bims-mepmim 2024-04-28 papers

bims-mepmim

Biomed News

on Metabolites in pathological microenvironments and immunometabolism

Issue of 2024‒04‒28
27 papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism

Presenting metabolomics analyses: what is in a number?
Fatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring.
Regulation of mitochondrial fission by fatty acyl-coenzyme A.
A 30-color spectral flow cytometry panel for comprehensive analysis of immune cell composition and macrophage subsets in mouse metabolic organs.
SLC7A11-ROS/αKG-AMPK axis regulates liver inflammation through mitophagy and impairs liver fibrosis and NASH progression.
Sphingolipid biosynthesis is essential for metabolic rewiring during TH17 cell differentiation.
BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.
Batf3+ DCs and the 4-1BB/4-1BBL axis are required at the effector phase in the tumor microenvironment for PD-1/PD-L1 blockade efficacy.
LPCAT1-mediated membrane phospholipid remodelling promotes ferroptosis evasion and tumour growth.
A tryptophan-derived uremic metabolite-Ahr-Pdk4 axis governs skeletal muscle mitochondrial energetics in chronic kidney disease.
PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function.
Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver.
Dietary docosahexaenoic acid (DHA) downregulates liver DHA synthesis by inhibiting eicosapentaenoic acid elongation.
Integrative spatial analysis reveals a multi-layered organization of glioblastoma.
IL-23 regulation of myeloid cell biology during inflammation.
Trem2 promotes foamy macrophage lipid uptake and survival in atherosclerosis.
Tumor cell-intrinsic epigenetic SETpoint of cancer-associated fibroblasts.
High clonal diversity and spatial genetic admixture in early prostate cancer and surrounding normal tissue.
Single-chain fluorescent integrators for mapping G-protein-coupled receptor agonists.
Single-cell analysis reveals context-dependent, cell-level selection of mtDNA.
Cancer cell metabolism and antitumour immunity.
DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.
Periportal macrophages protect against commensal-driven liver inflammation.
ACSM1 and ACSM3 regulate fatty acid metabolism to support prostate cancer growth and constrain ferroptosis.
Systematic characterization of multi-omics landscape between gut microbial metabolites and GPCRome in Alzheimer's disease.
Mitochondrial sites of contact with the nucleus.
SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.

EMBO J. 2024 Apr 25.

Presenting metabolomics analyses: what is in a number?

Johannes Meiser, Christian Frezza.

DOI: https://doi.org/10.1038/s44318-024-00098-1
Nat Metab. 2024 Apr;6(4): 741-763

Fatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring.

Jonathan Sun, Enric Esplugues, Alicia Bort, Magdalena P Cardelo, Inmaculada Ruz-Maldonado, Pablo Fernández-Tussy, Clara Wong, Hehe Wang, Iwao Ojima, Martin Kaczocha, Rachel Perry, Yajaira Suárez, Carlos Fernández-Hernando.

Due to the rise in overnutrition, the incidence of obesity-induced hepatocellular carcinoma (HCC) will continue to escalate; however, our understanding of the obesity to HCC developmental axis is limited. We constructed a single-cell atlas to interrogate the dynamic transcriptomic changes during hepatocarcinogenesis in mice. Here we identify fatty acid binding protein 5 (FABP5) as a driver of obesity-induced HCC. Analysis of transformed cells reveals that FABP5 inhibition and silencing predispose cancer cells to lipid peroxidation and ferroptosis-induced cell death. Pharmacological inhibition and genetic ablation of FABP5 ameliorates the HCC burden in male mice, corresponding to enhanced ferroptosis in the tumour. Moreover, FABP5 inhibition induces a pro-inflammatory tumour microenvironment characterized by tumour-associated macrophages with increased expression of the co-stimulatory molecules CD80 and CD86 and increased CD8+ T cell activation. Our work unravels the dual functional role of FABP5 in diet-induced HCC, inducing the transformation of hepatocytes and an immunosuppressive phenotype of tumour-associated macrophages and illustrates FABP5 inhibition as a potential therapeutic approach.

DOI: https://doi.org/10.1038/s42255-024-01019-6
Nat Cell Biol. 2024 Apr 23.

Regulation of mitochondrial fission by fatty acyl-coenzyme A.

DOI: https://doi.org/10.1038/s41556-024-01406-x
Cytometry A. 2024 Apr 23.

A 30-color spectral flow cytometry panel for comprehensive analysis of immune cell composition and macrophage subsets in mouse metabolic organs.

Joost M Lambooij, Tamar Tak, Arnaud Zaldumbide, Bruno Guigas.

  Obesity-induced chronic low-grade inflammation, also known as metaflammation, results from alterations of the immune response in metabolic organs and contributes to the development of fatty liver diseases and type 2 diabetes. The diversity of tissue-resident leukocytes involved in these metabolic dysfunctions warrants an in-depth immunophenotyping in order to elucidate disease etiology. Here, we present a 30-color, full spectrum flow cytometry panel, designed to (i) identify the major innate and adaptive immune cell subsets in murine liver and white adipose tissues and (ii) discriminate various tissue-specific myeloid subsets known to contribute to the development of metabolic dysfunctions. This panel notably allows for distinguishing embryonically-derived liver-resident Kupffer cells from newly recruited monocyte-derived macrophages and KCs. Furthermore, several adipose tissue macrophage (ATM) subsets, including perivascular macrophages, lipid-associated macrophages, and pro-inflammatory CD11c+ ATMs, can also be identified. Finally, the panel includes cell-surface markers that have been associated with metabolic activation of different macrophage and dendritic cell subsets. Altogether, our spectral flow cytometry panel allows for an extensive immunophenotyping of murine metabolic tissues, with a particular focus on metabolically-relevant myeloid cell subsets, and can easily be adjusted to include various new markers if needed.

