bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2024‒07‒28
39 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. Coexisting mechanisms of luminogenesis in pancreatic cancer-derived organoids.
  2. Scribble Deficiency Promotes Pancreatic Ductal Adenocarcinoma Development and Metastasis.
  3. 100 years of the Warburg effect: A cancer metabolism endeavor.
  4. A Live Tracker of Dormant Disseminated Tumor Cells.
  5. Power-law growth models explain incidences and sizes of pancreatic cancer precursor lesions and confirm spatial genomic findings.
  6. MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer.
  7. Low dose orthotopic cancer implantation permits measurement of longitudinal functional changes associated with cachexia.
  8. 13C Tracer Analysis and Metabolomics in Dormant Cancer Cells.
  9. Molecular mechanisms of cancer cachexia. Role of exercise training.
  10. Non-invasive optoacoustic imaging of dermal microcirculatory revascularization in diet-induced obese mice undergoing exercise intervention.
  11. Investigation of a fluorescent reporter microenvironment niche labeling strategy in experimental brain metastasis.
  12. Mechanisms of lipid droplet degradation.
  13. Exploiting the tumor microenvironment and tumor mechanobiology for the treatment of cancer cachexia.
  14. Alterations of ceramide synthesis induce PD-L1 internalization and signaling to regulate tumor metastasis and immunotherapy response.
  15. Cryo-EM architecture of a near-native stretch-sensitive membrane microdomain.
  16. Protocol for the characterization of the pancreatic tumor microenvironment using organoid-derived mouse models and single-nuclei RNA sequencing.
  17. Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice.
  18. Sensory neurons: unveiling the symphony of wound healing.
  19. MetalinksDB: a flexible and contextualizable resource of metabolite-protein interactions.
  20. Connexin43 promotes exocytosis of damaged lysosomes through actin remodelling.
  21. Therapy-induced senescent tumor cells in cancer relapse.
  22. Challenges of Spatially Resolved Metabolism in Cancer Research.
  23. Overcoming underestimation of the association of excess weight with pancreatic cancer due to prediagnostic weight loss: Umbrella review of systematic reviews, meta-analyses, and pooled-analyses.
  24. In vivo interaction screening reveals liver-derived constraints to metastasis.
  25. Patient-derived organoids (PDOs) and PDO-derived xenografts (PDOXs): New opportunities in establishing faithful pre-clinical cancer models.
  26. Side-chain-engineered fluorescent dyes for 3D and long-term dynamic tracking of the plasma membrane in living cells.
  27. Integrating bioengineering, super-resolution microscopy and mechanobiology in autophagy research: addendum to the guidelines (4th edition).
  28. Correlative Raman Imaging: Development and Cancer Applications.
  29. Modeling Tumor Cell Dormancy in an Ex Vivo Liver Metastatic Niche.
  30. Decoding ribosome complexity: role of ribosomal proteins in cancer and disease.
  31. Barcoding distinct neurons.
  32. AFDN deficiency promotes liver tropism of metastatic colorectal cancer.
  33. SLC25A48 influences plasma levels of choline and localizes to the inner mitochondrial membrane.
  34. Phospholipid biosynthesis modulates nucleotide metabolism and reductive capacity.
  35. A Fast-Tracking Sample Preparation Protocol for Proteomics of Formalin-Fixed Paraffin-Embedded Tumor Tissues.
  36. The HuMet Repository: Watching human metabolism at work.
  37. Comparative analyses of gene networks mediating cancer metastatic potentials across lineage types.
  38. Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression.
  39. Lipids and chromatin: a tale of intriguing connections shaping genomic landscapes.
  1. iScience. 2024 Jul 19. 27(7): 110299
    Coexisting mechanisms of luminogenesis in pancreatic cancer-derived organoids.
    Samuel J Randriamanantsoa, Marion K Raich, Dieter Saur, Maximilian Reichert, Andreas R Bausch.
      Lumens are crucial features of the tissue architecture in both the healthy exocrine pancreas, where ducts shuttle enzymes from the acini to the intestine, and in the precancerous lesions of the highly lethal pancreatic ductal adenocarcinoma (PDAC), similarly displaying lumens that can further develop into cyst-like structures. Branched pancreatic-cancer derived organoids capture key architectural features of both the healthy and diseased pancreas, including lumens. However, their transition from a solid mass of cells to a hollow tissue remains insufficiently explored. Here, we show that organoids display two orthogonal but complementary lumen formation mechanisms: one relying on fluid intake for multiple microlumen nucleation, swelling and fusion, and the other involving the death of a central cell population, thereby hollowing out cavities. These results shed further light on the processes of luminogenesis, deepening our understanding of the early formation of PDAC precancerous lesions, including cystic neoplasia.
    Keywords:  Biological sciences; Cancer; Cell biology; Morphogenesis; Organoids
    DOI:  https://doi.org/10.1016/j.isci.2024.110299
  2. Cancer Res. 2024 Jul 22.
    Scribble Deficiency Promotes Pancreatic Ductal Adenocarcinoma Development and Metastasis.
    Camino Bermejo-Rodriguez, Joaquín Araos Henríquez, Giuseppina Caligiuri, Sara Pinto Teles, Youngkyu Park, Anthony Evans, Lawrence N Barrera, Albrecht Neesse, Robert Grutzmann, Daniela Aust, Petra Rümmele, Thomas Knösel, Masako Narita, Masashi Narita, Fiona Campbell, Daniel Öhlund, Christian Pilarsky, Lukas E Dow, Patrick O Humbert, Giulia Biffi, David A Tuveson, Pedro A Perez-Mancera.
      Perturbation of cell polarity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) progression. Scribble (SCRIB) is a well characterized polarity regulator that has diverse roles in the pathogenesis of human neoplasms. To investigate the impact of SCRIB deficiency on PDAC development and progression, Scrib was genetically ablated in well-established mouse models of PDAC. Scrib loss in combination with KrasG12D did not influence development of pancreatic intraepithelial neoplasms (PanIN) in mice. However, Scrib deletion cooperated with KrasG12D and concomitant Trp53 heterozygous deletion to promote invasive PDAC and metastatic dissemination, leading to reduced overall survival. Immunohistochemical and transcriptome analyses revealed that Scrib-null tumors display a pronounced reduction of collagen content and cancer associated fibroblast (CAF) abundance. Mechanistically, interleukin 1α (IL1α) levels were reduced in Scrib deficient tumors, and Scrib knockdown downregulated IL1α in mouse PDAC organoids (mPDOs), which impaired CAF activation. Furthermore, Scrib loss increased YAP activation in mPDOs and established PDAC cell lines, enhancing cell survival. Clinically, SCRIB expression was decreased in human PDAC, and SCRIB mislocalization was associated with poorer patient outcome. These results indicate that SCRIB deficiency enhances cancer cell survival and remodels the tumor microenvironment to accelerate PDAC development and progression, establishing the tumor suppressor function of SCRIB in advanced pancreatic cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3419
  3. Cell. 2024 Jul 25. pii: S0092-8674(24)00700-1. [Epub ahead of print]187(15): 3824-3828
    100 years of the Warburg effect: A cancer metabolism endeavor.
    Sarah-Maria Fendt.
      If you are a scientist and you only know one thing about tumor metabolism, it's likely the Warburg effect. But who was Otto Warburg, and how did his discoveries regarding the metabolism of tumors shape our current thinking about the metabolic needs of cancer cells?
