bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2024–11–24
eightteen papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Impaired branched chain amino acid (BCAA) catabolism during adipocyte differentiation decreases glycolytic flux.
  2. Cold-induced thermogenesis requires neutral-lipase-mediated intracellular lipolysis in brown adipocytes.
  3. Human metabolic chambers reveal a coordinated metabolic-physiologic response to nutrition.
  4. Ablation of FAS confers allogeneic CD3- CAR T cells with resistance to rejection by T cells and natural killer cells.
  5. A pan-family screen of nuclear receptors in immunocytes reveals ligand-dependent inflammasome control.
  6. PDCD6 regulates lactate metabolism to modulate LC3-associated phagocytosis and antibacterial defense.
  7. Liver X receptor unlinks intestinal regeneration and tumorigenesis.
  8. Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.
  9. Exposing 24-hour cycles in bile acids of male humans.
  10. ATP dynamics as a predictor of future podocyte structure and function after acute ischemic kidney injury in female mice.
  11. Spatially restricted immune and microbiota-driven adaptation of the gut.
  12. Nitric Oxide and Mitochondrial Function in Cardiovascular diseases.
  13. Macrophage modulation of tumor immunity.
  14. Cancer cells restrict immunogenicity of retrotransposon expression via distinct mechanisms.
  15. Human monocyte-derived macrophages shift subcellular metalloprotease activity depending on their activation state.
  16. The tumor-neutrophil interactions in the microenvironment of brain metastases with different primary sites.
  17. Single cell and spatial transcriptomics highlight the interaction of club-like cells with immunosuppressive myeloid cells in prostate cancer.
  18. NAD reloaded: Hacking bacterial defenses.
  1. J Biol Chem. 2024 Nov 15. pii: S0021-9258(24)02506-7. [Epub ahead of print] 108004
    Impaired branched chain amino acid (BCAA) catabolism during adipocyte differentiation decreases glycolytic flux.
    Courtney R Green, Lynn M Alaeddine, Karl A Wessendorf-Rodriguez, Rory Turner, Merve Elmastas, Justin D Hover, Anne N Murphy, Mikael Ryden, Niklas Mejhert, Christian M Metallo, Martina Wallace.
      Dysregulated branched chain amino acid (BCAA) metabolism has emerged as a key metabolic feature associated with the obese insulin resistant state, and adipose BCAA catabolism is decreased in this context. BCAA catabolism is upregulated early in adipogenesis, but the impact of suppressing this pathway on the broader metabolic functions of the resultant adipocyte remains unclear. Here, we use CRISPR/Cas9 to decrease BCKDHA in 3T3-L1 and human pre-adipocytes, and ACAD8 in 3T3-L1 pre-adipocytes to induce a deficiency in BCAA catabolism through differentiation. We characterize the transcriptional and metabolic phenotype of 3T1-L1 cells using RNAseq and 13C metabolic flux analysis within a network spanning glycolysis, tricarboxylic acid (TCA) metabolism, BCAA catabolism, and fatty acid synthesis. While lipid droplet accumulation is maintained in Bckdha-deficient adipocytes, they display a more fibroblast-like transcriptional signature. In contrast, Acad8 deficiency minimally impacts gene expression. Decreased glycolytic flux emerges as the most distinct metabolic feature of 3T3-L1 Bckdha-deficient cells, accompanied by a ∼40% decrease in lactate secretion, yet pyruvate oxidation and utilization for de novo lipogenesis are increased to compensate for loss of BCAA carbon. Deletion of BCKDHA in human adipocyte progenitors also led to a decrease in glucose uptake and lactate secretion, however these cells did not upregulate pyruvate utilisation and lipid droplet accumulation and expression of adipocyte differentiation markers was decreased in BCKDH knockout cells. Overall our data suggest that human adipocyte differentiation may be more sensitive to the impact of decreased BCKDH activity than 3T3-L1 cells, and that both metabolic and regulatory cross-talk exists between BCAA catabolism and glycolysis in adipocytes. Suppression of BCAA catabolism associated with metabolic syndrome may result in a metabolically compromised adipocyte.