Keywords:  NAFLD; adipose tissue; immunometabolism; innate and adaptive immunity; liver; macrophages; obesity; spectral flow cytometry

DOI:  https://doi.org/10.1002/cyto.a.24845
Redox Biol. 2024 Apr 16. pii: S2213-2317(24)00135-6. [Epub ahead of print]72 103159

SLC7A11-ROS/αKG-AMPK axis regulates liver inflammation through mitophagy and impairs liver fibrosis and NASH progression.

Tingting Lv, Xiude Fan, Chang He, Suwei Zhu, Xiaofeng Xiong, Wei Yan, Mei Liu, Hongwei Xu, Ruihua Shi, Qin He.

  The changes of inflammation and metabolism are two features in nonalcoholic steatohepatitis (NASH). However, how they interact to regulate NASH progression remains largely unknown. Our works have demonstrated the importance of solute carrier family 7 member 11 (SLC7A11) in inflammation and metabolism. Nevertheless, whether SLC7A11 regulates NASH progression through mediating inflammation and metabolism is unclear. In this study, we found that SLC7A11 expression was increased in liver samples from patients with NASH. Upregulated SLC7A11 level was also detected in two murine NASH models. Functional studies showed that SLC7A11 knockdown or knockout had augmented steatohepatitis with suppression of inflammatory markers in mice. However, overexpression of SLC7A11 dramatically alleviated diet-induced NASH pathogenesis. Mechanically, SLC7A11 decreased reactive oxygen species (ROS) level and promoted α-ketoglutarate (αKG)/prolyl hydroxylase (PHD) activity, which activated AMPK pathway. Furthermore, SLC7A11 impaired expression of NLRP3 inflammasome components through AMPK-mitophagy axis. IL-1β release through NLRP3 inflammasome recruited myeloid cells and promoted hepatic stellate cells (HSCs) activation, which contributed to the progression of liver injury and fibrosis. Anti-IL-1β and anakinra might attenuate the hepatic inflammatory response evoked by SLC7A11 knockdown. Moreover, the upregulation of SLC7A11 in NASH was contributed by lipid overload-induced JNK-c-Jun pathway. In conclusions, SLC7A11 acts as a protective factor in controlling the development of NASH. Upregulation of SLC7A11 is protective by regulating oxidation, αKG and energy metabolism, decreasing inflammation and fibrosis.

Keywords:  AMPK; Mitophagy; NLRP3 inflammasome; Nonalcoholic steatohepatitis; SLC7A11

DOI:  https://doi.org/10.1016/j.redox.2024.103159
Sci Adv. 2024 Apr 26. 10(17): eadk1045

Sphingolipid biosynthesis is essential for metabolic rewiring during TH17 cell differentiation.

Thiruvaimozhi Abimannan, Velayoudame Parthibane, Si-Hung Le, Nagampalli Vijaykrishna, Stephen D Fox, Baktiar Karim, Govind Kunduri, Daniel Blankenberg, Thorkell Andresson, Takeshi Bamba, Usha Acharya, Jairaj K Acharya.

T helper 17 (TH17) cells are implicated in autoimmune diseases, and several metabolic processes are shown to be important for their development and function. In this study, we report an essential role for sphingolipids synthesized through the de novo pathway in TH17 cell development. Deficiency of SPTLC1, a major subunit of serine palmitoyl transferase enzyme complex that catalyzes the first and rate-limiting step of de novo sphingolipid synthesis, impaired glycolysis in differentiating TH17 cells by increasing intracellular reactive oxygen species (ROS) through enhancement of nicotinamide adenine dinucleotide phosphate oxidase 2 activity. Increased ROS leads to impaired activation of mammalian target of rapamycin C1 and reduced expression of hypoxia-inducible factor 1-alpha and c-Myc-induced glycolytic genes. SPTLCI deficiency protected mice from developing experimental autoimmune encephalomyelitis and experimental T cell transfer colitis. Our results thus show a critical role for de novo sphingolipid biosynthetic pathway in shaping adaptive immune responses with implications in autoimmune diseases.

DOI: https://doi.org/10.1126/sciadv.adk1045
Cell. 2024 Apr 17. pii: S0092-8674(24)00346-5. [Epub ahead of print]

BCAA-nitrogen flux in brown fat controls metabolic health independent of thermogenesis.

Anthony R P Verkerke, Dandan Wang, Naofumi Yoshida, Zachary H Taxin, Xu Shi, Shuning Zheng, Yuka Li, Christopher Auger, Satoshi Oikawa, Jin-Seon Yook, Melia Granath-Panelo, Wentao He, Guo-Fang Zhang, Mami Matsushita, Masayuki Saito, Robert E Gerszten, Evanna L Mills, Alexander S Banks, Yasushi Ishihama, Phillip J White, Robert W McGarrah, Takeshi Yoneshiro, Shingo Kajimura.

  Brown adipose tissue (BAT) is best known for thermogenesis. Rodent studies demonstrated that enhanced BAT thermogenesis is tightly associated with increased energy expenditure, reduced body weight, and improved glucose homeostasis. However, human BAT is protective against type 2 diabetes, independent of body weight. The mechanism underlying this dissociation remains unclear. Here, we report that impaired mitochondrial catabolism of branched-chain amino acids (BCAAs) in BAT, by deleting mitochondrial BCAA carriers (MBCs), caused systemic insulin resistance without affecting energy expenditure and body weight. Brown adipocytes catabolized BCAA in the mitochondria as nitrogen donors for the biosynthesis of non-essential amino acids and glutathione. Impaired mitochondrial BCAA-nitrogen flux in BAT resulted in increased oxidative stress, decreased hepatic insulin signaling, and decreased circulating BCAA-derived metabolites. A high-fat diet attenuated BCAA-nitrogen flux and metabolite synthesis in BAT, whereas cold-activated BAT enhanced the synthesis. This work uncovers a metabolite-mediated pathway through which BAT controls metabolic health beyond thermogenesis.

