bims-cagime Biomed News
on Cancer, aging and metabolism
Issue of 2023–04–09
24 papers selected by
Kıvanç Görgülü, Technical University of Munich
  1. CD73 Is a Critical Immune Checkpoint in a Molecular Subtype of Pancreatic Cancer.
  2. Analysis of donor pancreata defines the transcriptomic signature and microenvironment of early neoplastic lesions.
  3. A novel orthotopic mouse model replicates human lung cancer cachexia.
  4. Lung adenocarcinoma promotion by air pollutants.
  5. NAD+ repletion with niacin counteracts cancer cachexia.
  6. Lipocalin-2 and neutrophil activation in pancreatic cancer cachexia.
  7. Specific miRNAs are associated with human cancer cachexia in an organ-specific manner.
  8. Light-Deactivated Fluorescent Probes (FLASH-Off) for Multiplexed Imaging.
  9. Monitoring the Activation of Selective Autophagy via N-Terminal Arginylation.
  10. LC3-independent autophagy is vital to prevent TNF cytotoxicity.
  11. A lysosome membrane regeneration pathway depends on TBC1D15 and autophagic lysosomal reformation proteins.
  12. Structural and functional properties of mSWI/SNF chromatin remodeling complexes revealed through single-cell perturbation screens.
  13. Transitions in the framework of condensate biology.
  14. Moving Spatially Resolved Multiplexed Protein Profiling toward Clinical Oncology.
  15. Global determination of reaction rates and lipid turnover kinetics in Mus musculus.
  16. Researchers dig into cancer niches.
  17. Oncogenic signaling is coupled to colorectal cancer cell differentiation state.
  18. The Hallmarks of a Cancer Discovery.
  19. Neurons require glucose uptake and glycolysis in vivo.
  20. Sodium ion influx regulates liquidity of biomolecular condensates in hyperosmotic stress response.
  21. Visualizing intratumoural heterogeneity with EpicMIBI.
  22. Workflow enabling deepscale immunopeptidome, proteome, ubiquitylome, phosphoproteome, and acetylome analyses of sample-limited tissues.
  23. Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells.
  24. A stress-induced cilium-to-PML-NB route drives senescence initiation.
  1. Cancer Res. 2023 Apr 04. 83(7): 977-978
    CD73 Is a Critical Immune Checkpoint in a Molecular Subtype of Pancreatic Cancer.
    Kathleen DelGiorno.
      Molecular stratification of patients with pancreatic ductal adenocarcinoma (PDAC) has the potential to guide clinical decision-making for therapeutic intervention. Investigating mechanisms by which different molecular subtypes of PDAC form and progress will improve patient responses to existing therapies and aid in identifying new, more specific therapeutic approaches. In this issue of Cancer Research, Faraoni and colleagues identified CD73/Nt5e-generated adenosine as a mechanism of immunosuppression specifically in pancreatic ductal-derived basal/squamous-type PDAC. Using genetically engineered mouse models targeting key genetic mutations to pancreatic acinar or ductal cells and an array of experimental and computational biology approaches, the authors found that adenosine signaling through receptor ADORA2B induces immunosuppression and tumor progression in ductal cell-derived tumors. These data demonstrate how molecular stratification of PDAC in combination with targeted approaches may enhance patient responses to therapy in this deadly cancer. See related article by Faraoni et al., p. 1111.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0268
  2. Cancer Discov. 2023 Apr 06. pii: CD-23-0013. [Epub ahead of print]
    Analysis of donor pancreata defines the transcriptomic signature and microenvironment of early neoplastic lesions.
    Eileen S Carpenter, Ahmed M Elhossiny, Padma Kadiyala, Jay Li, Jake McGue, Brian D Griffith, Yaqing Zhang, Jacob Edwards, Sarah Nelson, Fatima Lima, Katelyn L Donahue, Wenting Du, Allison C Bischoff, Danyah Alomari, Hannah R Watkoske, Michael Mattea, Stephanie The, Carlos E Espinoza, Meredith Barrett, Christopher J Sonnenday, Nicholas Olden, Chin-Tung Chen, Nicole Peterson, Valerie Gunchick, Vaibhav Sahai, Arvind Rao, Filip Bednar, Jiaqi Shi, Timothy L Frankel, Marina Pasca di Magliano.