    DOI:  https://doi.org/10.1016/j.cell.2024.06.026
  4. Methods Mol Biol. 2024 ;2811 155-164
    A Live Tracker of Dormant Disseminated Tumor Cells.
    Francisco Landum, Ana Luísa Correia.
      The high prevalence of dormant disseminated tumor cells (DTCs) persisting systemically in patients with metastatic cancer is a major threat to long-lasting cure (Aguirre-Ghiso, Nat Rev Cancer 7:834-846, 2007; Klein, Nat Rev Cancer 20(11):681-694, 2020; Lyden et al. Cancer Cell 40:787-791, 2022). Despite its clinical significance, the study of what drives DTCs in and out of dormancy while they linger in distant sites has been challenged by the lack of tools to find and follow dormant DTCs inside a living organism. Here, leveraging the fact that dormant DTCs are mostly quiescent, we describe a live cell reporter to distinguish dormant from cycling DTCs (Correia, Nat Rev Cancer 22(7):379, 2022; Correia et al. Nature 594(7864):566-571, 2021). Cancer cell lines are engineered to coexpress a luciferase-tdTomato reporter and a fluorescent fusion protein of mVenus with a mutant form of the cell cycle inhibitor p27 (mVenus-p27K-) that identifies quiescent cells. When implanted in animal models or assembled in cocultures in vitro, labeled cells can be imaged longitudinally over time or retrieved alive alongside their surrounding microenvironment for downstream gene, protein, and metabolite profiling, allowing the mapping of tissue-specific determinants of cancer dormancy and metastasis.
    Keywords:  Cancer Dormancy; Disseminated tumor cells; Dormancy live tracker; Metastasis
    DOI:  https://doi.org/10.1007/978-1-0716-3882-8_11
  5. Sci Adv. 2024 Jul 26. 10(30): eado5103
    Power-law growth models explain incidences and sizes of pancreatic cancer precursor lesions and confirm spatial genomic findings.
    Ashley L Kiemen, Pei-Hsun Wu, Alicia M Braxton, Toby C Cornish, Ralph H Hruban, Laura D Wood, Denis Wirtz, David Zwicker.
      Pancreatic ductal adenocarcinoma is a rare but lethal cancer. Recent evidence suggests that pancreatic intraepithelial neoplasia (PanIN), a microscopic precursor lesion that gives rise to pancreatic cancer, is larger and more prevalent than previously believed. Better understanding of the growth-law dynamics of PanINs may improve our ability to understand how a miniscule fraction makes the transition to invasive cancer. Here, using three-dimensional tissue mapping, we analyzed >1000 PanINs and found that lesion size is distributed according to a power law. Our data suggest that in bulk, PanIN size can be predicted by general growth behavior without consideration for the heterogeneity of the pancreatic microenvironment or an individual's age, history, or lifestyle. Our models suggest that intraductal spread and fusing of lesions drive our observed size distribution. This analysis lays the groundwork for future mathematical modeling efforts integrating PanIN incidence, morphology, and molecular features to understand tumorigenesis and demonstrates the utility of combining experimental measurement with dynamic modeling in understanding tumorigenesis.
    DOI:  https://doi.org/10.1126/sciadv.ado5103
  6. Cancer Discov. 2024 Jul 26.
    MARK2/MARK3 kinases are catalytic co-dependencies of YAP/TAZ in human cancer.
    Olaf Klingbeil, Damianos Skopelitis, Claudia Tonelli, Toyoki Yoshimoto, Aktan Alpsoy, Maria C Panepinto, Francesca Minicozzi, Joseph R Merrill, Amanda M Cafiero, Disha Aggarwal, Suzanne Russo, Taehoon Ha, Osama E Demerdash, Tse-Luen Wee, David L Spector, Scott K Lyons, David A Tuveson, Paolo Cifani, Christopher R Vakoc.
      The Hippo signaling pathway is commonly dysregulated in human cancer, which leads to a powerful tumor dependency on the YAP/TAZ transcriptional coactivators. Here, we used paralog co-targeting CRISPR screens to identify the kinases MARK2/3 as absolute catalytic requirements for YAP/TAZ function in diverse carcinoma and sarcoma contexts. Underlying this observation is direct MARK2/3-dependent phosphorylation of NF2 and YAP/TAZ, which effectively reverses the tumor suppressive activity of the Hippo module kinases LATS1/2. To simulate targeting of MARK2/3, we adapted the CagA protein from H. pylori as a catalytic inhibitor of MARK2/3, which we show can regress established tumors in vivo. Together, these findings reveal MARK2/3 as powerful co-dependencies of YAP/TAZ in human cancer; targets that may allow for pharmacology that restores Hippo pathway-mediated tumor suppression.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1529
  7. J Appl Physiol (1985). 2024 Jul 25.
    Low dose orthotopic cancer implantation permits measurement of longitudinal functional changes associated with cachexia.
    Ishan Roy, Ben Binder-Markey, Amber Willbanks, Danielle Sychowski, Tenisha Phipps, Addison Barber, Donna McAllister, Dominic D'Andrea, Colin Franz, Rajeswari Pichika, Michael B Dwinell, Richard L Lieber.
      BACKGROUND: Progressive functional decline is a key element of cancer-associated cachexia. Major barriers to translating pre-clinical therapies into the clinic include lack of cancer models that accurately mimic functional decline, which develops over time, and use of non-specific measures, like grip strength, as surrogates for physical function. In this study, we aimed to extend the survival and longevity of a cancer model, in order to investigate cachexia-related function at the basic science level.METHODS: Survival extension studies were performed by testing multiple cell lines, dilutions, and vehicle-types in orthotopic implantation of K-rasLSL.G12D/+; Trp53R172H/+; Pdx-1-Cre (KPC) derived cells. 128 animals in this new model were assessed for cachexia syndrome phenotype using a battery of anatomical, biochemical, and behavioral techniques.
    RESULTS: We extended the survival of the KPC orthotopic model to 8-9 weeks post-implantation using a relatively low 100-cell dose of DT10022 KPC cells (p<0.001). In this Low-dose Orthotopic (LO) model, progressive muscle wasting was detected in parallel to systemic inflammation; skeletal muscle atrophy at the fiber level was detected as early as 3 weeks post-implantation compared to controls (p<0.001). Gait speed in LO animals declined as early 2-weeks post-implantation while grip strength change was a late event. Principle component and regression analyses revealed distinct cachectic and non-cachectic animal populations, which we leveraged to show that the gait speed decline was specific to cachexia (p<0.01) while grip strength decline was not (p=0.19).
    CONCLUSION: Gait speed represents an accurate surrogate for cachexia related physical function as opposed to grip strength.
    Keywords:  Rehabilitation; muscles; pancreatic neoplasm; physical functional performance
    DOI:  https://doi.org/10.1152/japplphysiol.00173.2024
  8. Methods Mol Biol. 2024 ;2811 195-206
    13C Tracer Analysis and Metabolomics in Dormant Cancer Cells.
    Patricia Altea-Manzano, Sarah-Maria Fendt, Laura Vera-Ramirez.
      Over the last two decades, major advances in the field of tumor dormancy have been made. Yet, it is not completely understood how dormant disseminated tumor cells survive and transition to a proliferative state to generate a metastatic lesion. On the other hand, metabolic rewiring has been shown to influence metastasis development through the modulation of both intracellular signaling and the crosstalk between metastatic cells and their microenvironment. Thus, studying the metabolic features of dormant disseminated tumor cells has gained importance in understanding the dormancy process. Here, we describe a method to perform metabolomics and 13C tracer analysis in 3D cultures of dormant breast cancer cells.