Keywords:  amino acid metabolism; bioenergetics; brown adipose tissue; diabetes; glucose homeostasis; insulin resistance; inter-organ communication; mitochondria; thermogenesis

DOI:  https://doi.org/10.1016/j.cell.2024.03.030
Cell Rep. 2024 Apr 23. pii: S2211-1247(24)00469-8. [Epub ahead of print]43(5): 114141

Batf3+ DCs and the 4-1BB/4-1BBL axis are required at the effector phase in the tumor microenvironment for PD-1/PD-L1 blockade efficacy.

Andrea Ziblat, Brendan L Horton, Emily F Higgs, Ken Hatogai, Anna Martinez, Jason W Shapiro, Danny E C Kim, YuanYuan Zha, Randy F Sweis, Thomas F Gajewski.

  The cellular source of positive signals that reinvigorate T cells within the tumor microenvironment (TME) for the therapeutic efficacy of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade has not been clearly defined. We now show that Batf3-lineage dendritic cells (DCs) are essential in this process. Flow cytometric analysis, gene-targeted mice, and blocking antibody studies revealed that 4-1BBL is a major positive co-stimulatory signal provided by these DCs within the TME that translates to CD8+ T cell functional reinvigoration and tumor regression. Immunofluorescence and spatial transcriptomics on human tumor samples revealed clustering of Batf3+ DCs and CD8+ T cells, which correlates with anti-PD-1 efficacy. In addition, proximity to Batf3+ DCs within the TME is associated with CD8+ T cell transcriptional states linked to anti-PD-1 response. Our results demonstrate that Batf3+ DCs within the TME are critical for PD-1/PD-L1 blockade efficacy and indicate a major role for the 4-1BB/4-1BB ligand (4-1BBL) axis during this process.

Keywords:  4-1BB; 4-1BBL; Batf3-lineage dendritic cells; CD8(+) T cells; CP: Cancer; CP: Immunology; DC1s; PD-1/PD-L1 blockade; immunotherapy; immunotherapy efficacy; spatial transcriptomics

DOI:  https://doi.org/10.1016/j.celrep.2024.114141
Nat Cell Biol. 2024 Apr 26.

LPCAT1-mediated membrane phospholipid remodelling promotes ferroptosis evasion and tumour growth.

Ziwen Li, Yameng Hu, Haiqing Zheng, Man Li, Yuanji Liu, Rongni Feng, Xincheng Li, Shuxia Zhang, Miaoling Tang, Meisongzhu Yang, Ruyuan Yu, Yingru Xu, Xinyi Liao, Suwen Chen, Wanying Qian, Qiliang Zhang, Daolin Tang, Bo Li, Libing Song, Jun Li.

The mechanisms underlying the dynamic remodelling of cellular membrane phospholipids to prevent phospholipid peroxidation-induced membrane damage and evade ferroptosis, a non-apoptotic form of cell death driven by iron-dependent lipid peroxidation, remain poorly understood. Here we show that lysophosphatidylcholine acyltransferase 1 (LPCAT1) plays a critical role in ferroptosis resistance by increasing membrane phospholipid saturation via the Lands cycle, thereby reducing membrane levels of polyunsaturated fatty acids, protecting cells from phospholipid peroxidation-induced membrane damage and inhibiting ferroptosis. Furthermore, the enhanced in vivo tumour-forming capability of tumour cells is closely associated with the upregulation of LPCAT1 and emergence of a ferroptosis-resistant state. Combining LPCAT1 inhibition with a ferroptosis inducer synergistically triggers ferroptosis and suppresses tumour growth. Therefore, our results unveil a plausible role for LPCAT1 in evading ferroptosis and suggest it as a promising target for clinical intervention in human cancer.

DOI: https://doi.org/10.1038/s41556-024-01405-y
JCI Insight. 2024 Apr 23. pii: e178372. [Epub ahead of print]

A tryptophan-derived uremic metabolite-Ahr-Pdk4 axis governs skeletal muscle mitochondrial energetics in chronic kidney disease.

Trace Thome, Nicholas A Vugman, Lauren E Stone, Keon Wimberly, Salvatore T Scali, Terence E Ryan.

  Chronic kidney disease (CKD) causes an accumulation of uremic metabolites that negatively impact skeletal muscle function. Tryptophan-derived uremic metabolites are agonists of the aryl hydrocarbon receptor (AHR) which has been shown to be activated in the blood of CKD patients. This study investigated the role of the AHR in skeletal muscle pathology of CKD. Compared to control participants with normal kidney function, AHR-dependent gene expression (CYP1A1 and CYP1B1) was significantly upregulated in skeletal muscle of patients with CKD (P=0.032) and the magnitude of AHR activation was inversely correlated with mitochondrial respiration (P<0.001). In mice with CKD, muscle mitochondrial oxidative phosphorylation (OXPHOS) was significantly impaired and strongly correlated with both the serum level of tryptophan-derived uremic metabolites and AHR activation. Muscle-specific deletion of the AHR significantly improved mitochondrial OXPHOS in male mice with the greatest uremic toxicity (CKD+probenecid) and abolished the relationship between uremic metabolites and OXPHOS. The uremic metabolite-AHR-mitochondrial axis in skeletal muscle was further confirmed using muscle-specific AHR knockdown in C57BL6J that harbour a high-affinity AHR allele, as well as ectopic viral expression of constitutively active mutant AHR in mice with normal renal function. Notably, OXPHOS changes in AHRmKO mice were only present when mitochondria were fueled by carbohydrates. Further analyses revealed that AHR activation in mice led to significant increases in Pdk4 expression (P<0.05) and phosphorylation of pyruvate dehydrogenase enzyme (P<0.05). These findings establish a uremic metabolite-AHR-Pdk4 axis in skeletal muscle that governs mitochondrial deficits in carbohydrate oxidation during CKD.