      The adult healthy human pancreas has been poorly studied given lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors thus avoiding any warm ischemia time. The 30 donors were diverse in age and race and had no known pancreas disease. Histopathological analysis of the samples revealed PanIN lesions in most individuals irrespective of age. Using a combination of multiplex immunohistochemistry, single cell RNA sequencing, and spatial transcriptomics, we provide the first ever characterization of the unique microenvironment of the adult human pancreas and of sporadic PanIN lesions. We compared healthy pancreata to pancreatic cancer and peritumoral tissue and observed distinct transcriptomic signatures in fibroblasts, and, to a lesser extent, macrophages. PanIN epithelial cells from healthy pancreata were remarkably transcriptionally similar to cancer cells, suggesting that neoplastic pathways are initiated early in tumorigenesis.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0013
  3. J Cachexia Sarcopenia Muscle. 2023 Apr 06.
    A novel orthotopic mouse model replicates human lung cancer cachexia.
    Wouter R P H van de Worp, Jan Theys, Alba Sanz González, Brent van der Heyden, Frank Verhaegen, Duncan Hauser, Florian Caiment, Hubertus J M Smeets, Annemie M W J Schols, Ardy van Helvoort, Ramon C J Langen.
       INTRODUCTION: Cancer cachexia, highly prevalent in lung cancer, is a debilitating syndrome characterized by involuntary loss of skeletal muscle mass and is associated with poor clinical outcome, decreased survival and negative impact on tumour therapy. Various lung tumour-bearing animal models have been used to explore underlying mechanisms of cancer cachexia. However, these models do not simulate anatomical and immunological features key to lung cancer and associated muscle wasting. Overcoming these shortcomings is essential to translate experimental findings into the clinic. We therefore evaluated whether a syngeneic, orthotopic lung cancer mouse model replicates systemic and muscle-specific alterations associated with human lung cancer cachexia.
    METHODS: Immune competent, 11 weeks old male 129S2/Sv mice, were randomly allocated to either (1) sham control group or (2) tumour-bearing group. Syngeneic lung epithelium-derived adenocarcinoma cells (K-rasG12D ; p53R172HΔG ) were inoculated intrapulmonary into the left lung lobe of the mice. Body weight and food intake were measured daily. At baseline and weekly after surgery, grip strength was measured and tumour growth and muscle volume were assessed using micro cone beam CT imaging. After reaching predefined surrogate survival endpoint, animals were euthanized, and skeletal muscles of the lower hind limbs were collected for biochemical analysis.
    RESULTS: Two-third of the tumour-bearing mice developed cachexia based on predefined criteria. Final body weight (-13.7 ± 5.7%; P < 0.01), muscle mass (-13.8 ± 8.1%; P < 0.01) and muscle strength (-25.5 ± 10.5%; P < 0.001) were reduced in cachectic mice compared with sham controls and median survival time post-surgery was 33.5 days until humane endpoint. Markers for proteolysis, both ubiquitin proteasome system (Fbxo32 and Trim63) and autophagy-lysosomal pathway (Gabarapl1 and Bnip3), were significantly upregulated, whereas markers for protein synthesis (relative phosphorylation of Akt, S6 and 4E-BP1) were significantly decreased in the skeletal muscle of cachectic mice compared with control. The cachectic mice exhibited increased pentraxin-2 (P < 0.001) and CXCL1/KC (P < 0.01) expression levels in blood plasma and increased mRNA expression of IκBα (P < 0.05) in skeletal muscle, indicative for the presence of systemic inflammation. Strikingly, RNA sequencing, pathway enrichment and miRNA expression analyses of mouse skeletal muscle strongly mirrored alterations observed in muscle biopsies of patients with lung cancer cachexia.
    CONCLUSIONS: We developed an orthotopic model of lung cancer cachexia in immune competent mice. Because this model simulates key aspects specific to cachexia in lung cancer patients, it is highly suitable to further investigate the underlying mechanisms of lung cancer cachexia and to test the efficacy of novel intervention strategies.
    Keywords:  Cancer cachexia; Lung cancer; Mouse model; Muscle wasting; OLCC; Orthotopic mouse model
    DOI:  https://doi.org/10.1002/jcsm.13222
  4. Nature. 2023 Apr;616(7955): 159-167
    Lung adenocarcinoma promotion by air pollutants.
    TRACERx Consortium
      A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development1. Here we propose that environmental particulate matter measuring ≤2.5 μm (PM2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM2.5 levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1β. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for  PM2.5 air pollutants  and provide impetus for public health policy initiatives to address air pollution to reduce disease burden.
    DOI:  https://doi.org/10.1038/s41586-023-05874-3
  5. Nat Commun. 2023 Apr 03. 14(1): 1849
    NAD+ repletion with niacin counteracts cancer cachexia.
    Marc Beltrà, Noora Pöllänen, Claudia Fornelli, Kialiina Tonttila, Myriam Y Hsu, Sandra Zampieri, Lucia Moletta, Samantha Corrà, Paolo E Porporato, Riikka Kivelä, Carlo Viscomi, Marco Sandri, Juha J Hulmi, Roberta Sartori, Eija Pirinen, Fabio Penna.