    Keywords:  adipogenesis; adipose; branched chain amino acids; glycolysis; metabolic flux
    DOI:  https://doi.org/10.1016/j.jbc.2024.108004
  2. Cell Metab. 2024 Nov 13. pii: S1550-4131(24)00414-5. [Epub ahead of print]
    Cold-induced thermogenesis requires neutral-lipase-mediated intracellular lipolysis in brown adipocytes.
    Etienne Mouisel, Anaïs Bodon, Christophe Noll, Stéphanie Cassant-Sourdy, Marie-Adeline Marques, Remy Flores-Flores, Elodie Riant, Camille Bergoglio, Pierre Vezin, Sylvie Caspar-Bauguil, Camille Fournes-Fraresso, Geneviève Tavernier, Khalil Acheikh Ibn Oumar, Pierre Gourdy, Denis P Blondin, Pierre-Damien Denechaud, André C Carpentier, Dominique Langin.
      Long-chain fatty acids (FAs) are the major substrates fueling brown adipose tissue (BAT) thermogenesis. Investigation of mouse models has previously called into question the contribution of brown adipocyte intracellular lipolysis to cold-induced non-shivering thermogenesis. Here, we determined the role of the lipolytic enzymes, adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), in BAT thermogenesis. Brown fat from mice with inducible brown-adipocyte-specific deletion of ATGL and HSL (BAHKO) is hypertrophied with increased lipid droplet size and preserved mitochondria area and density. Maintenance of body temperature during cold exposure is compromised in BAHKO mice in the fasted but not in the fed state. This altered response to cold is observed in various thermal and nutritional conditions. Positron emission tomography-computed tomography using [11C]-acetate and [11C]-palmitate shows abolished cold-induced BAT oxidative activity and impaired FA metabolism in BAHKO mice. Our findings show that brown adipocyte intracellular lipolysis is required for BAT thermogenesis.
    Keywords:  PET/CT; adipose triglyceride lipase; body temperature; brown adipose tissue; hormone-sensitive lipase; lipid droplet; lipolysis; mouse models; obesity; oxidative metabolism; thermogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.018
  3. JCI Insight. 2024 Nov 22. pii: e184279. [Epub ahead of print]9(22):
    Human metabolic chambers reveal a coordinated metabolic-physiologic response to nutrition.
    Andrew S Perry, Paolo Piaggi, Shi Huang, Matthew Nayor, Jane Freedman, Kari E North, Jennifer E Below, Clary B Clish, Venkatesh L Murthy, Jonathan Krakoff, Ravi V Shah.
      Human studies linking metabolism with organism-wide physiologic function have been challenged by confounding, adherence, and precisionHere, we united physiologic and molecular phenotypes of metabolism during controlled dietary intervention to understand integrated metabolic-physiologic responses to nutrition. In an inpatient study of individuals who underwent serial 24-hour metabolic chamber experiments (indirect calorimetry) and metabolite profiling, we mapped a human metabolome onto substrate oxidation rates and energy expenditure across up to 7 dietary conditions (energy balance, fasting, multiple 200% caloric excess overfeeding of varying fat, protein, and carbohydrate composition). Diets exhibiting greater fat oxidation (e.g., fasting, high-fat) were associated with changes in metabolites within pathways of mitochondrial β-oxidation, ketogenesis, adipose tissue fatty acid liberation, and/or multiple anapleurotic substrates for tricarboxylic acid cycle flux, with inverse associations for diets with greater carbohydrate availability. Changes in each of these metabolite classes were strongly related to 24-hour respiratory quotient (RQ) and substrate oxidation rates (e.g., acylcarnitines related to lower 24-hour RQ and higher 24-hour lipid oxidation), underscoring links between substrate availability, physiology, and metabolism in humans. Physiologic responses to diet determined by gold-standard human metabolic chambers are strongly coordinated with biologically consistent, interconnected metabolic pathways encoded in the metabolome.
