabolism; P-cadherin; adhesion; glycolysis; lipogenesis; mechanotransduction; metabolic reprogramming; ovarian cancer; peritoneal metastasis; tumor mesothelium

DOI:  https://doi.org/10.1016/j.celrep.2024.115096
Blood. 2024 Dec 18. pii: blood.2024025690. [Epub ahead of print]

Heme promotes venetoclax resistance in multiple myeloma through MEK-ERK signaling and purine biosynthesis.

Remya Nair, An Vu, Abigail K Freer, Karanpreet S Bhatia, Dongxue Wang, Milan R Savani, Shannon M Matulis, Sagar Lonial, David L Jaye, Lawrence H Boise, Seung-Yong Seo, Timothy William Corson, Ajay K Nooka, Shruti Bhatt, Samuel K McBrayer, Vikas A Gupta, Xin Hu, Benjamin G Barwick, Amit R Reddi, Mala Shanmugam.

We previously demonstrated that reduced intrinsic electron transport chain (ETC) activity predicts and promotes sensitivity to the BCL-2 antagonist, venetoclax (Ven) in multiple myeloma (MM). Heme, an iron-containing prosthetic group, and metabolite is fundamental to maintaining ETC activity. Interrogation of the CD2 subgroup of MM from the CoMMpass trial (NCT01454297), which can be used as a proxy for Ven-sensitive MM (VS MM), shows reduced expression of the conserved heme biosynthesis pathway gene signature. Consistent with this, we identified that VS MM exhibit reduced heme biosynthesis and curiously elevated hemin (oxidized heme) uptake. Supplementation with hemin or protoporphyrin IX (heme lacking iron) promotes Ven resistance while targeting ferrochetalase, the penultimate enzyme involved in heme biosynthesis, increases Ven sensitivity in cell lines and primary MM cells. Mechanistically, heme-mediated activation of pro-survival RAS-RAF-MEK signaling and metabolic rewiring, increasing de novo purine synthesis, were found to contribute to heme-induced Ven resistance. Co-targeting BCL-2 and MCL-1 suppresses heme-induced Ven resistance. Interrogation of the MMRF CoMMpass study of patients shows increased purine and pyrimidine biosynthesis to corelate with poor progression free survival and overall survival. Elevated heme and purine biosynthesis gene signatures were also observed in matched relapse refractory MM, underscoring the relevance of heme metabolism in therapy refractory MM. Overall, our findings reveal for the first time a role for extrinsic heme, a physiologically relevant metabolite, in modulating proximity to the apoptotic threshold with translational implications for BCL-2 antagonism in MM therapy.

DOI: https://doi.org/10.1182/blood.2024025690
Proc Natl Acad Sci U S A. 2024 Dec 24. 121(52): e2408049121

ACSL4-mediated H3K9 and H3K27 hyperacetylation upregulates SNAIL to drive TNBC metastasis.

Abhipsa Sinha, Krishan Kumar Saini, Aakash Chandramouli, Kiran Tripathi, Muqtada Ali Khan, Saumya Ranjan Satrusal, Ayushi Verma, Biswajit Mandal, Priyanka Rai, Sanjeev Meena, Mushtaq Ahmad Nengroo, Manish Pratap Singh, Namratha Shashi Bhushan, Madavan Vasudevan, Atin Singhai, Kulranjan Singh, Anand Kumar Mishra, Siddhesh S Kamat, Dipak Datta.

  Triple-negative breast cancer (TNBC) has profound unmet medical need globally for its devastating clinical outcome associated with rapid metastasis and lack of targeted therapies. Recently, lipid metabolic reprogramming especially fatty acid oxidation (FAO) has emerged as a major driver of breast cancer metastasis. Analyzing the expression of major FAO regulatory genes in breast cancer, we found selective overexpression of acyl-CoA synthetase 4 (ACSL4) in TNBC, which is primarily attributed to the absence of progesterone receptor. Loss of ACSL4 function, by genetic ablation or pharmacological inhibition significantly reduces metastatic potential of TNBC. Global transcriptome analysis reveals that ACSL4 activity positively influences the gene expression related to TNBC migration and invasion. Mechanistically, ACSL4 modulates FAO and intracellular acetyl-CoA levels, leading to hyperacetylation of particularly H3K9ac and H3K27ac marks resulting in overexpression of SNAIL during the course of TNBC metastatic spread to lymph node and lung. Further, human TNBC metastasis exhibits positive correlation among ACSL4, H3K9ac, H3K27ac, and SNAIL expression. Altogether, our findings provide molecular insights regarding the intricate interplay between metabolic alterations and epigenetic modifications, intertwined to orchestrate TNBC metastasis, and posit a rational understanding for the development of ACSL4 inhibitors as a targeted therapy against TNBC.