      Cachexia is a debilitating wasting syndrome and highly prevalent comorbidity in cancer patients. It manifests especially with energy and mitochondrial metabolism aberrations that promote tissue wasting. We recently identified nicotinamide adenine dinucleotide (NAD+) loss to associate with muscle mitochondrial dysfunction in cancer hosts. In this study we confirm that depletion of NAD+ and downregulation of Nrk2, an NAD+ biosynthetic enzyme, are common features of severe cachexia in different mouse models. Testing NAD+ repletion therapy in cachectic mice reveals that NAD+ precursor, vitamin B3 niacin, efficiently corrects tissue NAD+ levels, improves mitochondrial metabolism and ameliorates cancer- and chemotherapy-induced cachexia. In a clinical setting, we show that muscle NRK2 is downregulated in cancer patients. The low expression of NRK2 correlates with metabolic abnormalities underscoring the significance of NAD+ in the pathophysiology of human cancer cachexia. Overall, our results propose NAD+ metabolism as a therapy target for cachectic cancer patients.
    DOI:  https://doi.org/10.1038/s41467-023-37595-6
  6. Front Immunol. 2023 ;14 1159411
    Lipocalin-2 and neutrophil activation in pancreatic cancer cachexia.
    Min Deng, Merel R Aberle, Annemarie A J H M van Bijnen, Gregory van der Kroft, Kaatje Lenaerts, Ulf P Neumann, Georg Wiltberger, Frank G Schaap, Steven W M Olde Damink, Sander S Rensen.
       Background: Cancer cachexia is a multifactorial syndrome characterized by body weight loss and systemic inflammation. The characterization of the inflammatory response in patients with cachexia is still limited. Lipocalin-2, a protein abundant in neutrophils, has recently been implicated in appetite suppression in preclinical models of pancreatic cancer cachexia. We hypothesized that lipocalin-2 levels could be associated with neutrophil activation and nutritional status of pancreatic ductal adenocarcinoma (PDAC) patients.
    Methods: Plasma levels of neutrophil activation markers calprotectin, myeloperoxidase, elastase, and bactericidal/permeability-increasing protein (BPI) were compared between non-cachectic PDAC patients (n=13) and cachectic PDAC patients with high (≥26.9 ng/mL, n=34) or low (<26.9 ng/mL, n=34) circulating lipocalin-2 levels. Patients' nutritional status was assessed by the patient-generated subjective global assessment (PG-SGA) and through body composition analysis using CT-scan slices at the L3 level.
    Results: Circulating lipocalin-2 levels did not differ between cachectic and non-cachectic PDAC patients (median 26.7 (IQR 19.7-34.8) vs. 24.8 (16.6-29.4) ng/mL, p=0.141). Cachectic patients with high systemic lipocalin-2 levels had higher concentrations of calprotectin, myeloperoxidase, and elastase than non-cachectic patients or cachectic patients with low lipocalin-2 levels (calprotectin: 542.3 (355.8-724.9) vs. 457.5 (213.3-606.9), p=0.448 vs. 366.5 (294.5-478.5) ng/mL, p=0.009; myeloperoxidase: 30.3 (22.1-37.9) vs. 16.3 (12.0-27.5), p=0.021 vs. 20.2 (15.0-29.2) ng/mL, p=0.011; elastase: 137.1 (90.8-253.2) vs. 97.2 (28.8-215.7), p=0.410 vs. 95.0 (72.2-113.6) ng/mL, p=0.006; respectively). The CRP/albumin ratio was also higher in cachectic patients with high lipocalin-2 levels (2.3 (1.3-6.0) as compared to non-cachectic patients (1.0 (0.7-4.2), p=0.041). Lipocalin-2 concentrations correlated with those of calprotectin (rs =0.36, p<0.001), myeloperoxidase (rs =0.48, p<0.001), elastase (rs =0.50, p<0.001), and BPI (rs =0.22, p=0.048). Whereas no significant correlations with weight loss, BMI, or L3 skeletal muscle index were observed, lipocalin-2 concentrations were associated with subcutaneous adipose tissue index (rs =-0.25, p=0.034). Moreover, lipocalin-2 tended to be elevated in severely malnourished patients compared with well-nourished patients (27.2 (20.3-37.2) vs. 19.9 (13.4-26.4) ng/mL, p=0.058).
    Conclusions: These data suggest that lipocalin-2 levels are associated with neutrophil activation in patients with pancreatic cancer cachexia and that it may contribute to their poor nutritional status.
    Keywords:  appetite; cancer cachexia; complement; innate immunity; lipocalin-2; neutrophil activation; nutritional status
    DOI:  https://doi.org/10.3389/fimmu.2023.1159411
  7. J Cachexia Sarcopenia Muscle. 2023 Apr 06.
    Specific miRNAs are associated with human cancer cachexia in an organ-specific manner.