    Keywords:  13C tracing; 3D cell culture; Cancer; Disseminated tumor cells; Mass spectrometry; Metabolomics; Metastasis; Tumor cell dormancy
    DOI:  https://doi.org/10.1007/978-1-0716-3882-8_15
  9. Mol Aspects Med. 2024 Jul 25. pii: S0098-2997(24)00052-9. [Epub ahead of print]99 101293
    Molecular mechanisms of cancer cachexia. Role of exercise training.
    Eva Tamayo-Torres, Amanda Garrido, Rafael de Cabo, Julián Carretero, María Carmen Gómez-Cabrera.
      Cancer-associated cachexia represents a multifactorial syndrome mainly characterized by muscle mass loss, which causes both a decrease in quality of life and anti-cancer therapy failure, among other consequences. The definition and diagnostic criteria of cachexia have changed and improved over time, including three different stages (pre-cachexia, cachexia, and refractory cachexia) and objective diagnostic markers. This metabolic wasting syndrome is characterized by a negative protein balance, and anti-cancer drugs like chemotherapy or immunotherapy exacerbate it through relatively unknown mechanisms. Due to its complexity, cachexia management involves a multidisciplinary strategy including not only nutritional and pharmacological interventions. Physical exercise has been proposed as a strategy to counteract the effects of cachexia on skeletal muscle, as it influences the mechanisms involved in the disease such as protein turnover, inflammation, oxidative stress, and mitochondrial dysfunction. This review will summarize the experimental and clinical evidence of the impact of physical exercise on cancer-associated cachexia.
    Keywords:  Cachexia; Cancer; Cancer patients; Experimental models; Molecular mechanisms; Physical exercise
    DOI:  https://doi.org/10.1016/j.mam.2024.101293
  10. Photoacoustics. 2024 Aug;38 100628
    Non-invasive optoacoustic imaging of dermal microcirculatory revascularization in diet-induced obese mice undergoing exercise intervention.
    Shan Huang, Hailong He, Robby Zachariah Tom, Sarah Glasl, Pia Anzenhofer, Andre C Stiel, Susanna M Hofmann, Vasilis Ntziachristos.
      Microcirculatory dysfunction has been observed in the dermal white adipose tissue (dWAT) and subcutaneous white adipose tissue (scWAT) of obese humans and has been proposed as an early prediction marker for cardio-metabolic disease progression. In-vivo visualization and longitudinal monitoring of microvascular remodeling in these tissues remains challenging. We compare the performance of two optoacoustic imaging methods, i.e. multi-spectral optoacoustic tomography (MSOT) and raster-scanning optoacoustic mesoscopy (RSOM) in visualizing lipid and hemoglobin contrast in scWAT and dWAT in a mouse model of diet-induced obesity (DIO) undergoing voluntary wheel running intervention for 32 weeks. MSOT visualized lipid and hemoglobin contrast in murine fat depots in a quantitative manner even at early stages of DIO. We show for the first time to our knowledge that RSOM allows precise visualization of the dWAT microvasculature and provides quantitative readouts of skin layer thickness and vascular density in dWAT and dermis. Combination of MSOT and RSOM resolved exercise-induced morphological changes in microvasculature density, tissue oxygen saturation, lipid and blood volume content in dWAT and scWAT. The combination of MSOT and RSOM may allow precise monitoring of microcirculatory dysfunction and intervention response in dWAT and scWAT in a mouse model for DIO. Our findings have laid out the foundation for future clinical studies using optoacoustic-derived vascular readouts from adipose tissues as a biomarker for monitoring microcirculatory function in metabolic disease.
    Keywords:  Cardio-metabolic disease; Dermal microvascular function; Exercise-induced revascularization; Non-invasive optoacoustic imaging; Obesity
    DOI:  https://doi.org/10.1016/j.pacs.2024.100628
  11. iScience. 2024 Jul 19. 27(7): 110284
    Investigation of a fluorescent reporter microenvironment niche labeling strategy in experimental brain metastasis.
    Matteo Massara, Bastien Dolfi, Vladimir Wischnewski, Emma Nolan, Werner Held, Ilaria Malanchi, Johanna A Joyce.
      Brain metastases are the most common brain tumors in patients and are associated with poor prognosis. Investigating the colonization and outgrowth of brain metastases is challenging given the complexity of the organ, tissue sampling difficulty, and limited experimental models. To address this challenge, we employed a strategy to analyze the metastatic niche in established lesions, based on the release of a cell-penetrating mCherry tag from labeled tumor cells to neighboring niche cells, using different brain metastasis mouse models. We found that CD206+ macrophages were the most abundant cells taking up the mCherry label in established metastases. In vitro and in vivo experiments demonstrated that macrophages uptake and retain the canonical form of mCherry, even without the cell-penetrating portion of the tag. These results identify a specific macrophage subset in the brain that retains tumor-supplied fluorescent molecules, thereby complicating the long-term use of niche labeling strategies in established experimental brain metastasis.
    Keywords:  Cancer; Cell biology; Microenvironment
    DOI:  https://doi.org/10.1016/j.isci.2024.110284
  12. Curr Opin Cell Biol. 2024 Jul 24. pii: S0955-0674(24)00081-4. [Epub ahead of print]90 102402
    Mechanisms of lipid droplet degradation.
    J H Corbo, J Chung.
      Lipid droplets (LDs) are subcellular organelles that play an integral role in lipid metabolism by regulating the storage and release of fatty acids, which are essential for energy production and various cellular processes. Lipolysis and lipophagy are the two major LD degradation pathways that mediate the utilization of lipids stored in these organelles. Recent studies have further uncovered alternative pathways, including direct lysosomal LD degradation and LD exocytosis. Here, we highlight recent findings that dissect the molecular basis of these diverse LD degradation pathways. Then, we discuss speculations on the crosstalk among these pathways and the potential unconventional roles of LD degradation.
    DOI:  https://doi.org/10.1016/j.ceb.2024.102402
  13. Ann Oncol. 2024 Jul 23. pii: S0923-7534(24)01495-9. [Epub ahead of print]
    Exploiting the tumor microenvironment and tumor mechanobiology for the treatment of cancer cachexia.
    Kostas A Papavassiliou, Athanasios G Papavassiliou.
      
    Keywords:  Cancer cachexia; Fibrosis; Inhibitors; Mechanosignaling; Targeting; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.annonc.2024.07.721
  14. Cell Rep. 2024 Jul 23. pii: S2211-1247(24)00861-1. [Epub ahead of print]43(8): 114532
    Alterations of ceramide synthesis induce PD-L1 internalization and signaling to regulate tumor metastasis and immunotherapy response.
    Wyatt Wofford, Jisun Kim, Dosung Kim, Alhaji H Janneh, Han Gyul Lee, F Cansu Atilgan, Natalia Oleinik, Mohamed Faisal Kassir, Ozge Saatci, Paramita Chakraborty, Unal Metin Tokat, Salih Gencer, Breege Howley, Philip Howe, Shikhar Mehrotra, Ozgur Sahin, Besim Ogretmen.