    Keywords:  Amino acid metabolism; Carbohydrate metabolism; Intermediary metabolism; Metabolism
    DOI:  https://doi.org/10.1172/jci.insight.184279
  4. Nat Biomed Eng. 2024 Nov 18.
    Ablation of FAS confers allogeneic CD3- CAR T cells with resistance to rejection by T cells and natural killer cells.
    Silvia Menegatti, Sheila Lopez-Cobo, Aurelien Sutra Del Galy, Jaime Fuentealba, Lisseth Silva, Laetitia Perrin, Sandrine Heurtebise-Chrétien, Valentine Pottez-Jouatte, Aurelie Darbois, Nina Burgdorf, Anne-Laure Privat, Albane Simon, Marguerite Laprie-Sentenac, Michael Saitakis, Bryce Wick, Beau R Webber, Branden S Moriarity, Olivier Lantz, Sebastian Amigorena, Laurie Menger.
      Allogeneic chimaeric antigen receptor T cells (allo-CAR T cells) derived from healthy donors could provide rapid access to standardized and affordable batches of therapeutic cells if their rejection by the host's immune system is avoided. Here, by means of an in vivo genome-wide CRISPR knockout screen, we show that the deletion of Fas or B2m in allo- T cells increases their survival in immunocompetent mice. Human B2M- allo-CAR T cells become highly sensitive to rejection mediated by natural killer (NK) cells, whereas FAS- CAR T cells expressing normal levels of human leukocyte antigen I remain resistant to NK cells. CD3- FAS- CAR T cells outperformed CD3- B2M- CAR T cells in the control of leukaemia growth in mice under allogeneic pressure by T cells and NK cells. The partial protection of CD3- FAS- allo-CAR T cells from cellular rejection may improve the efficacy of allogeneic cellular therapies in patients with cancer.
    DOI:  https://doi.org/10.1038/s41551-024-01282-8
  5. Immunity. 2024 Nov 14. pii: S1074-7613(24)00490-4. [Epub ahead of print]
    A pan-family screen of nuclear receptors in immunocytes reveals ligand-dependent inflammasome control.
    Yutao Wang, Yanbo Zhang, Kyungsub Kim, Jichang Han, Daniel Okin, Zhaozhao Jiang, Liang Yang, Arum Subramaniam, Terry K Means, Frank O Nestlé, Katherine A Fitzgerald, Gwendalyn J Randolph, Cammie F Lesser, Jonathan C Kagan, Diane Mathis, Christophe Benoist.
      Ligand-dependent transcription factors of the nuclear receptor (NR) family regulate diverse aspects of metazoan biology, enabling communications between distant organs via small lipophilic molecules. Here, we examined the impact of each of 35 NRs on differentiation and homeostatic maintenance of all major immunological cell types in vivo through a "Rainbow-CRISPR" screen. Receptors for retinoic acid exerted the most frequent cell-specific roles. NR requirements varied for resident macrophages of different tissues. Deletion of either Rxra or Rarg reduced frequencies of GATA6+ large peritoneal macrophages (LPMs). Retinoid X receptor alpha (RXRα) functioned conventionally by orchestrating LPM differentiation through chromatin and transcriptional regulation, whereas retinoic acid receptor gamma (RARγ) controlled LPM survival by regulating pyroptosis via association with the inflammasome adaptor ASC. RARγ antagonists activated caspases, and RARγ agonists inhibited cell death induced by several inflammasome activators. Our findings provide a broad view of NR function in the immune system and reveal a noncanonical role for a retinoid receptor in modulating inflammasome pathways.
    DOI:  https://doi.org/10.1016/j.immuni.2024.10.010
  6. Nat Commun. 2024 Nov 23. 15(1): 10157
    PDCD6 regulates lactate metabolism to modulate LC3-associated phagocytosis and antibacterial defense.
    Lulu Sun, Sijin Wu, Hui Wang, Tianyu Zhang, Mengyu Zhang, Xuepeng Bai, Xiumei Zhang, Bingqing Li, Cai Zhang, Yan Li, Jun Zhou, Tianliang Li.