Keywords:  Chronic kidney disease; Mitochondria; Muscle biology; Nephrology; Skeletal muscle

DOI:  https://doi.org/10.1172/jci.insight.178372
Nature. 2024 Apr 24.

PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function.

Matteo Morotti, Alizee J Grimm, Helen Carrasco Hope, Marion Arnaud, Mathieu Desbuisson, Nicolas Rayroux, David Barras, Maria Masid, Baptiste Murgues, Bovannak S Chap, Marco Ongaro, Ioanna A Rota, Catherine Ronet, Aspram Minasyan, Johanna Chiffelle, Sebastian B Lacher, Sara Bobisse, Clément Murgues, Eleonora Ghisoni, Khaoula Ouchen, Ribal Bou Mjahed, Fabrizio Benedetti, Naoill Abdellaoui, Riccardo Turrini, Philippe O Gannon, Khalil Zaman, Patrice Mathevet, Loic Lelievre, Isaac Crespo, Marcus Conrad, Gregory Verdeil, Lana E Kandalaft, Julien Dagher, Jesus Corria-Osorio, Marie-Agnes Doucey, Ping-Chih Ho, Alexandre Harari, Nicola Vannini, Jan P Böttcher, Denarda Dangaj Laniti, George Coukos.

Expansion of antigen-experienced CD8+ T cells is critical for the success of tumour-infiltrating lymphocyte (TIL)-adoptive cell therapy (ACT) in patients with cancer1. Interleukin-2 (IL-2) acts as a key regulator of CD8+ cytotoxic T lymphocyte functions by promoting expansion and cytotoxic capability2,3. Therefore, it is essential to comprehend mechanistic barriers to IL-2 sensing in the tumour microenvironment to implement strategies to reinvigorate IL-2 responsiveness and T cell antitumour responses. Here we report that prostaglandin E2 (PGE2), a known negative regulator of immune response in the tumour microenvironment4,5, is present at high concentrations in tumour tissue from patients and leads to impaired IL-2 sensing in human CD8+ TILs via the PGE2 receptors EP2 and EP4. Mechanistically, PGE2 inhibits IL-2 sensing in TILs by downregulating the IL-2Rγc chain, resulting in defective assembly of IL-2Rβ-IL2Rγc membrane dimers. This results in impaired IL-2-mTOR adaptation and PGC1α transcriptional repression, causing oxidative stress and ferroptotic cell death in tumour-reactive TILs. Inhibition of PGE2 signalling to EP2 and EP4 during TIL expansion for ACT resulted in increased IL-2 sensing, leading to enhanced proliferation of tumour-reactive TILs and enhanced tumour control once the cells were transferred in vivo. Our study reveals fundamental features that underlie impairment of human TILs mediated by PGE2 in the tumour microenvironment. These findings have therapeutic implications for cancer immunotherapy and cell therapy, and enable the development of targeted strategies to enhance IL-2 sensing and amplify the IL-2 response in TILs, thereby promoting the expansion of effector T cells with enhanced therapeutic potential.

DOI: https://doi.org/10.1038/s41586-024-07352-w
Science. 2024 Apr 26. 384(6694): 438-446

Food perception promotes phosphorylation of MFFS131 and mitochondrial fragmentation in liver.

Sinika Henschke, Hendrik Nolte, Judith Magoley, Tatjana Kleele, Claus Brandt, A Christine Hausen, Claudia M Wunderlich, Corinna A Bauder, Philipp Aschauer, Suliana Manley, Thomas Langer, F Thomas Wunderlich, Jens C Brüning.

Liver mitochondria play a central role in metabolic adaptations to changing nutritional states, yet their dynamic regulation upon anticipated changes in nutrient availability has remained unaddressed. Here, we found that sensory food perception rapidly induced mitochondrial fragmentation in the liver through protein kinase B/AKT (AKT)-dependent phosphorylation of serine 131 of the mitochondrial fission factor (MFFS131). This response was mediated by activation of hypothalamic pro-opiomelanocortin (POMC)-expressing neurons. A nonphosphorylatable MFFS131G knock-in mutation abrogated AKT-induced mitochondrial fragmentation in vitro. In vivo, MFFS131G knock-in mice displayed altered liver mitochondrial dynamics and impaired insulin-stimulated suppression of hepatic glucose production. Thus, rapid activation of a hypothalamus-liver axis can adapt mitochondrial function to anticipated changes of nutritional state in control of hepatic glucose metabolism.

DOI: https://doi.org/10.1126/science.adk1005
J Lipid Res. 2024 Apr 20. pii: S0022-2275(24)00053-1. [Epub ahead of print] 100548

Dietary docosahexaenoic acid (DHA) downregulates liver DHA synthesis by inhibiting eicosapentaenoic acid elongation.

Adam H Metherel, Rodrigo Valenzuela, Brinley J Klievik, Giulia Cisbani, Ruxandra D Rotarescu, Melissa Gonzalez-Soto, Céline Cruciani-Guglielmacci, Sophie Layé, Christophe Magnan, David M Mutch, Richard P Bazinet.

  DHA is abundant in brain where it regulates cell survival, neurogenesis and neuroinflammation. DHA can be obtained from the diet or synthesized from alpha-linolenic acid (ALA; 18:3n-3) via a series of desaturation and elongation reactions occurring in the liver. Tracer studies suggest that dietary DHA can downregulate its own synthesis, but the mechanism remains undetermined and is the primary objective of this paper. First, we show by tracing 13C content (δ13C) of DHA via compound-specific isotope analysis (CSIA), that following low dietary DHA, the brain receives DHA synthesized from ALA. We then show that dietary DHA increases mouse liver and serum EPA, which is dependant on ALA. Furthermore, by CSIA we demonstrate that the source of increased EPA is slowed EPA metabolism, not increased DHA retroconversion as previously assumed. DHA feeding alone or with ALA lowered liver elongation of very long-chain (ELOVL2, EPA elongation) enzyme activity despite no change in protein content. To further evaluate the role of ELOVL2, a liver-specific Elovl2 knockout was generated showing that DHA feeding in the presence or absence of a functional liver ELOVL2 yields similar results. An enzyme competition assay for EPA elongation suggests both uncompetitive and non-competitive inhibition by DHA depending on DHA levels. To translate our findings, we show that DHA supplementation in men and women increases EPA levels in a manner dependent on a SNP (rs953413) in the ELOVL2 gene. In conclusion, we identify a novel feedback inhibition pathway where dietary DHA downregulates its liver synthesis by inhibiting EPA elongation.