    Tanja Krauss, Simone Heisz, Julius Honecker, Olga Prokopchuk, Marc Martignoni, Klaus-Peter Janssen, Melina Claussnitzer, Hans Hauner, Claudine Seeliger.
       BACKGROUND: Cancer cachexia (CCx) is a complex and multi-organ wasting syndrome characterized by substantial weight loss and poor prognosis. An improved understanding of the mechanisms involved in the onset and progression of cancer cachexia is essential. How microRNAs contribute to the clinical manifestation and progression of CCx remains elusive. The aim of this study was to identify specific miRNAs related to organ-specific CCx and explore their functional role in humans.
    METHODS: miRNA patterns in serum and in cachexia target organs (liver, muscle and adipose tissue) from weight stable (N ≤ 12) and cachectic patients (N ≤ 23) with gastrointestinal cancer were analysed. As a first step, a miRNA array (158 miRNAs) was performed in pooled serum samples. Identified miRNAs were validated in serum and corresponding tissue samples. Using in silico prediction, related genes were identified and evaluated. The findings were confirmed in vitro by siRNA knock-down experiments in human visceral preadipocytes and C2C12 myoblast cells and consecutive gene expression analyses.
    RESULTS: Validating the results of the array, a 2-fold down-regulation of miR-122-5p (P = 0.0396) and a 4.5-fold down-regulation of miR-194-5p (P < 0.0001) in serum of CCx patients in comparison with healthy controls were detected. Only miR-122-5p correlated with weight loss and CCx status (P = 0.0367). Analysing corresponding tissues six muscle and eight visceral adipose tissue (VAT) cachexia-associated miRNAs were identified. miR-27b-3p, miR-375 and miR-424-5p were the most consistently affected miRNAs in tissues of CCx patients correlating negatively with the severity of body weight loss (P = 0.0386, P = 0.0112 and P = 0.0075, respectively). We identified numerous putative target genes of the miRNAs in association with muscle atrophy and lipolysis pathways. Knock-down experiments in C2C12 myoblast cells revealed an association of miR-27b-3p and the in silico predicted atrophy-related target genes IL-15 and TRIM63. Both were up-regulated in miR-27b-3p knock-down cells (P < 0.05). Concordantly, in muscle tissue of CCx individuals, significant higher expression levels of IL-15 (P = 0.0237) and TRIM63 (P = 0.0442) were detected. miR-424-5p was identified to regulate the expression of lipase genes. Knock-down experiments in human visceral preadipocytes revealed an inverse association of miR-424-5p with its predicted target genes LIPE, PNPLA2, MGLL and LPL (P < 0.01).
    CONCLUSIONS: The identified miRNAs, in particular miR-122-5p, miR-27b-3p, miR-375 and miR-424-5p, represent features of human CCx and may contribute to tissue wasting and skeletal muscle atrophy through the regulation of catabolic signals. Further studies are needed to explore the potential of the identified miRNAs as a screening tool for early detection of cancer cachexia.
    Keywords:  Cancer cachexia; Pathway genes; Weight loss; miRNAs
    DOI:  https://doi.org/10.1002/jcsm.13224
  8. J Am Chem Soc. 2023 Apr 05.
    Light-Deactivated Fluorescent Probes (FLASH-Off) for Multiplexed Imaging.
    Elias A Halabi, Ralph Weissleder.
      Highly multiplexed, cyclic fluorescence imaging has advanced our understanding of the biology, evolution, and complexity of human diseases. Currently available cyclic methods still have considerable limitations including the need for long quenching times and extensive wash steps. Here, we report a new series of fluorochromes that can be efficiently inactivated by a single light pulse (∼405 nm) by means of a photo-immolating triazene linker. Upon UV-light irradiation, the rhodamines are cleaved off from the antibody conjugates and undergo a fast intramolecular spirocyclization that inherently switches off their fluorescence emission without the need to wash or add exogenous chemicals. We show that these switch-off probes are fast, highly controllable, biocompatible, and allow spatiotemporal quenching control of live and fixed samples.
    DOI:  https://doi.org/10.1021/jacs.3c00170
  9. Methods Mol Biol. 2023 ;2620 243-252
    Monitoring the Activation of Selective Autophagy via N-Terminal Arginylation.
    Chang Hoon Ji, Su Bin Kim, Min Ju Lee, Yong Tae Kwon.