      LC3-associated phagocytosis (LAP) is critical in host defense against invading pathogens, but the molecular mechanism for LAP activation is still unclear. Here, we find programmed cell death 6 (PDCD6) as a negative regulator of LAP. PDCD6 deficiency in mice and macrophages induces enhanced bactericidal activity and LAP formation. In parallel, lactate dehydrogenase A (LDHA) activity and lactate production is induced in macrophages challenged with bacteria, Zymosan or Pam3CSK4, while genetic ablation or pharmacological inhibition of LDHA reduces lactate levels and impairs bactericidal activity in vivo and in vitro. Mechanistically, PDCD6 interacts with LDHA to downregulate lactate metabolism, leading to reduced RUBCN lactylation at lysine33 (K33). By contrast, PDCD6-deficiency increases RUBCN lactylation, thereby promotes RUBCN interaction with VPS34, LAP formation, and protective responses. Our results thus suggest a PDCD6-LDHA-lactate-RUBCN axis of innate immunity regulation that may both contribute to protection from infectious diseases and serve as targets for therapeutic development.
    DOI:  https://doi.org/10.1038/s41467-024-54377-w
  7. Nature. 2024 Nov 20.
    Liver X receptor unlinks intestinal regeneration and tumorigenesis.
    Srustidhar Das, S Martina Parigi, Xinxin Luo, Jennifer Fransson, Bianca C Kern, Ali Okhovat, Oscar E Diaz, Chiara Sorini, Paulo Czarnewski, Anna T Webb, Rodrigo A Morales, Sacha Lebon, Gustavo Monasterio, Francisca Castillo, Kumar P Tripathi, Ning He, Penelope Pelczar, Nicola Schaltenberg, Marjorie De la Fuente, Francisco López-Köstner, Susanne Nylén, Hjalte List Larsen, Raoul Kuiper, Per Antonson, Marcela A Hermoso, Samuel Huber, Moshe Biton, Sandra Scharaw, Jan-Åke Gustafsson, Pekka Katajisto, Eduardo J Villablanca.
      Uncontrolled regeneration leads to neoplastic transformation1-3. The intestinal epithelium requires precise regulation during continuous homeostatic and damage-induced tissue renewal to prevent neoplastic transformation, suggesting that pathways unlinking tumour growth from regenerative processes must exist. Here, by mining RNA-sequencing datasets from two intestinal damage models4,5 and using pharmacological, transcriptomics and genetic tools, we identified liver X receptor (LXR) pathway activation as a tissue adaptation to damage that reciprocally regulates intestinal regeneration and tumorigenesis. Using single-cell RNA sequencing, intestinal organoids, and gain- and loss-of-function experiments, we demonstrate that LXR activation in intestinal epithelial cells induces amphiregulin (Areg), enhancing regenerative responses. This response is coordinated by the LXR-ligand-producing enzyme CYP27A1, which was upregulated in damaged intestinal crypt niches. Deletion of Cyp27a1 impaired intestinal regeneration, which was rescued by exogenous LXR agonists. Notably, in tumour models, Cyp27a1 deficiency led to increased tumour growth, whereas LXR activation elicited anti-tumour responses dependent on adaptive immunity. Consistently, human colorectal cancer specimens exhibited reduced levels of CYP27A1, LXR target genes, and B and CD8 T cell gene signatures. We therefore identify an epithelial adaptation mechanism to damage, whereby LXR functions as a rheostat, promoting tissue repair while limiting tumorigenesis.
    DOI:  https://doi.org/10.1038/s41586-024-08247-6
  8. J Clin Invest. 2024 Nov 19. pii: e177824. [Epub ahead of print]
    Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.