      Programmed death ligand 1, PD-L1 (CD274), facilitates immune evasion and exerts pro-survival functions in cancer cells. Here, we report a mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic hedgehog (Shh) and transforming growth factor β receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBCs), exhibiting immunotherapy resistance. Mechanistically, data showed that internalized PD-L1 interacts with an RNA-binding protein, caprin-1, to stabilize Shh/TGFBR1/Wnt mRNAs to induce β-catenin signaling and TNBC growth/metastasis, consistent with increased infiltration of FoxP3+ regulatory T cells and resistance to immunotherapy. While mammary tumors developed in MMTV-PyMT/CerS4-/- were highly metastatic, targeting the Shh/PD-L1 axis using sonidegib and anti-PD-L1 antibody vastly decreased tumor growth and metastasis, consistent with the inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and databases, provide a mechanism-based therapeutic strategy to improve immunotherapy responses in metastatic TNBCs.
    Keywords:  CP: Cancer; CP: Metabolism; CerS4; PD-L1; ceramide; immunotherapy; metastasis; sonic hedgehog; sphingolipid
    DOI:  https://doi.org/10.1016/j.celrep.2024.114532
  15. Nature. 2024 Jul 24.
    Cryo-EM architecture of a near-native stretch-sensitive membrane microdomain.
    Jennifer M Kefauver, Markku Hakala, Luoming Zou, Josephine Alba, Javier Espadas, Maria G Tettamanti, Jelena Gajić, Caroline Gabus, Pablo Campomanes, Leandro F Estrozi, Nesli E Sen, Stefano Vanni, Aurélien Roux, Ambroise Desfosses, Robbie Loewith.
      Biological membranes are partitioned into functional zones termed membrane microdomains, which contain specific lipids and proteins1-3. The composition and organization of membrane microdomains remain controversial because few techniques are available that allow the visualization of lipids in situ without disrupting their native behaviour3,4. The yeast eisosome, composed of the BAR-domain proteins Pil1 and Lsp1 (hereafter, Pil1/Lsp1), scaffolds a membrane compartment that senses and responds to mechanical stress by flattening and releasing sequestered factors5-9. Here we isolated near-native eisosomes as helical tubules made up of a lattice of Pil1/Lsp1 bound to plasma membrane lipids, and solved their structures by helical reconstruction. Our structures reveal a striking organization of membrane lipids, and, using in vitro reconstitutions and molecular dynamics simulations, we confirmed the positioning of individual PI(4,5)P2, phosphatidylserine and sterol molecules sequestered beneath the Pil1/Lsp1 coat. Three-dimensional variability analysis of the native-source eisosomes revealed a dynamic stretching of the Pil1/Lsp1 lattice that affects the sequestration of these lipids. Collectively, our results support a mechanism in which stretching of the Pil1/Lsp1 lattice liberates lipids that would otherwise be anchored by the Pil1/Lsp1 coat, and thus provide mechanistic insight into how eisosome BAR-domain proteins create a mechanosensitive membrane microdomain.
    DOI:  https://doi.org/10.1038/s41586-024-07720-6
  16. STAR Protoc. 2024 Jul 24. pii: S2666-1667(24)00368-X. [Epub ahead of print]5(3): 103203
    Protocol for the characterization of the pancreatic tumor microenvironment using organoid-derived mouse models and single-nuclei RNA sequencing.
    Muntadher Jihad, Gianluca Mucciolo, Wenlong Li, Akanksha Anand, Joaquín Araos Henríquez, Sara Pinto Teles, Judhell S Manansala, Sally Ashworth, Eloise G Lloyd, Priscilla S W Cheng, Weike Luo, Ashley Sawle, Anna Piskorz, Giulia Biffi.
      Single-nuclei RNA sequencing (snRNA-seq) allows for obtaining gene expression profiles from frozen or hard-to-dissociate tissues at the single-nuclei level. Here, we describe a protocol to obtain snRNA-seq data of pancreatic tumors from orthotopically grafted organoid-derived mouse models. We provide details on the establishment of these mouse models, the isolation of single nuclei from pancreatic tumors, and the analysis of the snRNA-seq datasets. For complete details on the use and execution of this protocol, please refer to Mucciolo et al.1.
    Keywords:  Cancer; Genomics; Model Organisms; Organoids; RNAseq; Sequence analysis; Sequencing
    DOI:  https://doi.org/10.1016/j.xpro.2024.103203
  17. Nat Commun. 2024 Jul 22. 15(1): 6162
    Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice.
    Benjamin Assouline, Rachel Kahn, Lutfi Hodali, Reba Condiotti, Yarden Engel, Ela Elyada, Tzlil Mordechai-Heyn, Jason R Pitarresi, Dikla Atias, Eliana Steinberg, Tirza Bidany-Mizrahi, Esther Forkosh, Lior H Katz, Ofra Benny, Talia Golan, Matan Hofree, Sheila A Stewart, Karine A Atlan, Gideon Zamir, Ben Z Stanger, Michael Berger, Ittai Ben-Porath.
      Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions. However, the identities and traits of these cells, and the potential for improving cancer therapy through their targeting, remain poorly characterized. Here, we identify a senescent subset within previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs isolated from mouse and humans expressed elevated levels of immune-regulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8+ T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8+ T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-024-50441-7
  18. Signal Transduct Target Ther. 2024 Jul 24. 9(1): 177
    Sensory neurons: unveiling the symphony of wound healing.
    Dongsheng Jiang, Hans-Günther Machens, Yuval Rinkevich.
      
    DOI:  https://doi.org/10.1038/s41392-024-01880-7
  19. Brief Bioinform. 2024 May 23. pii: bbae347. [Epub ahead of print]25(4):
    MetalinksDB: a flexible and contextualizable resource of metabolite-protein interactions.
    Elias Farr, Daniel Dimitrov, Christina Schmidt, Denes Turei, Sebastian Lobentanzer, Aurelien Dugourd, Julio Saez-Rodriguez.
      From the catalytic breakdown of nutrients to signaling, interactions between metabolites and proteins play an essential role in cellular function. An important case is cell-cell communication, where metabolites, secreted into the microenvironment, initiate signaling cascades by binding to intra- or extracellular receptors of neighboring cells. Protein-protein cell-cell communication interactions are routinely predicted from transcriptomic data. However, inferring metabolite-mediated intercellular signaling remains challenging, partially due to the limited size of intercellular prior knowledge resources focused on metabolites. Here, we leverage knowledge-graph infrastructure to integrate generalistic metabolite-protein with curated metabolite-receptor resources to create MetalinksDB. MetalinksDB is an order of magnitude larger than existing metabolite-receptor resources and can be tailored to specific biological contexts, such as diseases, pathways, or tissue/cellular locations. We demonstrate MetalinksDB's utility in identifying deregulated processes in renal cancer using multi-omics bulk data. Furthermore, we infer metabolite-driven intercellular signaling in acute kidney injury using spatial transcriptomics data. MetalinksDB is a comprehensive and customizable database of intercellular metabolite-protein interactions, accessible via a web interface (https://metalinks.omnipathdb.org/) and programmatically as a knowledge graph (https://github.com/biocypher/metalinks). We anticipate that by enabling diverse analyses tailored to specific biological contexts, MetalinksDB will facilitate the discovery of disease-relevant metabolite-mediated intercellular signaling processes.