      In addition to generating N-degron-carrying substrates destined for proteolysis, N-terminal arginylation can globally upregulate selective macroautophagy via activation of the autophagic N-recognin and archetypal autophagy cargo receptor p62/SQSTM1/sequestosome-1. To evaluate the macroautophagic turnover of cellular substrates, including protein aggregates (aggrephagy) and subcellular organelles (organellophagy) mediated by N-terminal arginylation in vivo, we report here a protocol for assaying the activation of the autophagic Arg/N-degron pathway and degradation of cellular cargoes via N-terminal arginylation. These methods, reagents, and conditions are applicable across a wide spectrum of different cell lines, primary cultures, and/or animal tissues, thereby providing a general means for identification and validation of putative cellular cargoes degraded by Nt-arginylation-activated selective autophagy.
    Keywords:  ATE1; Autophagic flux; Detergent-insoluble/soluble fractionation; In vitro p62/SQSTM1 self-oligomerization; Nt-arginylation; Punctate formation/co-localization
    DOI:  https://doi.org/10.1007/978-1-0716-2942-0_26
  10. Autophagy. 2023 Apr 04.
    LC3-independent autophagy is vital to prevent TNF cytotoxicity.
    Dario Priem, Jon Huyghe, Mathieu Jm Bertrand.
      The (macro)autophagy field is facing a paradigm shift after the recent discovery that cytosolic cargoes can still be selectively targeted to phagophores (the precursors to autophagosomes) even in the absence of LC3 or other Atg8-protein family members. Several in vitro studies have indeed reported on the existence of an unconventional selective autophagic pathway that involves the in-situ formation of an autophagosome around the cargo through the direct selective autophagy receptor-mediated recruitment of RB1CC1/FIP200, thereby bypassing the requirement of LC3. In an article recently published in Science, we demonstrate the physiological importance of this unconventional autophagic pathway in the context of TNF (tumor necrosis factor) signaling. We show that it promotes the degradation of the cytotoxic TNFRSF1A/TNFR1 (TNF receptor superfamily member 1A) complex II that assembles upon TNF sensing and thereby protects mice from TNFRSF1A-driven embryonic lethality and skin inflammation.
    Keywords:  ATG9A; Apoptosis; LC3-independent autophagy; RB1CC1; TAX1BP1; cell death; embryogenesis; mouse development; skin disease; unconventional autophagy
    DOI:  https://doi.org/10.1080/15548627.2023.2197760
  11. Nat Cell Biol. 2023 Apr 06.
    A lysosome membrane regeneration pathway depends on TBC1D15 and autophagic lysosomal reformation proteins.
    Anshu Bhattacharya, Rukmini Mukherjee, Santosh Kumar Kuncha, Melinda Elaine Brunstein, Rajeshwari Rathore, Stephan Junek, Christian Münch, Ivan Dikic.
      Acute lysosomal membrane damage reduces the cellular population of functional lysosomes. However, these damaged lysosomes have a remarkable recovery potential independent of lysosomal biogenesis and remain unaffected in cells depleted in TFEB and TFE3. We combined proximity-labelling-based proteomics, biochemistry and high-resolution microscopy to unravel a lysosomal membrane regeneration pathway that depends on ATG8, the lysosomal membrane protein LIMP2, the RAB7 GTPase-activating protein TBC1D15 and proteins required for autophagic lysosomal reformation, including dynamin-2, kinesin-5B and clathrin. Following lysosomal damage, LIMP2 acts as a lysophagy receptor to bind ATG8, which in turn recruits TBC1D15 to damaged membranes. TBC1D15 interacts with ATG8 proteins on damaged lysosomes and provides a scaffold to assemble and stabilize the autophagic lysosomal reformation machinery. This potentiates the formation of lysosomal tubules and subsequent dynamin-2-dependent scission. TBC1D15-mediated lysosome regeneration was also observed in a cell culture model of oxalate nephropathy.
    DOI:  https://doi.org/10.1038/s41556-023-01125-9
  12. Mol Cell. 2023 Apr 01. pii: S1097-2765(23)00203-4. [Epub ahead of print]
    Structural and functional properties of mSWI/SNF chromatin remodeling complexes revealed through single-cell perturbation screens.
    Jordan E Otto, Oana Ursu, Alexander P Wu, Evan B Winter, Michael S Cuoco, Sai Ma, Kristin Qian, Brittany C Michel, Jason D Buenrostro, Bonnie Berger, Aviv Regev, Cigall Kadoch.
      The mammalian SWI/SNF (mSWI/SNF or BAF) family of chromatin remodeling complexes play critical roles in regulating DNA accessibility and gene expression. The three final-form subcomplexes-cBAF, PBAF, and ncBAF-are distinct in biochemical componentry, chromatin targeting, and roles in disease; however, the contributions of their constituent subunits to gene expression remain incompletely defined. Here, we performed Perturb-seq-based CRISPR-Cas9 knockout screens targeting mSWI/SNF subunits individually and in select combinations, followed by single-cell RNA-seq and SHARE-seq. We uncovered complex-, module-, and subunit-specific contributions to distinct regulatory networks and defined paralog subunit relationships and shifted subcomplex functions upon perturbations. Synergistic, intra-complex genetic interactions between subunits reveal functional redundancy and modularity. Importantly, single-cell subunit perturbation signatures mapped across bulk primary human tumor expression profiles both mirror and predict cBAF loss-of-function status in cancer. Our findings highlight the utility of Perturb-seq to dissect disease-relevant gene regulatory impacts of heterogeneous, multi-component master regulatory complexes.