    Kristen E Kay, Juyeun Lee, Ellen S Hong, Julia Beilis, Sahil Dayal, Emily R Wesley, Sofia Mitchell, Sabrina Z Wang, Daniel J Silver, Josephine Volovetz, Sarah Johnson, Mary McGraw, Matthew Grabowski, Tianyao Lu, Lutz Freytag, Vinod K Narayana, Saskia Freytag, Sarah A Best, James R Whittle, Zeneng Wang, Ofer Reizes, Jennifer S Yu, Stanley L Hazen, J Mark Brown, Defne Bayik, Justin Lathia.
      The glioblastoma (GBM) microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine (SPD) is elevated in the GBM tumor microenvironment. Exogenous administration of SPD drives tumor aggressiveness in an immune-dependent manner in pre-clinical mouse models via reduction of CD8+ T cell frequency and reduced cytotoxic function. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in spermidine synthesis, did not impact cancer cell growth in vitro but did result in extended survival. Furthermore, glioblastoma patients with a more favorable outcome had a significant reduction in spermidine compared to patients with a poor prognosis. Our results demonstrate that spermidine functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+ T cell number and function.
    Keywords:  Adaptive immunity; Brain cancer; Immunology; Oncology; Polyamines
    DOI:  https://doi.org/10.1172/JCI177824
  9. Nat Commun. 2024 Nov 19. 15(1): 10014
    Exposing 24-hour cycles in bile acids of male humans.
    Adesola T Bello, Magali H Sarafian, Elizabeth A Wimborne, Benita Middleton, Victoria L Revell, Florence I Raynaud, Namrata R Chowdhury, Daan R van der Veen, Debra J Skene, Jonathan R Swann.
      Bile acids are trans-genomic molecules arising from the concerted metabolism of the human host and the intestinal microbiota and are important for digestion, energy homeostasis and metabolic regulation. While diurnal variation has been demonstrated in the enterohepatic circulation and the gut microbiota, existing human data are poorly resolved, and the influence of the host circadian system has not been determined. Using entrained laboratory protocols, we demonstrate robust daily rhythms in the circulating bile acid pool in healthy male participants. We identify temporal relationships between bile acids and plasma lipids and show that these relationships are lost following sleep deprivation. We also highlight that bile acid rhythmicity is predominantly lost when environmental timing cues are held constant. Here we show that the environment is a stronger determinant of these temporal dynamics than the intrinsic circadian system of the host. This has significance for the intimate relationship between circadian timing and metabolism.
    DOI:  https://doi.org/10.1038/s41467-024-53673-9
  10. Nat Commun. 2024 Nov 22. 15(1): 9977
    ATP dynamics as a predictor of future podocyte structure and function after acute ischemic kidney injury in female mice.
    Masahiro Takahashi, Shinya Yamamoto, Shigenori Yamamoto, Akihiro Okubo, Yasuaki Nakagawa, Koichiro Kuwahara, Taiji Matsusaka, Shingo Fukuma, Masamichi Yamamoto, Michiyuki Matsuda, Motoko Yanagita.
      Acute kidney injury (AKI), typically caused by ischemia, is a common clinical complication with a poor prognosis. Although proteinuria is an important prognostic indicator of AKI, the underlying causal mechanism remains unclear. In vitro studies suggest that podocytes have high ATP demands to maintain their structure and function, however, analyzing their ATP dynamics in living kidneys has been technically challenging. Here, using intravital imaging to visualize a FRET-based ATP biosensor expressed systemically in female mice due to their suitability for glomerular imaging, we monitor the in vivo ATP dynamics in podocytes during ischemia reperfusion injury. ATP levels decrease during ischemia, but recover after reperfusion in podocytes, exhibiting better recovery than in glomerular endothelial cells. However, prolonged ischemia results in insufficient ATP recovery in podocytes, which is inversely correlated with mitochondrial fragmentation and foot process effacement during the chronic phase. Furthermore, preventing mitochondrial fission via pharmacological inhibition ameliorates podocyte injury in vitro, ex vivo, and in vivo. Thus, these findings provide several insights into how ATP depletion and mitochondrial fragmentation contribute to podocyte injury after ischemic AKI and could potentially be therapeutic targets.