Keywords:  dietary fat; elongation of very long-chain; enzyme inhibition; fatty acid metabolism; kinetics; liver; nutrition; omega-3 fatty acids; polyunsaturated fatty acid

DOI:  https://doi.org/10.1016/j.jlr.2024.100548
Cell. 2024 Apr 16. pii: S0092-8674(24)00320-9. [Epub ahead of print]

Integrative spatial analysis reveals a multi-layered organization of glioblastoma.

Alissa C Greenwald, Noam Galili Darnell, Rouven Hoefflin, Dor Simkin, Christopher W Mount, L Nicolas Gonzalez Castro, Yotam Harnik, Sydney Dumont, Dana Hirsch, Masashi Nomura, Tom Talpir, Merav Kedmi, Inna Goliand, Gioele Medici, Julie Laffy, Baoguo Li, Vamsi Mangena, Hadas Keren-Shaul, Michael Weller, Yoseph Addadi, Marian C Neidert, Mario L Suvà, Itay Tirosh.

  Glioma contains malignant cells in diverse states. Here, we combine spatial transcriptomics, spatial proteomics, and computational approaches to define glioma cellular states and uncover their organization. We find three prominent modes of organization. First, gliomas are composed of small local environments, each typically enriched with one major cellular state. Second, specific pairs of states preferentially reside in proximity across multiple scales. This pairing of states is consistent across tumors. Third, these pairwise interactions collectively define a global architecture composed of five layers. Hypoxia appears to drive the layers, as it is associated with a long-range organization that includes all cancer cell states. Accordingly, tumor regions distant from any hypoxic/necrotic foci and tumors that lack hypoxia such as low-grade IDH-mutant glioma are less organized. In summary, we provide a conceptual framework for the organization of cellular states in glioma, highlighting hypoxia as a long-range tissue organizer.

Keywords:  glioblastoma; glioma; hypoxia; intratumor heterogeneity; spatial proteomics; spatial transcriptomics

DOI:  https://doi.org/10.1016/j.cell.2024.03.029
Cytokine. 2024 Apr 25. pii: S1043-4666(24)00122-4. [Epub ahead of print]179 156619

IL-23 regulation of myeloid cell biology during inflammation.

Kevin M-C Lee, Tanya Lupancu, Leon Chang, Carl L Manthey, Martha Zeeman, Anne M Fourie, John A Hamilton.

  Interleukin (IL)-23 is implicated in the pathogenesis of several inflammatory diseases and is usually linked with helper T cell (Th17) biology. However, there is some data linking IL-23 with innate immune biology in such diseases. We therefore examined the effects of IL-23p19 genetic deletion and/or neutralization on in vitro macrophage activation and in an innate immune-driven peritonitis model. We report that endogenous IL-23 was required for maximal macrophage activation by zymosan as determined by pro-inflammatory cytokine production, including a dramatic upregulation of granulocyte-colony stimulating factor (G-CSF). Furthermore, both IL-23p19 genetic deletion and neutralization in zymosan-induced peritonitis (ZIP) led to a specific reduction in the neutrophil numbers, as well as a reduction in the G-CSF levels in exudate fluids. We conclude that endogenous IL-23 can contribute significantly to macrophage activation during an inflammatory response, mostly likely via an autocrine/paracrine mechanism; of note, endogenous IL-23 can directly up-regulate macrophage G-CSF expression, which in turn is likely to contribute to the regulation of IL-23-dependent neutrophil number and function during an inflammatory response, with potential significance for IL-23 targeting particularly in neutrophil-associated inflammatory diseases.

Keywords:  G-CSF; IL-23; Inflammation; Neutrophils

DOI:  https://doi.org/10.1016/j.cyto.2024.156619
Nat Cardiovasc Res. 2023 Nov;2(11): 1015-1031

Trem2 promotes foamy macrophage lipid uptake and survival in atherosclerosis.

Michael T Patterson, Maria M Firulyova, Yingzheng Xu, Hannah Hillman, Courtney Bishop, Alisha Zhu, Grant H Hickok, Patricia R Schrank, Christine E Ronayne, Zakariya Caillot, Gavin Fredrickson, Ainsley E Kennedy, Nisha Acharya, Jaap G Neels, Giulia Chinetti, Xavier Revelo, Ingunn M Stromnes, Stoyan Ivanov, Tyler D Bold, Konstantin Zaitsev, Jesse W Williams.

Atherosclerosis is driven by the expansion of cholesterol-loaded 'foamy' macrophages in the arterial intima. Factors regulating foamy macrophage differentiation and survival in plaque remain poorly understood. Here we show, using trajectory analysis of integrated single-cell RNA sequencing data and a genome-wide CRISPR screen, that triggering receptor expressed on myeloid cells 2 (Trem2) is associated with foamy macrophage specification. Loss of Trem2 led to a reduced ability of foamy macrophages to take up oxidized low-density lipoprotein (oxLDL). Myeloid-specific deletion of Trem2 showed an attenuation of plaque progression, even when targeted in established atherosclerotic lesions, and was independent of changes in circulating cytokines, monocyte recruitment or cholesterol levels. Mechanistically, we link Trem2-deficient macrophages with a failure to upregulate cholesterol efflux molecules, resulting in impaired proliferation and survival. Overall, we identify Trem2 as a regulator of foamy macrophage differentiation and atherosclerotic plaque growth and as a putative therapeutic target for atherosclerosis.