    Keywords:  cell–cell communication; database; metabolomics; single-cell; spatial; transcriptomics
    DOI:  https://doi.org/10.1093/bib/bbae347
  20. EMBO J. 2024 Jul 23.
    Connexin43 promotes exocytosis of damaged lysosomes through actin remodelling.
    Neuza Domingues, Steve Catarino, Beatriz Cristóvão, Lisa Rodrigues, Filomena A Carvalho, Maria João Sarmento, Mónica Zuzarte, Jani Almeida, Teresa Ribeiro-Rodrigues, Ânia Correia-Rodrigues, Fábio Fernandes, Paulo Rodrigues-Santos, Trond Aasen, Nuno C Santos, Viktor I Korolchuk, Teresa Gonçalves, Ira Milosevic, Nuno Raimundo, Henrique Girão.
      A robust and efficient cellular response to lysosomal membrane damage prevents leakage from the lysosome lumen into the cytoplasm. This response is understood to happen through either lysosomal membrane repair or lysophagy. Here we report exocytosis as a third response mechanism to lysosomal damage, which is further potentiated when membrane repair or lysosomal degradation mechanisms are impaired. We show that Connexin43 (Cx43), a protein canonically associated with gap junctions, is recruited from the plasma membrane to damaged lysosomes, promoting their secretion and accelerating cell recovery. The effects of Cx43 on lysosome exocytosis are mediated by a reorganization of the actin cytoskeleton that increases plasma membrane fluidity and decreases cell stiffness. Furthermore, we demonstrate that Cx43 interacts with the actin nucleator Arp2, the activity of which was shown to be necessary for Cx43-mediated actin rearrangement and lysosomal exocytosis following damage. These results define a novel mechanism of lysosomal quality control whereby Cx43-mediated actin remodelling potentiates the secretion of damaged lysosomes.
    Keywords:  Actin-remodelling; Arp2; Connexin43; Exocytosis; Lysosomal Damage
    DOI:  https://doi.org/10.1038/s44318-024-00177-3
  21. J Natl Cancer Cent. 2023 Dec;3(4): 273-278
    Therapy-induced senescent tumor cells in cancer relapse.
    Ke-Xin Song, Jun-Xian Wang, De Huang.
      Cellular senescence is characterized by a generally irreversible cell cycle arrest and the secretion of bioactive factors known as the senescence-associated secretory phenotype (SASP). In an oncogenic context, senescence is considered a tumor suppressive mechanism as it prevents cell proliferation and inhibits the progression from pre-malignant to malignant disease. However, recent studies have demonstrated that senescent tumor cells, which could spontaneously exist within cancer tissues or arise in response to various cancer interventions (the so-called therapy-induced senescence, TIS), can acquire pro-tumorigenic properties and are capable of driving local and metastatic relapse. This highlights the complex and multifaceted nature of cellular senescence in cancer biology. Here, we summarize the current knowledge of the pathological function of therapy-induced senescent tumor cells and discuss possible mechanisms by which tumor cell senescence contributes to cancer relapse. We also discuss implications for future studies toward targeting these less appreciated cells.
    Keywords:  Cancer therapy; Relapse; Tumor cell senescence
    DOI:  https://doi.org/10.1016/j.jncc.2023.09.001
  22. Metabolites. 2024 Jul 11. pii: 383. [Epub ahead of print]14(7):
    Challenges of Spatially Resolved Metabolism in Cancer Research.
    Andrew N Lane, Richard M Higashi, Teresa W-M Fan.
      Stable isotope-resolved metabolomics comprises a critical set of technologies that can be applied to a wide variety of systems, from isolated cells to whole organisms, to define metabolic pathway usage and responses to perturbations such as drugs or mutations, as well as providing the basis for flux analysis. As the diversity of stable isotope-enriched compounds is very high, and with newer approaches to multiplexing, the coverage of metabolism is now very extensive. However, as the complexity of the model increases, including more kinds of interacting cell types and interorgan communication, the analytical complexity also increases. Further, as studies move further into spatially resolved biology, new technical problems have to be overcome owing to the small number of analytes present in the confines of a single cell or cell compartment. Here, we review the overall goals and solutions made possible by stable isotope tracing and their applications to models of increasing complexity. Finally, we discuss progress and outstanding difficulties in high-resolution spatially resolved tracer-based metabolic studies.
    Keywords:  cancer metabolism; experimental models; spatially resolved metabolism; stable isotope-resolved metabolomics
    DOI:  https://doi.org/10.3390/metabo14070383
  23. Obes Rev. 2024 Jul 25. e13799
    Overcoming underestimation of the association of excess weight with pancreatic cancer due to prediagnostic weight loss: Umbrella review of systematic reviews, meta-analyses, and pooled-analyses.
    Marko Mandic, Dianne Pulte, Fatemeh Safizadeh, Tobias Niedermaier, Michael Hoffmeister, Hermann Brenner.
      Elevated body mass index (BMI) is linked to increased pancreatic cancer (PC) risk. Cancer-associated weight loss can occur years before the malignancy is diagnosed. This might have led to underestimation of the BMI-PC association. However, it is unknown if and to what extent this issue has been considered in previous epidemiological studies. We searched two databases through February 19, 2024 for systematic reviews, meta-analyses, and pooled analyses examining the BMI-PC association. We extracted information on study design with a special focus on the article's examination of prediagnostic weight loss as a potential source of bias, as well as how included cohort studies addressed this concern. Thirteen review articles, meta-analyses, and pooled analyses were identified. Only five (four pooled analyses, one systematic review) considered prediagnostic weight loss in their analyses. Twenty-four of 32 identified cohort studies reported having excluded initial years of follow-up. However, only 13 studies reported results after such exclusions, and effect estimates generally increased with longer periods of exclusion. We conclude that the association of overweight and obesity with PC risk is likely larger than suggested by published epidemiological evidence. Future studies should pay careful attention to avoid or minimize potential bias resulting from prediagnostic weight loss.
    Keywords:  obesity; overweight; pancreatic cancer; weight loss
    DOI:  https://doi.org/10.1111/obr.13799
  24. Nature. 2024 Jul 24.
    In vivo interaction screening reveals liver-derived constraints to metastasis.
    Costanza Borrelli, Morgan Roberts, Davide Eletto, Marie-Didiée Hussherr, Hassan Fazilaty, Tomas Valenta, Atefeh Lafzi, Jonas A Kretz, Elena Guido Vinzoni, Andromachi Karakatsani, Srivathsan Adivarahan, Ardian Mannhart, Shoichiro Kimura, Ab Meijs, Farah Baccouche Mhamedi, Ilhan E Acar, Kristina Handler, Xenia Ficht, Randall J Platt, Salvatore Piscuoglio, Andreas E Moor.
      It is estimated that only 0.02% of disseminated tumour cells are able to seed overt metastases1. While this suggests the presence of environmental constraints to metastatic seeding, the landscape of host factors controlling this process remains largely unclear. Here, combining transposon technology2 and fluorescence niche labelling3, we developed an in vivo CRISPR activation screen to systematically investigate the interactions between hepatocytes and metastatic cells. We identify plexin B2 as a critical host-derived regulator of liver colonization in colorectal and pancreatic cancer and melanoma syngeneic mouse models. We dissect a mechanism through which plexin B2 interacts with class IV semaphorins on tumour cells, leading to KLF4 upregulation and thereby promoting the acquisition of epithelial traits. Our results highlight the essential role of signals from the liver parenchyma for the seeding of disseminated tumour cells before the establishment of a growth-promoting niche. Our findings further suggest that epithelialization is required for the adaptation of CRC metastases to their new tissue environment. Blocking the plexin-B2-semaphorin axis abolishes metastatic colonization of the liver and therefore represents a therapeutic strategy for the prevention of hepatic metastases. Finally, our screening approach, which evaluates host-derived extrinsic signals rather than tumour-intrinsic factors for their ability to promote metastatic seeding, is broadly applicable and lays a framework for the screening of environmental constraints to metastasis in other organs and cancer types.