    DOI:  https://doi.org/10.1038/s41467-024-54222-0
  11. Nature. 2024 Nov 20.
    Spatially restricted immune and microbiota-driven adaptation of the gut.
    Toufic Mayassi, Chenhao Li, Åsa Segerstolpe, Eric M Brown, Rebecca Weisberg, Toru Nakata, Hiroshi Yano, Paula Herbst, David Artis, Daniel B Graham, Ramnik J Xavier.
      The intestine is characterized by an environment in which host requirements for nutrient and water absorption are consequently paired with the requirements to establish tolerance to the outside environment. To better understand how the intestine functions in health and disease, large efforts have been made to characterize the identity and composition of cells from different intestinal regions1-8. However, the robustness, nature of adaptability and extent of resilience of the transcriptional landscape and cellular underpinning of the intestine in space are still poorly understood. Here we generated an integrated resource of the spatial and cellular landscape of the murine intestine in the steady and perturbed states. Leveraging these data, we demonstrated that the spatial landscape of the intestine was robust to the influence of the microbiota and was adaptable in a spatially restricted manner. Deploying a model of spatiotemporal acute inflammation, we demonstrated that both robust and adaptable features of the landscape were resilient. Moreover, highlighting the physiological relevance and value of our dataset, we identified a region of the middle colon characterized by an immune-driven multicellular spatial adaptation of structural cells to the microbiota. Our results demonstrate that intestinal regionalization is characterized by robust and resilient structural cell states and that the intestine can adapt to environmental stress in a spatially controlled manner through the crosstalk between immunity and structural cell homeostasis.
    DOI:  https://doi.org/10.1038/s41586-024-08216-z
  12. Nitric Oxide. 2024 Nov 20. pii: S1089-8603(24)00150-2. [Epub ahead of print]
    Nitric Oxide and Mitochondrial Function in Cardiovascular diseases.
    Haoqi Li, Zijie Cheng, Dan Wu, Qingxun Hu.
      Nitric oxide (NO) has been highlighted as an important factor in cardiovascular system. As a signaling molecule in the cardiovascular system, NO can relax blood vessels, lower blood pressure, and prevent platelet aggregation. Mitochondria serve as a central hub for cellular metabolism and intracellular signaling, and their dysfunction can lead to a variety of diseases. Accumulating evidence suggests that NO can act as a regulator of mitochondria, affecting mitochondrial function and cellular activity, which in turn mediates the onset and progression of disease. However, there is a lack of comprehensive understanding of how NO regulates mitochondrial function in the cardiovascular system. This review aims to summarize the regulation of mitochondrial function by nitric oxide in cardiovascular related diseases, as well as the multifaceted and complex roles of NO in the cardiovascular system. Understanding the mechanism of NO mediated mitochondrial function can provide new insights for the prevention and treatment of cardiovascular diseases.
    Keywords:  Cardiovascular diseases; Mitochondria; Nitric oxide; cell metabolism
    DOI:  https://doi.org/10.1016/j.niox.2024.11.007
  13. Science. 2024 Nov 22. 386(6724): 850-851
    Macrophage modulation of tumor immunity.
    Peter Savage.
      Macrophages deliver polarizing messages to promote immune suppression in tumors.
    DOI:  https://doi.org/10.1126/science.adt5661
  14. Immunity. 2024 Nov 20. pii: S1074-7613(24)00494-1. [Epub ahead of print]
    Cancer cells restrict immunogenicity of retrotransposon expression via distinct mechanisms.
    Siyu Sun, Eunae You, Jungeui Hong, David Hoyos, Isabella S Del Priore, Kaloyan M Tsanov, Om Mattagajasingh, Andrea Di Gioacchino, Sajid A Marhon, Jonathan Chacon-Barahona, Hao Li, Hua Jiang, Samira Hozeifi, Omar Rosas-Bringas, Katherine H Xu, Yuhui Song, Evan R Lang, Alexandra S Rojas, Linda T Nieman, Bidish K Patel, Rajmohan Murali, Pharto Chanda, Ali Karacay, Nicolas Vabret, Daniel D De Carvalho, Daniel Zenklusen, John LaCava, Scott W Lowe, David T Ting, Christine A Iacobuzio-Donahue, Alexander Solovyov, Benjamin D Greenbaum.