DOI: https://doi.org/10.1038/s44161-023-00354-3
Cancer Cell. 2024 Apr 09. pii: S1535-6108(24)00125-9. [Epub ahead of print]

Tumor cell-intrinsic epigenetic SETpoint of cancer-associated fibroblasts.

Xiongfeng Chen, Huocong Huang.

Cancer-associated fibroblasts (CAFs) exhibit spatial and functional diversity. Here, Niu et al. unveil SETD2's function in lipid metabolism and CAF heterogeneity in pancreatic ductal adenocarcinoma. SETD2 deficiency boosts oxidative phosphorylation activity, prompting lipid-laden CAF formation through BMP2 signaling, offering promising therapeutic avenues in personalized cancer treatment.

DOI: https://doi.org/10.1016/j.ccell.2024.04.001
Nat Commun. 2024 Apr 24. 15(1): 3475

High clonal diversity and spatial genetic admixture in early prostate cancer and surrounding normal tissue.

Ning Zhang, Luuk Harbers, Michele Simonetti, Constantin Diekmann, Quentin Verron, Enrico Berrino, Sara E Bellomo, Gabriel M C Longo, Michael Ratz, Niklas Schultz, Firas Tarish, Peng Su, Bo Han, Wanzhong Wang, Sofia Onorato, Dora Grassini, Roberto Ballarino, Silvia Giordano, Qifeng Yang, Anna Sapino, Jonas Frisén, Kanar Alkass, Henrik Druid, Vassilis Roukos, Thomas Helleday, Caterina Marchiò, Magda Bienko, Nicola Crosetto.

Somatic copy number alterations (SCNAs) are pervasive in advanced human cancers, but their prevalence and spatial distribution in early-stage, localized tumors and their surrounding normal tissues are poorly characterized. Here, we perform multi-region, single-cell DNA sequencing to characterize the SCNA landscape across tumor-rich and normal tissue in two male patients with localized prostate cancer. We identify two distinct karyotypes: 'pseudo-diploid' cells harboring few SCNAs and highly aneuploid cells. Pseudo-diploid cells form numerous small-sized subclones ranging from highly spatially localized to broadly spread subclones. In contrast, aneuploid cells do not form subclones and are detected throughout the prostate, including normal tissue regions. Highly localized pseudo-diploid subclones are confined within tumor-rich regions and carry deletions in multiple tumor-suppressor genes. Our study reveals that SCNAs are widespread in normal and tumor regions across the prostate in localized prostate cancer patients and suggests that a subset of pseudo-diploid cells drive tumorigenesis in the aging prostate.

DOI: https://doi.org/10.1038/s41467-024-47664-z
Proc Natl Acad Sci U S A. 2024 Apr 30. 121(18): e2307090121

Single-chain fluorescent integrators for mapping G-protein-coupled receptor agonists.

Kayla Kroning, Noam Gannot, Xingyu Li, Aubrey Putansu, Guanwei Zhou, Jennifer Sescil, Jiaqi Shen, Avery Wilson, Hailey Fiel, Peng Li, Wenjing Wang.

  G protein-coupled receptors (GPCRs) transduce the effects of many neuromodulators including dopamine, serotonin, epinephrine, acetylcholine, and opioids. The localization of synthetic or endogenous GPCR agonists impacts their action on specific neuronal pathways. In this paper, we show a series of single-protein chain integrator sensors that are highly modular and could potentially be used to determine GPCR agonist localization across the brain. We previously engineered integrator sensors for the mu- and kappa-opioid receptor agonists called M- and K-Single-chain Protein-based Opioid Transmission Indicator Tool (SPOTIT), respectively. Here, we engineered red versions of the SPOTIT sensors for multiplexed imaging of GPCR agonists. We also modified SPOTIT to create an integrator sensor design platform called SPOTIT for all GPCRs (SPOTall). We used the SPOTall platform to engineer sensors for the beta 2-adrenergic receptor (B2AR), the dopamine receptor D1, and the cholinergic receptor muscarinic 2 agonists. Finally, we demonstrated the application of M-SPOTIT and B2AR-SPOTall in detecting exogenously administered morphine, isoproterenol, and epinephrine in the mouse brain via locally injected viruses. The SPOTIT and SPOTall sensor design platform has the potential for unbiased agonist detection of many synthetic and endogenous neuromodulators across the brain.

Keywords:  G protein-coupled receptor; fluorescent sensor; integrator sensor; neuromodulator detection

DOI:  https://doi.org/10.1073/pnas.2307090121
Nature. 2024 Apr 24.

Single-cell analysis reveals context-dependent, cell-level selection of mtDNA.

Anna V Kotrys, Timothy J Durham, Xiaoyan A Guo, Venkata R Vantaku, Sareh Parangi, Vamsi K Mootha.

Heteroplasmy occurs when wild-type and mutant mitochondrial DNA (mtDNA) molecules co-exist in single cells1. Heteroplasmy levels change dynamically in development, disease and ageing2,3, but it is unclear whether these shifts are caused by selection or drift, and whether they occur at the level of cells or intracellularly. Here we investigate heteroplasmy dynamics in dividing cells by combining precise mtDNA base editing (DdCBE)4 with a new method, SCI-LITE (single-cell combinatorial indexing leveraged to interrogate targeted expression), which tracks single-cell heteroplasmy with ultra-high throughput. We engineered cells to have synonymous or nonsynonymous complex I mtDNA mutations and found that cell populations in standard culture conditions purge nonsynonymous mtDNA variants, whereas synonymous variants are maintained. This suggests that selection dominates over simple drift in shaping population heteroplasmy. We simultaneously tracked single-cell mtDNA heteroplasmy and ancestry, and found that, although the population heteroplasmy shifts, the heteroplasmy of individual cell lineages remains stable, arguing that selection acts at the level of cell fitness in dividing cells. Using these insights, we show that we can force cells to accumulate high levels of truncating complex I mtDNA heteroplasmy by placing them in environments where loss of biochemical complex I activity has been reported to benefit cell fitness. We conclude that in dividing cells, a given nonsynonymous mtDNA heteroplasmy can be harmful, neutral or even beneficial to cell fitness, but that the 'sign' of the effect is wholly dependent on the environment.