    DOI:  https://doi.org/10.1038/s41586-024-07715-3
  25. J Natl Cancer Cent. 2022 Dec;2(4): 263-276
    Patient-derived organoids (PDOs) and PDO-derived xenografts (PDOXs): New opportunities in establishing faithful pre-clinical cancer models.
    Ergang Wang, Kun Xiang, Yun Zhang, Xiao-Fan Wang.
      One of the major bottlenecks in advancing basic cancer research and developing novel cancer therapies is the lack of in vitro pre-clinical models that faithfully recapitulate tumor properties in the patients. Monolayer cultures of cancer cell lines usually lose the heterogeneity of the parental tumors, while patient-derived xenograft (PDX) suffers from its time- and resource-intensive nature. The emergence of organoid culture system and its application in cancer research provides a unique opportunity to develop novel in vitro cancer pre-clinical models. Here we review the recent advances in utilizing organoids culture system and other related three-dimensional culture systems in studying cancer biology, performing drug screening, and developing cancer therapies. In particular, we discuss the advantages of applying xenograft initiated from patient-derived organoids (PDOs) as a faithful cancer pre-clinical model in basic cancer research and precision medicine.
    Keywords:  PDO-derived xenograft; Patient-derived organoid; Patient-derived xenograft
    DOI:  https://doi.org/10.1016/j.jncc.2022.10.001
  26. Talanta. 2024 Jul 17. pii: S0039-9140(24)00962-7. [Epub ahead of print]279 126583
    Side-chain-engineered fluorescent dyes for 3D and long-term dynamic tracking of the plasma membrane in living cells.
    Chuangye Yao, Aohui Peng, Penglei Wu, Jiaqi Zuo, Junjun Pan, Chuixi Kong, Zhaosheng Qian, Zhigang Jin, Hui Feng.
      The plasma membrane involves in many important biological events such as cell fusion and programmed cell death, but most of current plasma membrane probes cannot meet the requirement of long-term specific anchoring to the plasma membrane. Herein, we propose a molecular side-chain engineering strategy to modulate the long-term imaging performance of fluorescent dyes to the plasma membrane by regulating the cell permeability and anchoring ability. A series of FMR dyes with different lengths of side chains were designed and synthesized, and their transmembrane behaviours and staining performance were evaluated in living HeLa cells. We found that short-chain and medium-chain FMR dyes have excellent cell permeability without the labeling ability to the plasma membrane while the long-chain FMR dyes specifically stain the plasma membrane and can be firmly anchored to the plasma membrane for a long period of time. These long-chain FMR dyes have high stain specificality to the plasma membrane, and C10-FMR can be anchored to the plasma membrane of living cells for 2 h, which enables it to continuously monitor dynamic changes of the plasma membrane. The three-dimensional precision imaging of various cells was achieved using C10-FMR, which provides an opportunity to obtain complete information on the three-dimensional spatial morphology of the plasma membrane. The PEG-induced cell fusion of chicken red blood cells and H2O2-induced apoptosis of HeLa cells were monitored by real-time tracking of dynamic changes of the plasma membrane during these processes, which provide solid examples to prove the usefulness of these fluorescent dyes as long-term imaging tools. This work validates the hypothesis that cell permeability of membrane dyes can be readily regulated by tuning the side chains, and provides the effective design strategy of fluorescent dyes for 3D and long-term dynamic tracking of the plasma membrane of diverse animal cells.
    Keywords:  4D imaging; Cell permeability long-term imaging; Molecular engineering; Plasma membrane
    DOI:  https://doi.org/10.1016/j.talanta.2024.126583
  27. Autophagy. 2024 Jul 20. 1-4
    Integrating bioengineering, super-resolution microscopy and mechanobiology in autophagy research: addendum to the guidelines (4th edition).
    Andrea Ravasio, Daniel J Klionsky, Cristina Bertocchi.
      Recent key technological developments, such as super-resolution microscopy and microfabrication, enabled investigation of biological processes, including macroautophagy/autophagy, with unprecedented spatiotemporal resolution and control over experimental conditions. Such disruptive innovations deepened our capability to provide mechanistic understandings of the autophagic process and its causes. This addendum aims to expand the guidelines on autophagy in three key directions: optical methods enabling visualization of autophagic machinery beyond the diffraction-limited resolution; bioengineering enabling accurate designs and control over experimental conditions; and theoretical advances in mechanobiology connecting autophagy and mechanical processes of the cell. Abbreviation: 3D: three-dimensional; SIM: structured illumination microscopy; STORM: stochastic optical reconstruction microscopy.
    Keywords:  Bioengineering; interdisciplinarity; mechanoautophagy; microfabrication; microfluidics; super-resolution microscopy
    DOI:  https://doi.org/10.1080/15548627.2024.2379065
  28. Biosensors (Basel). 2024 Jun 28. pii: 324. [Epub ahead of print]14(7):
    Correlative Raman Imaging: Development and Cancer Applications.
    Hossein Khadem, Maria Mangini, Somayeh Farazpour, Anna Chiara De Luca.
      Despite extensive research efforts, cancer continues to stand as one of the leading causes of death on a global scale. To gain profound insights into the intricate mechanisms underlying cancer onset and progression, it is imperative to possess methodologies that allow the study of cancer cells at the single-cell level, focusing on critical parameters such as cell morphology, metabolism, and molecular characteristics. These insights are essential for effectively discerning between healthy and cancerous cells and comprehending tumoral progression. Recent advancements in microscopy techniques have significantly advanced the study of cancer cells, with Raman microspectroscopy (RM) emerging as a particularly powerful tool. Indeed, RM can provide both biochemical and spatial details at the single-cell level without the need for labels or causing disruptions to cell integrity. Moreover, RM can be correlated with other microscopy techniques, creating a synergy that offers a spectrum of complementary insights into cancer cell morphology and biology. This review aims to explore the correlation between RM and other microscopy techniques such as confocal fluoresce microscopy (CFM), atomic force microscopy (AFM), digital holography microscopy (DHM), and mass spectrometry imaging (MSI). Each of these techniques has their own strengths, providing different perspectives and parameters about cancer cell features. The correlation between information from these various analysis methods is a valuable tool for physicians and researchers, aiding in the comprehension of cancer cell morphology and biology, unraveling mechanisms underlying cancer progression, and facilitating the development of early diagnosis and/or monitoring cancer progression.
    Keywords:  Raman imaging; Raman spectroscopy; atomic force microscopy; cancer; correlative imaging; digital holography microscopy; fluorescence microscopy; mass spectroscopy imaging; quantitative phase imaging
    DOI:  https://doi.org/10.3390/bios14070324
  29. Methods Mol Biol. 2024 ;2811 37-53
    Modeling Tumor Cell Dormancy in an Ex Vivo Liver Metastatic Niche.
    Jacob C McDonald, Amanda M Clark.