      To thrive, cancer cells must navigate acute inflammatory signaling accompanying oncogenic transformation, such as via overexpression of repeat elements. We examined the relationship between immunostimulatory repeat expression, tumor evolution, and the tumor-immune microenvironment. Integration of multimodal data from a cohort of pancreatic ductal adenocarcinoma (PDAC) patients revealed expression of specific Alu repeats predicted to form double-stranded RNAs (dsRNAs) and trigger retinoic-acid-inducible gene I (RIG-I)-like-receptor (RLR)-associated type-I interferon (IFN) signaling. Such Alu-derived dsRNAs also anti-correlated with pro-tumorigenic macrophage infiltration in late stage tumors. We defined two complementary pathways whereby PDAC may adapt to such anti-tumorigenic signaling. In mutant TP53 tumors, ORF1p from long interspersed nuclear element (LINE)-1 preferentially binds Alus and decreases their expression, whereas adenosine deaminases acting on RNA 1 (ADAR1) editing primarily reduces dsRNA formation in wild-type TP53 tumors. Depletion of either LINE-1 ORF1p or ADAR1 reduced tumor growth in vitro. The fact that tumors utilize multiple pathways to mitigate immunostimulatory repeats implies the stress from their expression is a fundamental phenomenon to which PDAC, and likely other tumors, adapt.
    Keywords:  ADAR1; Tp53; cancer evolution; cancer immunity; inverted Alus; retrotransposons; tumor-immune microenvironment
    DOI:  https://doi.org/10.1016/j.immuni.2024.10.015
  15. iScience. 2024 Nov 15. 27(11): 111171
    Human monocyte-derived macrophages shift subcellular metalloprotease activity depending on their activation state.
    Eline Bernaerts, Kourosh Ahmadzadeh, Amber De Visscher, Bert Malengier-Devlies, Daniel Häuβler, Tania Mitera, Erik Martens, Achim Krüger, Lien De Somer, Patrick Matthys, Jennifer Vandooren.
      Proteases are key effectors in macrophage function during the initiation and resolution of inflammation. Recent studies have shown that some proteases, traditionally considered extracellular, also exhibit enzymatic and non-enzymatic functions within the cell. This study explores the differential protease landscapes of macrophages based on their phenotype. Human monocytes were isolated from healthy volunteers and stimulated with M-CSF (resting macrophages), LPS/IFN-γ (inflammatory macrophages), or IL-4 (immunosuppressive macrophages). IL-4-stimulated macrophages secreted higher levels of MMPs and natural protease inhibitors compared to LPS/IFN-γ-stimulated macrophages. Increased extracellular proteolytic activity was detected in LPS/IFN-γ-stimulated macrophages while IL-4 stimulation increased cell-associated proteolytic activity, particularly for MMPs. Subcellular fractionation and confocal microscopy revealed the uptake of extracellular MMP-9 and its relocation to the nucleus in IL-4-stimulated, though not in LPS/IFN-γ-stimulated macrophages. Collectively, macrophages alter the subcellular location and activity of their MMPs based on the stimuli received, suggesting another mechanism for protease regulation in macrophage biology.
    Keywords:  Biological sciences; Immune response; Immunology; Natural sciences
    DOI:  https://doi.org/10.1016/j.isci.2024.111171
  16. J Leukoc Biol. 2024 Nov 20. pii: qiae248. [Epub ahead of print]
    The tumor-neutrophil interactions in the microenvironment of brain metastases with different primary sites.
    Tamer A Kaya, Klaus-Peter Stein, Anna Schaufler, Belal Neyazi, Ali Rashidi, Ulf D Kahlert, Christian Mawrin, I Erol Sandalcioglu, Claudia A Dumitru.