DOI: https://doi.org/10.1038/s41586-024-07332-0
Nat Rev Immunol. 2024 Apr 22.

Cancer cell metabolism and antitumour immunity.

Mara De Martino, Jeffrey C Rathmell, Lorenzo Galluzzi, Claire Vanpouille-Box.

Accumulating evidence suggests that metabolic rewiring in malignant cells supports tumour progression not only by providing cancer cells with increased proliferative potential and an improved ability to adapt to adverse microenvironmental conditions but also by favouring the evasion of natural and therapy-driven antitumour immune responses. Here, we review cancer cell-intrinsic and cancer cell-extrinsic mechanisms through which alterations of metabolism in malignant cells interfere with innate and adaptive immune functions in support of accelerated disease progression. Further, we discuss the potential of targeting such alterations to enhance anticancer immunity for therapeutic purposes.

DOI: https://doi.org/10.1038/s41577-024-01026-4
Cell. 2024 Apr 17. pii: S0092-8674(24)00318-0. [Epub ahead of print]

DrugMap: A quantitative pan-cancer analysis of cysteine ligandability.

Mariko Takahashi, Harrison B Chong, Siwen Zhang, Tzu-Yi Yang, Matthew J Lazarov, Stefan Harry, Michelle Maynard, Brendan Hilbert, Ryan D White, Heather E Murrey, Chih-Chiang Tsou, Kira Vordermark, Jonathan Assaad, Magdy Gohar, Benedikt R Dürr, Marianne Richter, Himani Patel, Gregory Kryukov, Natasja Brooijmans, Aliyu Sidi Omar Alghali, Karla Rubio, Antonio Villanueva, Junbing Zhang, Maolin Ge, Farah Makram, Hanna Griesshaber, Drew Harrison, Ann-Sophie Koglin, Samuel Ojeda, Barbara Karakyriakou, Alexander Healy, George Popoola, Inbal Rachmin, Neha Khandelwal, Jason R Neil, Pei-Chieh Tien, Nicholas Chen, Tobias Hosp, Sanne van den Ouweland, Toshiro Hara, Lillian Bussema, Rui Dong, Lei Shi, Martin Q Rasmussen, Ana Carolina Domingues, Aleigha Lawless, Jacy Fang, Satoshi Yoda, Linh Phuong Nguyen, Sarah Marie Reeves, Farrah Nicole Wakefield, Adam Acker, Sarah Elizabeth Clark, Taronish Dubash, John Kastanos, Eugene Oh, David E Fisher, Shyamala Maheswaran, Daniel A Haber, Genevieve M Boland, Moshe Sade-Feldman, Russell W Jenkins, Aaron N Hata, Nabeel M Bardeesy, Mario L Suvà, Brent R Martin, Brian B Liau, Christopher J Ott, Miguel N Rivera, Michael S Lawrence, Liron Bar-Peled.

  Cysteine-focused chemical proteomic platforms have accelerated the clinical development of covalent inhibitors for a wide range of targets in cancer. However, how different oncogenic contexts influence cysteine targeting remains unknown. To address this question, we have developed "DrugMap," an atlas of cysteine ligandability compiled across 416 cancer cell lines. We unexpectedly find that cysteine ligandability varies across cancer cell lines, and we attribute this to differences in cellular redox states, protein conformational changes, and genetic mutations. Leveraging these findings, we identify actionable cysteines in NF-κB1 and SOX10 and develop corresponding covalent ligands that block the activity of these transcription factors. We demonstrate that the NF-κB1 probe blocks DNA binding, whereas the SOX10 ligand increases SOX10-SOX10 interactions and disrupts melanoma transcriptional signaling. Our findings reveal heterogeneity in cysteine ligandability across cancers, pinpoint cell-intrinsic features driving cysteine targeting, and illustrate the use of covalent probes to disrupt oncogenic transcription-factor activity.

Keywords:  chemical proteomics; covalent inhibitors; cysteine ligandability; transcription factors

DOI:  https://doi.org/10.1016/j.cell.2024.03.027
Nature. 2024 Apr 24.

Periportal macrophages protect against commensal-driven liver inflammation.

Yu Miyamoto, Junichi Kikuta, Takahiro Matsui, Tetsuo Hasegawa, Kentaro Fujii, Daisuke Okuzaki, Yu-Chen Liu, Takuya Yoshioka, Shigeto Seno, Daisuke Motooka, Yutaka Uchida, Erika Yamashita, Shogo Kobayashi, Hidetoshi Eguchi, Eiichi Morii, Karl Tryggvason, Takashi Shichita, Hisako Kayama, Koji Atarashi, Jun Kunisawa, Kenya Honda, Kiyoshi Takeda, Masaru Ishii.

The liver is the main gateway from the gut, and the unidirectional sinusoidal flow from portal to central veins constitutes heterogenous zones, including the periportal vein (PV) and the pericentral vein zones1-5. However, functional differences in the immune system in each zone remain poorly understood. Here intravital imaging revealed that inflammatory responses are suppressed in PV zones. Zone-specific single-cell transcriptomics detected a subset of immunosuppressive macrophages enriched in PV zones that express high levels of interleukin-10 and Marco, a scavenger receptor that sequesters pro-inflammatory pathogen-associated molecular patterns and damage-associated molecular patterns, and consequently suppress immune responses. Induction of Marco+ immunosuppressive macrophages depended on gut microbiota. In particular, a specific bacterial family, Odoribacteraceae, was identified to induce this macrophage subset through its postbiotic isoallolithocholic acid. Intestinal barrier leakage resulted in inflammation in PV zones, which was markedly augmented in Marco-deficient conditions. Chronic liver inflammatory diseases such as primary sclerosing cholangitis (PSC) and non-alcoholic steatohepatitis (NASH) showed decreased numbers of Marco+ macrophages. Functional ablation of Marco+ macrophages led to PSC-like inflammatory phenotypes related to colitis and exacerbated steatosis in NASH in animal experimental models. Collectively, commensal bacteria induce Marco+ immunosuppressive macrophages, which consequently limit excessive inflammation at the gateway of the liver. Failure of this self-limiting system promotes hepatic inflammatory disorders such as PSC and NASH.