    Keywords:  ATAC-seq; ATP-dependent chromatin remodeling; BAF complex; Perturb-seq; SHARE-Seq; cancer; chromatin accessibility; gene expression; mammalian SWI/SNF complexes; pediatric cancer; rare diseases
    DOI:  https://doi.org/10.1016/j.molcel.2023.03.013
  13. Mol Cell. 2023 Apr 06. pii: S1097-2765(23)00204-6. [Epub ahead of print]83(7): 1016-1021
    Transitions in the framework of condensate biology.
    Geraldine Seydoux, Mingjie Zhang, Julie D Forman-Kay, Brian McStay, Kathy Fange Liu, Pilong Li.
      As phase separation is found in an increasing variety of biological contexts, additional challenges have arisen in understanding the underlying principles of condensate formation and function. We spoke with researchers across disciplines about their views on the ever-changing landscape of biomolecular condensates.
    DOI:  https://doi.org/10.1016/j.molcel.2023.03.014
  14. Cancer Discov. 2023 Apr 03. 13(4): 824-828
    Moving Spatially Resolved Multiplexed Protein Profiling toward Clinical Oncology.
    Maryam Pourmaleki, Nicholas D Socci, Travis J Hollmann, Ingo K Mellinghoff.
      The shift in cancer therapy from broadly cytotoxic agents toward "personalized" treatments that target specific alterations in each patient's tumor requires diagnostic pathology approaches that are quantitative and biospecimen-friendly. Novel multiplexed antibody-based imaging technologies can measure single-cell expression of over 60 proteins in intact tumor sections and hold promise for clinical oncology.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-1015
  15. Cell Metab. 2023 Apr 04. pii: S1550-4131(23)00085-2. [Epub ahead of print]35(4): 711-721.e4
    Global determination of reaction rates and lipid turnover kinetics in Mus musculus.
    Qishan Chen, Hu Li, He Tian, Sin Man Lam, Yilie Liao, Ziyin Zhang, Manyuan Dong, Shaoru Chen, Yuxiao Yao, Jiemiao Meng, Yong Zhang, Lemin Zheng, Zhuo-Xian Meng, Weiping Han, Guanghou Shui, Dahai Zhu, Suneng Fu.
      Metabolism is fundamental to life, but measuring metabolic reaction rates remains challenging. Here, we applied C13 fluxomics to monitor the metabolism of dietary glucose carbon in 12 tissues, 9 brain compartments, and over 1,000 metabolite isotopologues over a 4-day period. The rates of 85 reactions surrounding central carbon metabolism are determined with elementary metabolite unit (EMU) modeling. Lactate oxidation, not glycolysis, occurs at a comparable pace with the tricarboxylic acid cycle (TCA), supporting lactate as the primary fuel. We expand the EMU framework to track and quantify metabolite flows across tissues. Specifically, multi-organ EMU simulation of uridine metabolism shows that tissue-blood exchange, not synthesis, controls nucleotide homeostasis. In contrast, isotopologue fingerprinting and kinetic analyses reveal the brown adipose tissue (BAT) having the highest palmitate synthesis activity but no apparent contribution to circulation, suggesting a tissue-autonomous synthesis-to-burn mechanism. Together, this study demonstrates the utility of dietary fluxomics for kinetic mapping in vivo and provides a rich resource for elucidating inter-organ metabolic cross talk.
    Keywords:  dietary fluxomics; elementary metabolite units; inter-organ metabolite flow; multi-organ EMU modeling
    DOI:  https://doi.org/10.1016/j.cmet.2023.03.007
  16. Nat Methods. 2023 Apr 03.
    Researchers dig into cancer niches.
    Vivien Marx.
      
    DOI:  https://doi.org/10.1038/s41592-023-01834-x
  17. J Cell Biol. 2023 Jun 05. pii: e202204001. [Epub ahead of print]222(6):
    Oncogenic signaling is coupled to colorectal cancer cell differentiation state.
    Thomas Sell, Christian Klotz, Matthias M Fischer, Rosario Astaburuaga-García, Susanne Krug, Jarno Drost, Hans Clevers, Christine Sers, Markus Morkel, Nils Blüthgen.