Keywords:  ACSL4; SNAIL; TNBC; histone acetylation; metastasis

DOI:  https://doi.org/10.1073/pnas.2408049121
Eur J Immunol. 2024 Dec 15. e202451150

Distinct Tissue-Dependent Composition and Gene Expression of Human Fetal Innate Lymphoid Cells.

Inga E Rødahl, Martin A Ivarsson, Liyen Loh, Jeff E Mold, Magnus Westgren, Danielle Friberg, Jenny Mjösberg, Niklas K Björkström, Nicole Marquardt, Douglas F Nixon, Jakob Michaëlsson.

The human fetal immune system starts to develop in the first trimester and likely plays a crucial role in fetal development and maternal-fetal tolerance. Innate lymphoid cells (ILCs) are the earliest lymphoid cells to arise in the human fetus. ILCs consist of natural killer (NK) cells, ILC1s, ILC2s, and ILC3s that all share a common lymphoid origin. Here, we studied fetal ILC subsets, mainly NK cells and ILC3s and their potential progenitors, across human fetal tissues. Our results show that fetal ILC subsets have distinct distribution, developmental kinetics, and gene expression profiles across human fetal tissues. Furthermore, we identify CD34+RORγt+Eomes- and CD34+RORγt+Eomes+ cells in the fetal intestine, indicating that tissue-specific ILC progenitors exist already during fetal development.

DOI: https://doi.org/10.1002/eji.202451150
J Biol Chem. 2024 Dec 13. pii: S0021-9258(24)02593-6. [Epub ahead of print] 108091

Phase Partitioning of the Neutrophil Oxidative Burst is Coordinated by Accessory Pathways of Glucose Metabolism and Mitochondrial Activity.

Tyler Jobe, Jonah Stephan, Collin K Wells, Maleesha De Silva, Pawel K Lorkiewicz, Bradford G Hill, Marcin Wysoczynski.

  Neutrophils are a part of the innate immune system and produce reactive oxygen species (ROS) to extinguish pathogens. The major source of ROS in neutrophils is NADPH oxidase, which is fueled by NADPH generated via the pentose phosphate pathway; however, it is unclear how other accessory glucose metabolism pathways and mitochondrial activity influence the respiratory burst. We examined the temporal dynamics of the respiratory burst and delineated how metabolism changes over time after neutrophil activation. Bone marrow-derived neutrophils were stimulated with phorbol 12-myristate 13-acetate (PMA), and the respiratory burst was measured via extracellular flux analysis. Metabolomics experiments utilizing 13C6-glucose highlighted the activation of glycolysis as well as ancillary pathways of glucose metabolism in activated neutrophils. PMA stimulation acutely increased 13C enrichment into glycerol 3-phosphate (G3P) and citrate, whereas increases in 13C enrichment in the glycogen intermediate, UDP-hexose, and end products of the hexosamine and serine biosynthetic pathways occurred only during the late phase of the oxidative burst. Targeted inhibition of the G3P shuttle, glycogenolysis, serine biosynthesis, and mitochondrial respiration demonstrated that the G3P shuttle contributes to the general magnitude of ROS production; that glycogen contributes solely to the early respiratory burst; and that the serine biosynthetic pathway activity and Complex III-driven mitochondrial activity influence respiratory burst duration. Collectively, these results show that the neutrophil oxidative burst is highly dynamic, with coordinated changes in metabolism that control the initiation, magnitude, and duration of ROS production.

Keywords:  glycolysis; innate immunity; mitochondria; pathogen; reactive oxygen species

DOI:  https://doi.org/10.1016/j.jbc.2024.108091
Oncogene. 2024 Dec 17.

Mitochondrial unfolded protein response-dependent β-catenin signaling promotes neuroendocrine prostate cancer.

Jordan Alyse Woytash, Rahul Kumar, Ajay K Chaudhary, Cullan Donnelly, Adam Wojtulski, Murali Bethu, Jianmin Wang, Joseph Spernyak, Peter Bross, Neelu Yadav, Joseph R Inigo, Dhyan Chandra.

The mitochondrial unfolded protein response (UPRmt) maintains mitochondrial quality control and proteostasis under stress conditions. However, the role of UPRmt in aggressive and resistant prostate cancer is not clearly defined. We show that castration-resistant neuroendocrine prostate cancer (CRPC-NE) harbored highly dysfunctional oxidative phosphorylation (OXPHOS) Complexes. However, biochemical and protein analyses of CRPC-NE tumors showed upregulation of nuclear-encoded OXPHOS proteins and UPRmt in this lethal subset of prostate cancer suggestive of compensatory upregulation of stress signaling. Genetic deletion and pharmacological inhibition of the main chaperone of UPRmt heat shock protein 60 (HSP60) reduced neuroendocrine prostate cancer (NEPC) growth in vivo as well as reverted NEPC cells to a more epithelial-like state. HSP60-dependent aggressive NEPC phenotypes was associated with upregulation of β-catenin signaling both in cancer cells and in vivo tumors. HSP60 expression rendered enrichment of aggressive prostate cancer signatures and metastatic potential were inhibited upon suppression of UPRmt. We discovered that UPRmt promoted OXPHOS functions including mitochondrial bioenergetics in CRPC-NE via regulation of β-catenin signaling. Mitochondrial biogenesis facilitated cisplatin resistance and inhibition of UPRmt resensitizes CRPC-NE cells to cisplatin. Together, our findings demonstrated that UPRmt promotes mitochondrial health via upregulating β-catenin signaling and UPRmt represents viable therapeutic target for NEPC.