      Despite decades of research into metastatic disease, our knowledge of the mechanisms governing dormancy are still limited. Unraveling the process will aid in developing effective therapies to either maintain or eliminate these dormant cells and thus prevent them from emerging into overt metastatic disease. To study the behavior of dormant tumor cells-mechanisms that promote, maintain, and disrupt this state-we utilize the Legacy LiverChip®, an all-human ex vivo hepatic microphysiological system. This complex, bioengineered system is able to recreate metastatic disease that is reflective of the human situation and is among only a handful of systems able to mimic spontaneous tumor cell dormancy. The dormant subpopulation reflects the defining traits of cellular dormancy-survival in a foreign microenvironment, chemoresistance, and reversible growth arrest. This microphysiological system has and continues to provide critical insights into the biology of dormant tumor cells. It also serves as an accessible tool to identify new therapeutic strategies targeting dormancy and concurrently evaluate the efficacy of therapeutic agents as well as their metabolism and dose-limiting toxicity.
    Keywords:  Metastasis; Micrometastases; Microphysiological system; Model of tumor dormancy; Organ-on-a-chip
    DOI:  https://doi.org/10.1007/978-1-0716-3882-8_3
  30. NAR Cancer. 2024 Sep;6(3): zcae032
    Decoding ribosome complexity: role of ribosomal proteins in cancer and disease.
    Pedro Fuentes, Joffrey Pelletier, Antonio Gentilella.
      The ribosome is a remarkably complex machinery, at the interface with diverse cellular functions and processes. Evolutionarily conserved, yet intricately regulated, ribosomes play pivotal roles in decoding genetic information into the synthesis of proteins and in the generation of biomass critical for cellular physiological functions. Recent insights have revealed the existence of ribosome heterogeneity at multiple levels. Such heterogeneity extends to cancer, where aberrant ribosome biogenesis and function contribute to oncogenesis. This led to the emergence of the concept of 'onco-ribosomes', specific ribosomal variants with altered structural dynamics, contributing to cancer initiation and progression. Ribosomal proteins (RPs) are involved in many of these alterations, acting as critical factors for the translational reprogramming of cancer cells. In this review article, we highlight the roles of RPs in ribosome biogenesis, how mutations in RPs and their paralogues reshape the translational landscape, driving clonal evolution and therapeutic resistance. Furthermore, we present recent evidence providing new insights into post-translational modifications of RPs, such as ubiquitylation, UFMylation and phosphorylation, and how they regulate ribosome recycling, translational fidelity and cellular stress responses. Understanding the intricate interplay between ribosome complexity, heterogeneity and RP-mediated regulatory mechanisms in pathology offers profound insights into cancer biology and unveils novel therapeutic avenues targeting the translational machinery in cancer.
    DOI:  https://doi.org/10.1093/narcan/zcae032
  31. Science. 2024 Jul 26. 385(6707): 370-371
    Barcoding distinct neurons.
    Jane Kawaoka, Stavros Lomvardas.
      The genomic landscape of a cell surface protein reveals how neuron identity is displayed.
    DOI:  https://doi.org/10.1126/science.adq5225
  32. Cancer Res. 2024 Jul 24.
    AFDN deficiency promotes liver tropism of metastatic colorectal cancer.
    Shaoxia Liao, Jingwen Deng, Mengli Deng, Chaoyi Chen, Fengyan Han, Kehong Ye, Chenxia Wu, Lvyuan Pan, Maode Lai, Zhe Tang, Honghe Zhang.
      Liver metastasis is a major cause of morbidity and mortality in patients with colorectal cancer. A better understanding of the biological mechanisms underlying liver tropism and metastasis in colorectal cancer could help to identify improved prevention and treatment strategies. In this study, we performed genome-side CRISPR loss-of-function screening in a mouse colorectal cancer model and identified deficiency of AFDN, a protein involved in establishing and maintaining cell-cell contacts, as a driver of liver metastasis. Elevated AFDN expression was correlated with prolonged survival in patients with colorectal cancer. AFDN-deficient colorectal cancer cells preferentially metastasized to the liver but not in the lungs. AFDN loss in colorectal cancer cells at the primary site promoted cancer cell migration and invasion by disrupting tight intercellular junctions. Additionally, CXCR4 expression was increased in AFDN-deficient colorectal cancer cells via the JAK-STAT signaling pathway, which reduced the motility of AFDN-deficient colorectal cancer cells and facilitated their colonization of the liver. Collectively, these data shed light on the mechanism by which AFDN deficiency promotes liver tropism in metastatic colorectal cancer.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3140
  33. Mol Genet Metab. 2024 Jun 20. pii: S1096-7192(24)00402-5. [Epub ahead of print]143(1-2): 108518
    SLC25A48 influences plasma levels of choline and localizes to the inner mitochondrial membrane.
    David J Bernard, Faith Pangilinan, Caitlin Mendina, Tara Desporte, Stephen M Wincovitch, Darren J Walsh, Richard K Porter, Anne M Molloy, Barry Shane, Lawrence C Brody.
      Choline contributes to the biogenesis of methyl groups, neurotransmitters, and cell membranes. Our genome-wide association study (GWAS) of circulating choline in 2228 college students found that alleles in SLC25A48 (rs6596270) influence choline concentrations in men (p = 9.6 × 10-8), but not women. Previously, the subcellular location and function of SLC25A48 were unknown. Using super-resolution immunofluorescence microscopy, we localized SLC25A48 to the inner mitochondrial membrane. Our results suggest that SLC25A48 transports choline across the inner mitochondrial membrane.
    Keywords:  Betaine; Choline; Inner mitochondrial membrane transport; Mitochondria; One carbon metabolism; SLC25A48
    DOI:  https://doi.org/10.1016/j.ymgme.2024.108518
  34. Nat Chem Biol. 2024 Jul 26.
    Phospholipid biosynthesis modulates nucleotide metabolism and reductive capacity.
    Yibing Zhu, Xiaomeng Tong, Jingyuan Xue, Hong Qiu, Dan Zhang, Dao-Qiong Zheng, Zong-Cai Tu, Cunqi Ye.
      Phospholipid and nucleotide syntheses are fundamental metabolic processes in eukaryotic organisms, with their dysregulation implicated in various disease states. Despite their importance, the interplay between these pathways remains poorly understood. Using genetic and metabolic analyses in Saccharomyces cerevisiae, we elucidate how cytidine triphosphate usage in the Kennedy pathway for phospholipid synthesis influences nucleotide metabolism and redox balance. We find that deficiencies in the Kennedy pathway limit nucleotide salvage, prompting compensatory activation of de novo nucleotide synthesis and the pentose phosphate pathway. This metabolic shift enhances the production of antioxidants such as NADPH and glutathione. Moreover, we observe that the Kennedy pathway for phospholipid synthesis is inhibited during replicative aging, indicating its role in antioxidative defense as an adaptive mechanism in aged cells. Our findings highlight the critical role of phospholipid synthesis pathway choice in the integrative regulation of nucleotide metabolism, redox balance and membrane properties for cellular defense.
    DOI:  https://doi.org/10.1038/s41589-024-01689-z
  35. Methods Mol Biol. 2024 ;2823 193-223
    A Fast-Tracking Sample Preparation Protocol for Proteomics of Formalin-Fixed Paraffin-Embedded Tumor Tissues.
    Lancia N F Darville, John H Lockhart, Sudhir Putty Reddy, Bin Fang, Victoria Izumi, Theresa A Boyle, Eric B Haura, Elsa R Flores, John M Koomen.