      Colorectal cancer progression is intrinsically linked to stepwise deregulation of the intestinal differentiation trajectory. In this process, sequential mutations of APC, KRAS, TP53, and SMAD4 enable oncogenic signaling and establish the hallmarks of cancer. Here, we use mass cytometry of isogenic human colon organoids and patient-derived cancer organoids to capture oncogenic signaling, cell phenotypes, and differentiation states in a high-dimensional single-cell map. We define a differentiation axis in all tumor progression states from normal to cancer. Our data show that colorectal cancer driver mutations shape the distribution of cells along the differentiation axis. In this regard, subsequent mutations can have stem cell promoting or restricting effects. Individual nodes of the cancer cell signaling network remain coupled to the differentiation state, regardless of the presence of driver mutations. We use single-cell RNA sequencing to link the (phospho-)protein signaling network to transcriptomic states with biological and clinical relevance. Our work highlights how oncogenes gradually shape signaling and transcriptomes during tumor progression.
    DOI:  https://doi.org/10.1083/jcb.202204001
  18. Cancer Discov. 2023 Apr 03. 13(4): 797-798
    The Hallmarks of a Cancer Discovery.
    Luis A Diaz, Lewis C Cantley.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0171
  19. Cell Rep. 2023 Apr 06. pii: S2211-1247(23)00346-7. [Epub ahead of print]42(4): 112335
    Neurons require glucose uptake and glycolysis in vivo.
    Huihui Li, Caroline Guglielmetti, Yoshitaka J Sei, Misha Zilberter, Lydia M Le Page, Lauren Shields, Joyce Yang, Kevin Nguyen, Brice Tiret, Xiao Gao, Neal Bennett, Iris Lo, Talya L Dayton, Martin Kampmann, Yadong Huang, Jeffrey C Rathmell, Matthew Vander Heiden, Myriam M Chaumeil, Ken Nakamura.
      Neurons require large amounts of energy, but whether they can perform glycolysis or require glycolysis to maintain energy remains unclear. Using metabolomics, we show that human neurons do metabolize glucose through glycolysis and can rely on glycolysis to supply tricarboxylic acid (TCA) cycle metabolites. To investigate the requirement for glycolysis, we generated mice with postnatal deletion of either the dominant neuronal glucose transporter (GLUT3cKO) or the neuronal-enriched pyruvate kinase isoform (PKM1cKO) in CA1 and other hippocampal neurons. GLUT3cKO and PKM1cKO mice show age-dependent learning and memory deficits. Hyperpolarized magnetic resonance spectroscopic (MRS) imaging shows that female PKM1cKO mice have increased pyruvate-to-lactate conversion, whereas female GLUT3cKO mice have decreased conversion, body weight, and brain volume. GLUT3KO neurons also have decreased cytosolic glucose and ATP at nerve terminals, with spatial genomics and metabolomics revealing compensatory changes in mitochondrial bioenergetics and galactose metabolism. Therefore, neurons metabolize glucose through glycolysis in vivo and require glycolysis for normal function.
    Keywords:  CP: Neuroscience; bioenergetics; brain energy; galactose metabolism; glucose transporter; glycolysis; hyperpolarized magnetic resonance spectroscopic imaging; metabolomics; neuronal glucose metabolism; pyruvate kinase
    DOI:  https://doi.org/10.1016/j.celrep.2023.112335
  20. Cell Rep. 2023 Mar 29. pii: S2211-1247(23)00326-1. [Epub ahead of print] 112315
    Sodium ion influx regulates liquidity of biomolecular condensates in hyperosmotic stress response.
    Kazuhiro Morishita, Kengo Watanabe, Isao Naguro, Hidenori Ichijo.
      Biomolecular condensates are membraneless structures formed through phase separation. Recent studies have demonstrated that the material properties of biomolecular condensates are crucial for their biological functions and pathogenicity. However, the phase maintenance of biomolecular condensates in cells remains elusive. Here, we show that sodium ion (Na+) influx regulates the condensate liquidity under hyperosmotic stress. ASK3 condensates have higher fluidity at the high intracellular Na+ concentration derived from extracellular hyperosmotic solution. Moreover, we identified TRPM4 as a cation channel that allows Na+ influx under hyperosmotic stress. TRPM4 inhibition causes the liquid-to-solid phase transition of ASK3 condensates, leading to impairment of the ASK3 osmoresponse. In addition to ASK3 condensates, intracellular Na+ widely regulates the condensate liquidity and aggregate formation of biomolecules, including DCP1A, TAZ, and polyQ-protein, under hyperosmotic stress. Our findings demonstrate that changes in Na+ contribute to the cellular stress response via liquidity maintenance of biomolecular condensates.