      Brain metastases (BrM) originating from lung and breast cancer can recruit and activate neutrophils to acquire a tumor-promoting phenotype. It is currently unclear if this phenomenon also occurs in BrM arising from other primary sites. Here, we investigated the effect of tumor cells isolated from melanoma, lung and gastrointestinal (GI) cancer BrM on neutrophil biology and functions. We found that lung and GI, but not melanoma BrM cells produced CXCL8/IL-8, and promoted neutrophil recruitment. Similarly, lung and GI, but not melanoma BrM cells, prolonged the survival of neutrophils, and stimulated them to release MMP9 and CCL4/MIP1β. In situ, lung and GI BrM tissues contained significantly higher numbers of tumor-infiltrating neutrophils compared to melanoma BrM. The levels of neutrophil infiltration significantly correlated with the proliferation index of these tumors. Our findings identify variabilities in the immune microenvironment of BrM with different primary sites, which may ultimately affect their pathophysiology and progression.
    Keywords:  brain metastases; histologic origin; neutrophils; tumor proliferation
    DOI:  https://doi.org/10.1093/jleuko/qiae248
  17. Nat Commun. 2024 Nov 16. 15(1): 9949
    Single cell and spatial transcriptomics highlight the interaction of club-like cells with immunosuppressive myeloid cells in prostate cancer.
    Antti Kiviaho, Sini K Eerola, Heini M L Kallio, Maria K Andersen, Miina Hoikka, Aliisa M Tiihonen, Iida Salonen, Xander Spotbeen, Alexander Giesen, Charles T A Parker, Sinja Taavitsainen, Olli Hantula, Mikael Marttinen, Ismaïl Hermelo, Mazlina Ismail, Elise Midtbust, Maximilian Wess, Wout Devlies, Abhibhav Sharma, Sebastian Krossa, Tomi Häkkinen, Ebrahim Afyounian, Katy Vandereyken, Sam Kint, Juha Kesseli, Teemu Tolonen, Teuvo L J Tammela, Trond Viset, Øystein Størkersen, Guro F Giskeødegård, Morten B Rye, Teemu Murtola, Andrew Erickson, Leena Latonen, G Steven Bova, Ian G Mills, Steven Joniau, Johannes V Swinnen, Thierry Voet, Tuomas Mirtti, Gerhardt Attard, Frank Claessens, Tapio Visakorpi, Kirsi J Rautajoki, May-Britt Tessem, Alfonso Urbanucci, Matti Nykter.
      Prostate cancer treatment resistance is a significant challenge facing the field. Genomic and transcriptomic profiling have partially elucidated the mechanisms through which cancer cells escape treatment, but their relation toward the tumor microenvironment (TME) remains elusive. Here we present a comprehensive transcriptomic landscape of the prostate TME at multiple points in the standard treatment timeline employing single-cell RNA-sequencing and spatial transcriptomics data from 120 patients. We identify club-like cells as a key epithelial cell subtype that acts as an interface between the prostate and the immune system. Tissue areas enriched with club-like cells have depleted androgen signaling and upregulated expression of luminal progenitor cell markers. Club-like cells display a senescence-associated secretory phenotype and their presence is linked to increased polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) activity. Our results indicate that club-like cells are associated with myeloid inflammation previously linked to androgen deprivation therapy resistance, providing a rationale for their therapeutic targeting.
    DOI:  https://doi.org/10.1038/s41467-024-54364-1
  18. Cell Chem Biol. 2024 Nov 21. pii: S2451-9456(24)00451-3. [Epub ahead of print]31(11): 1872-1873
    NAD reloaded: Hacking bacterial defenses.
    Arturo Carabias, Guillermo Montoya.
      Nicotinamide adenine dinucleotide (NAD) is an essential metabolite, and its depletion serves as a common bacterial immune strategy against bacteriophages (phages). In a recent issue of Nature, Osterman et al.1 reveal two phage-encoded NAD restoration pathways, showcasing the phages' innovative counterstrategies against bacterial immunity and providing insights for developing novel antimicrobial approaches.
    DOI:  https://doi.org/10.1016/j.chembiol.2024.10.012
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