      Archived tumor specimens are routinely preserved by formalin fixation and paraffin embedding. Despite the conventional wisdom that proteomics might be ineffective due to the cross-linking and pre-analytical variables, these samples have utility for both discovery and targeted proteomics. Building on this capability, proteomics approaches can be used to maximize our understanding of cancer biology and clinical relevance by studying preserved tumor tissues annotated with the patients' medical histories. Proteomics of formalin-fixed paraffin-embedded (FFPE) tissues also integrates with histological evaluation and molecular pathology strategies, so that additional collection of research biopsies or resected tumor aliquots is not needed. The acquisition of data from the same tumor sample also overcomes concerns about biological variation between samples due to intratumoral heterogeneity. However, the protein extraction and proteomics sample preparation from FFPE samples can be onerous, particularly for small (i.e., limited or precious) samples. Therefore, we provide a protocol for a recently introduced kit-based EasyPep method with benchmarking against a modified version of the well-established filter-aided sample preparation strategy using laser-capture microdissected lung adenocarcinoma tissues from a genetically engineered mouse model. This model system allows control over the tumor preparation and pre-analytical variables while also supporting the development of methods for spatial proteomics to examine intratumoral heterogeneity. Data are posted in ProteomeXchange (PXD045879).
    Keywords:   EasyPep; Filter-aided sample preparation; Lung cancer; Proteomics; Formalin-fixed paraffin-embedded tissue
    DOI:  https://doi.org/10.1007/978-1-0716-3922-1_13
  36. Cell Rep. 2024 Jul 20. pii: S2211-1247(24)00745-9. [Epub ahead of print]43(8): 114416
    The HuMet Repository: Watching human metabolism at work.
    Patrick Weinisch, Johannes Raffler, Werner Römisch-Margl, Matthias Arnold, Robert P Mohney, Manuela J Rist, Cornelia Prehn, Thomas Skurk, Hans Hauner, Hannelore Daniel, Karsten Suhre, Gabi Kastenmüller.
      Metabolism oscillates between catabolic and anabolic states depending on food intake, exercise, or stresses that change a multitude of metabolic pathways simultaneously. We present the HuMet Repository for exploring dynamic metabolic responses to oral glucose/lipid loads, mixed meals, 36-h fasting, exercise, and cold stress in healthy subjects. Metabolomics data from blood, urine, and breath of 15 young, healthy men at up to 56 time points are integrated and embedded within an interactive web application, enabling researchers with and without computational expertise to search, visualize, analyze, and contextualize the dynamic metabolite profiles of 2,656 metabolites acquired on multiple platforms. With examples, we demonstrate the utility of the resource for research into the dynamics of human metabolism, highlighting differences and similarities in systemic metabolic responses across challenges and the complementarity of metabolomics platforms. The repository, providing a reference for healthy metabolite changes to six standardized physiological challenges, is freely accessible through a web portal.
    Keywords:  CP: Metabolism; dynamic metabolic responses in health; exercise metabolism; metabolic flexibility; metabolomics platform comparison; oral glucose tolerance test; oral lipid tolerance test; postprandial metabolism; prolonged/extended fasting; standardized physiological challenge tests; time-series metabolomics
    DOI:  https://doi.org/10.1016/j.celrep.2024.114416
  37. Brief Bioinform. 2024 May 23. pii: bbae357. [Epub ahead of print]25(4):
    Comparative analyses of gene networks mediating cancer metastatic potentials across lineage types.
    Sheng Wang, Emily K Stroup, Ting-You Wang, Rendong Yang, Zhe Ji.
      Studies have identified genes and molecular pathways regulating cancer metastasis. However, it remains largely unknown whether metastatic potentials of cancer cells from different lineage types are driven by the same or different gene networks. Here, we aim to address this question through integrative analyses of 493 human cancer cells' transcriptomic profiles and their metastatic potentials in vivo. Using an unsupervised approach and considering both gene coexpression and protein-protein interaction networks, we identify different gene networks associated with various biological pathways (i.e. inflammation, cell cycle, and RNA translation), the expression of which are correlated with metastatic potentials across subsets of lineage types. By developing a regularized random forest regression model, we show that the combination of the gene module features expressed in the native cancer cells can predict their metastatic potentials with an overall Pearson correlation coefficient of 0.90. By analyzing transcriptomic profile data from cancer patients, we show that these networks are conserved in vivo and contribute to cancer aggressiveness. The intrinsic expression levels of these networks are correlated with drug sensitivity. Altogether, our study provides novel comparative insights into cancer cells' intrinsic gene networks mediating metastatic potentials across different lineage types, and our results can potentially be useful for designing personalized treatments for metastatic cancers.
    Keywords:  cancer metastasis; drug response; gene network; lineage types
    DOI:  https://doi.org/10.1093/bib/bbae357
  38. Nat Commun. 2024 Jul 21. 15(1): 6152
    Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression.
    Gloria Asantewaa, Emily T Tuttle, Nathan P Ward, Yun Pyo Kang, Yumi Kim, Madeline E Kavanagh, Nomeda Girnius, Ying Chen, Katherine Rodriguez, Fabio Hecht, Marco Zocchi, Leonid Smorodintsev-Schiller, TashJaé Q Scales, Kira Taylor, Fatemeh Alimohammadi, Renae P Duncan, Zachary R Sechrist, Diana Agostini-Vulaj, Xenia L Schafer, Hayley Chang, Zachary R Smith, Thomas N O'Connor, Sarah Whelan, Laura M Selfors, Jett Crowdis, G Kenneth Gray, Roderick T Bronson, Dirk Brenner, Alessandro Rufini, Robert T Dirksen, Aram F Hezel, Aaron R Huber, Joshua Munger, Benjamin F Cravatt, Vasilis Vasiliou, Calvin L Cole, Gina M DeNicola, Isaac S Harris.
      Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we have developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are highest in liver tissue, which is also a hub for lipid production. While the loss of GSH does not cause liver failure, it decreases lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we find that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver's balance of redox buffering and triglyceride production.
    DOI:  https://doi.org/10.1038/s41467-024-50454-2
  39. Trends Cell Biol. 2024 Jul 25. pii: S0962-8924(24)00118-1. [Epub ahead of print]
    Lipids and chromatin: a tale of intriguing connections shaping genomic landscapes.
    Maria Laura Sosa Ponce, Jennifer A Cobb, Vanina Zaremberg.
      Recent studies in yeast reveal an intricate interplay between nuclear envelope (NE) architecture and lipid metabolism, and between lipid signaling and both epigenome and genome integrity. In this review, we highlight the reciprocal connection between lipids and histone modifications, which enable metabolic reprogramming in response to nutrients. The endoplasmic reticulum (ER)-NE regulates the compartmentalization and temporal availability of epigenetic metabolites and its lipid composition also impacts nuclear processes, such as transcriptional silencing and the DNA damage response (DDR). We also discuss recent work providing mechanistic insight into lipid droplet (LD) formation and sterols in the nucleus, and the collective data showing Opi1 as a central factor in both membrane sensing and transcriptional regulation of lipid-chromatin interrelated processes.
    Keywords:  DNA damage response; genome integrity; lipid droplets; lipid metabolism; membrane sensors; nuclear envelope
    DOI:  https://doi.org/10.1016/j.tcb.2024.06.004
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