    Keywords:  CP: Molecular biology; biomolecular condensate; liquidity; osmotic stress; phase separation; polyQ; protein aggregation; sodium ion
    DOI:  https://doi.org/10.1016/j.celrep.2023.112315
  21. Nat Rev Cancer. 2023 Apr 03.
    Visualizing intratumoural heterogeneity with EpicMIBI.
    Alexandros P Drainas.
      
    DOI:  https://doi.org/10.1038/s41568-023-00569-3
  22. Nat Commun. 2023 Apr 03. 14(1): 1851
    Workflow enabling deepscale immunopeptidome, proteome, ubiquitylome, phosphoproteome, and acetylome analyses of sample-limited tissues.
    Jennifer G Abelin, Erik J Bergstrom, Keith D Rivera, Hannah B Taylor, Susan Klaeger, Charles Xu, Eva K Verzani, C Jackson White, Hilina B Woldemichael, Maya Virshup, Meagan E Olive, Myranda Maynard, Stephanie A Vartany, Joseph D Allen, Kshiti Phulphagar, M Harry Kane, Suzanna Rachimi, D R Mani, Michael A Gillette, Shankha Satpathy, Karl R Clauser, Namrata D Udeshi, Steven A Carr.
      Serial multi-omic analysis of proteome, phosphoproteome, and acetylome provides insights into changes in protein expression, cell signaling, cross-talk and epigenetic pathways involved in disease pathology and treatment. However, ubiquitylome and HLA peptidome data collection used to understand protein degradation and antigen presentation have not together been serialized, and instead require separate samples for parallel processing using distinct protocols. Here we present MONTE, a highly sensitive multi-omic native tissue enrichment workflow, that enables serial, deep-scale analysis of HLA-I and HLA-II immunopeptidome, ubiquitylome, proteome, phosphoproteome, and acetylome from the same tissue sample. We demonstrate that the depth of coverage and quantitative precision of each 'ome is not compromised by serialization, and the addition of HLA immunopeptidomics enables the identification of peptides derived from cancer/testis antigens and patient specific neoantigens. We evaluate the technical feasibility of the MONTE workflow using a small cohort of patient lung adenocarcinoma tumors.
    DOI:  https://doi.org/10.1038/s41467-023-37547-0
  23. Nat Metab. 2023 Apr 03.
    Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells.
    Alanna C Green, Petra Marttila, Nicole Kiweler, Christina Chalkiadaki, Elisée Wiita, Victoria Cookson, Antoine Lesur, Kim Eiden, François Bernardin, Karl S A Vallin, Sanjay Borhade, Maeve Long, Elahe Kamali Ghahe, Julio J Jiménez-Alonso, Ann-Sofie Jemth, Olga Loseva, Oliver Mortusewicz, Marianne Meyers, Elodie Viry, Annika I Johansson, Ondřej Hodek, Evert Homan, Nadilly Bonagas, Louise Ramos, Lars Sandberg, Morten Frödin, Etienne Moussay, Ana Slipicevic, Elisabeth Letellier, Jérôme Paggetti, Claus Storgaard Sørensen, Thomas Helleday, Martin Henriksson, Johannes Meiser.
      Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase-cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a 'folate trap'. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.
    DOI:  https://doi.org/10.1038/s42255-023-00771-5
  24. Nat Commun. 2023 Apr 03. 14(1): 1840
    A stress-induced cilium-to-PML-NB route drives senescence initiation.
    Xiaoyu Ma, Yingyi Zhang, Yuanyuan Zhang, Xu Zhang, Yan Huang, Kai He, Chuan Chen, Jielu Hao, Debiao Zhao, Nathan K LeBrasseur, James L Kirkland, Eduardo N Chini, Qing Wei, Kun Ling, Jinghua Hu.
      Cellular senescence contributes to tissue homeostasis and age-related pathologies. However, how senescence is initiated in stressed cells remains vague. Here, we discover that exposure to irradiation, oxidative or inflammatory stressors induces transient biogenesis of primary cilia, which are then used by stressed cells to communicate with the promyelocytic leukemia nuclear bodies (PML-NBs) to initiate senescence responses in human cells. Mechanistically, a ciliary ARL13B-ARL3 GTPase cascade negatively regulates the association of transition fiber protein FBF1 and SUMO-conjugating enzyme UBC9. Irreparable stresses downregulate the ciliary ARLs and release UBC9 to SUMOylate FBF1 at the ciliary base. SUMOylated FBF1 then translocates to PML-NBs to promote PML-NB biogenesis and PML-NB-dependent senescence initiation. Remarkably, Fbf1 ablation effectively subdues global senescence burden and prevents associated health decline in irradiation-treated mice. Collectively, our findings assign the primary cilium a key role in senescence induction in mammalian cells and, also, a promising target in future senotherapy strategies.
    DOI:  https://doi.org/10.1038/s41467-023-37362-7
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