DOI: https://doi.org/10.1038/s41586-024-07372-6
Cancer Res. 2024 Apr 24.

ACSM1 and ACSM3 regulate fatty acid metabolism to support prostate cancer growth and constrain ferroptosis.

Raj Kumar Shrestha, Zeyad D Nassar, Adrienne R Hanson, Richard Iggo, Scott L Townley, Jonas Dehairs, Chui Yan Mah, Madison Helm, Mohammadreza Alizadeh-Ghodsi, Marie Pickering, Bart Ghesquiere, Matthew J Watt, Lake-Ee Quek, Andrew J Hoy, Wayne D Tilley, Johannes V Swinnen, Lisa M Butler, Luke A Selth.

Solid tumors are highly reliant on lipids for energy, growth, and survival. In prostate cancer, the activity of the androgen receptor (AR) is associated with reprogramming of lipid metabolic processes. Here, we identified acyl-CoA synthetase medium chain family members 1 and 3 (ACSM1 and ACSM3) as AR-regulated mediators of prostate cancer metabolism and growth. ACSM1 and ACSM3 were upregulated in prostate tumors compared to non-malignant tissues and other cancer types. Both enzymes enhanced proliferation and protected prostate cancer cells from death in vitro, while silencing ACSM3 led to reduced tumor growth in an orthotopic xenograft model. ACSM1 and ACSM3 were major regulators of the prostate cancer lipidome and enhanced energy production via fatty acid oxidation. Metabolic dysregulation caused by loss of ACSM1/3 led to mitochondrial oxidative stress, lipid peroxidation and cell death by ferroptosis. Conversely, elevated ACSM1/3 activity enabled prostate cancer cells to survive toxic levels of medium chain fatty acids and promoted resistance to ferroptosis-inducing drugs and AR antagonists. Collectively, this study reveals a tumor-promoting function for medium chain acyl-CoA synthetases and positions ACSM1 and ACSM3 as key players in prostate cancer progression and therapy resistance.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-1489
Cell Rep. 2024 Apr 21. pii: S2211-1247(24)00456-X. [Epub ahead of print]43(5): 114128

Systematic characterization of multi-omics landscape between gut microbial metabolites and GPCRome in Alzheimer's disease.

Yunguang Qiu, Yuan Hou, Dhruv Gohel, Yadi Zhou, Jielin Xu, Marina Bykova, Yuxin Yang, James B Leverenz, Andrew A Pieper, Ruth Nussinov, Jessica Z K Caldwell, J Mark Brown, Feixiong Cheng.

  Shifts in the magnitude and nature of gut microbial metabolites have been implicated in Alzheimer's disease (AD), but the host receptors that sense and respond to these metabolites are largely unknown. Here, we develop a systems biology framework that integrates machine learning and multi-omics to identify molecular relationships of gut microbial metabolites with non-olfactory G-protein-coupled receptors (termed the "GPCRome"). We evaluate 1.09 million metabolite-protein pairs connecting 408 human GPCRs and 335 gut microbial metabolites. Using genetics-derived Mendelian randomization and integrative analyses of human brain transcriptomic and proteomic profiles, we identify orphan GPCRs (i.e., GPR84) as potential drug targets in AD and that triacanthine experimentally activates GPR84. We demonstrate that phenethylamine and agmatine significantly reduce tau hyperphosphorylation (p-tau181 and p-tau205) in AD patient induced pluripotent stem cell-derived neurons. This study demonstrates a systems biology framework to uncover the GPCR targets of human gut microbiota in AD and other complex diseases if broadly applied.

Keywords:  AlphaFold2; Alzheimer's disease; CP: Microbiology; CP: Neuroscience; G-protein-coupled receptors; Mendelian randomization; gut microbial metabolite; gut microbiota; machine learning; metabolite-protein interaction; multi-omics; orphan GPCR

DOI:  https://doi.org/10.1016/j.celrep.2024.114128
J Cell Biol. 2024 Jun 03. pii: e202305010. [Epub ahead of print]223(6):

Mitochondrial sites of contact with the nucleus.

Michelangelo Campanella, Brindha Kannan.

Membrane contact sites (MCS) between mitochondria and the nucleus have been recently described. Termed nucleus associated mitochondria (NAM), they prime the expression of genes required for cellular resistance to stressors, thus offering a tethering mechanism for homeostatic communication. Here, we discuss the composition of NAM and their physiological and pathological significance.

DOI: https://doi.org/10.1083/jcb.202305010
EMBO J. 2024 Apr 22.

SUCLG1 restricts POLRMT succinylation to enhance mitochondrial biogenesis and leukemia progression.

Weiwei Yan, Chengmei Xie, Sijun Sun, Quan Zheng, Jingyi Wang, Zihao Wang, Cheuk-Him Man, Haiyan Wang, Yunfan Yang, Tianshi Wang, Leilei Shi, Shengjie Zhang, Chen Huang, Shuangnian Xu, Yi-Ping Wang.

  Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development.

Keywords:  FMS-like Tyrosine Kinase 3; Lysine Succinylation; Mitochondrial Biogenesis; Mitochondrial RNA Polymerase; Succinate-CoA Ligase

DOI:  https://doi.org/10.1038/s44318-024-00101-9