DOI: https://doi.org/10.1038/s41388-024-03261-4
Proc Natl Acad Sci U S A. 2024 Dec 24. 121(52): e2409668121

Imaging of tumor-associated macrophage dynamics during immunotherapy using a CD163-specific nanobody-based immunotracer.

Yoline Lauwers, Timo W M De Groof, Cécile Vincke, Jolien Van Craenenbroeck, Neema Ahishakiye Jumapili, Romina Mora Barthelmess, Guillaume Courtoy, Wim Waelput, Tessa De Pauw, Geert Raes, Nick Devoogdt, Jo A Van Ginderachter.

  Immunotherapies have emerged as an effective treatment option for immune-related diseases, such as cancer and inflammatory diseases. However, variations in patient responsiveness limit the broad applicability and success of these immunotherapies. Noninvasive whole-body imaging of the immune status of individual patients during immunotherapy could enable the prediction and monitoring of the patient's response, resulting in more personalized treatments. In this study, we developed a nanobody-based immunotracer targeting CD163, a receptor specifically expressed on macrophages. This anti-CD163 immunotracer bound to human and mouse CD163 with high affinity and specificity without competing for ligand binding. Furthermore, the tracer showed no unwanted immune cell activation and was nonimmunogenic. Upon radiolabeling of the anti-CD163 immunotracer, specific imaging of CD163+ macrophages using micro-single-photon emission computerized tomography/computed tomography or micro-positron emission tomography/CT was performed. The anti-CD163 immunotracer was able to stratify immunotherapy responders from nonresponders (NR) by visualizing differences in the intratumoral CD163+ TAM distribution in Lewis lung carcinoma-ovalbumin tumor-bearing mice receiving an anti-programmed cell death protein-1 (PD-1)/CSF1R combination treatment. Immunotherapy-responding mice showed a more homogeneous distribution of the PET signal in the middle of the tumor, while CD163+ TAMs were located at the tumor periphery in NR. As such, visualization of CD163+ TAM distribution in the tumor microenvironment could allow a prediction or follow-up of therapy response. Altogether, this study describes an immunotracer, specific for CD163+ macrophages, that allows same-day imaging and follow-up of these immune cells in the tumor microenvironment, providing a good basis for the prediction and follow-up of immunotherapy responses in cancer patients.

Keywords:  CD163; immuno-imaging; nanobody; tumor-associated macrophage

DOI:  https://doi.org/10.1073/pnas.2409668121
Elife. 2024 Dec 16. pii: RP99711. [Epub ahead of print]13

Distinct release properties of glutamate/GABA co-transmission serve as a frequency-dependent filtering of supramammillary inputs.

Himawari Hirai, Kohtarou Konno, Miwako Yamasaki, Masahiko Watanabe, Takeshi Sakaba, Yuki Hashimotodani.

  Glutamate and GABA co-transmitting neurons exist in several brain regions; however, the mechanism by which these two neurotransmitters are co-released from the same synaptic terminals remains unclear. Here, we show that the supramammillary nucleus (SuM) to dentate granule cell synapses, which co-release glutamate and GABA, exhibit differences between glutamate and GABA release properties in paired-pulse ratio, Ca2+-sensitivity, presynaptic receptor modulation, and Ca2+ channel-vesicle coupling configuration. Moreover, uniquantal synaptic responses show independent glutamatergic and GABAergic responses. Morphological analysis reveals that most SuM terminals form distinct glutamatergic and GABAergic synapses in proximity, each characterized by GluN1 and GABAAα1 labeling, respectively. Notably, glutamate/GABA co-transmission exhibits distinct short-term plasticities, with frequency-dependent depression of glutamate and frequency-independent stable depression of GABA. Our findings suggest that glutamate and GABA are co-released from different synaptic vesicles within the SuM terminals, and reveal that distinct transmission modes of glutamate/GABA co-release serve as frequency-dependent filters of SuM inputs.

Keywords:  co-release; dentate gyrus; hippocampus; mouse; neuroscience; short-term plasticity; supramammillary nucleus; synaptic transmission

DOI:  https://doi.org/10.7554/eLife.99711