bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2023–08–27
fifty papers selected by
Christian Frezza, Universität zu Köln
  1. Glutarate regulates T cell metabolism and anti-tumour immunity.
  2. Succinylation of a KEAP1 sensor lysine promotes NRF2 activation.
  3. Comprehensive isotopomer analysis of glutamate and aspartate in small tissue samples.
  4. Glutarate tunes T cell fate.
  5. The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease.
  6. Pyruvate Dehydrogenase-Dependent Metabolic Programming Affects the Oligodendrocyte Maturation and Remyelination.
  7. Mechanisms of Modulation of Mitochondrial Architecture.
  8. Structural mechanism of mitochondrial membrane remodelling by human OPA1.
  9. The pentose phosphate pathway in health and disease.
  10. Strategies for uncovering stable isotope tracing patterns between cell populations.
  11. Non-cell-autonomous cancer progression from chromosomal instability.
  12. The Transcription Factor ChREBP Links Mitochondrial Lipidomes to Mitochondrial Morphology and Progression of Diabetic Kidney Disease.
  13. The CTNS-MTORC1 axis couples lysosomal cystine to epithelial cell fate decisions and is a targetable pathway in cystinosis.
  14. A Caenorhabditis elegans model of adenylosuccinate lyase deficiency reveals neuromuscular and reproductive phenotypes of distinct etiology.
  15. Lipocalin-2 induces mitochondrial dysfunction in renal tubular cells via mTOR pathway activation.
  16. Deciphering the decline of metabolic elasticity in aging and obesity.
  17. Hypoxia induces a glycolytic complex in intestinal epithelial cells independent of HIF-1-driven glycolytic gene expression.
  18. Post-translational modifications and protein quality control of mitochondrial channels and transporters.
  19. A transcriptional response to replication stress selectively expands a subset of Brca2-mutant mammary epithelial cells.
  20. Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects.
  21. Distinct mutational processes shape selection of MHC class I and class II mutations across primary and metastatic tumors.
  22. 4-Octyl itaconate restricts STING activation by blocking its palmitoylation.
  23. Mitochondrial heterogeneity in diseases.
  24. Mitochondrial Volume Regulation and Swelling Mechanisms in Cardiomyocytes.
  25. An adult clock component links circadian rhythms to pancreatic β-cell maturation.
  26. Principles of metabolome conservation in animals.
  27. Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming.
  28. Promotion of oxidative phosphorylation by complex I-anchored carbonic anhydrases?
  29. A single inhibitor for all KRAS mutations.
  30. Dynamic links between mechanical forces and metabolism shape the tumor milieu.
  31. Pan-Cancer Proteogenomics Uncovers Phenotypes of Cancer Driver Events.
  32. Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression.
  33. cDC1 craves glutamine for its glory.
  34. The architecture of metabolic networks constrains the evolution of microbial resource hierarchies.
  35. A big picture of the mitochondria-mediated signals: From mitochondria to organism.
  36. Metabolic heterogeneity in adrenocortical carcinoma impacts patient outcomes.
  37. Elimination of oncogenic KRAS in genetic mouse models eradicates pancreatic cancer by inducing FAS-dependent apoptosis by CD8+ T cells.
  38. Convergent somatic evolution commences in utero in a germline ribosomopathy.
  39. mTORC1 regulates phagosome digestion of symbiotic bacteria for intracellular nutritional symbiosis in a deep-sea mussel.
  40. Folate trapping is lethal to cancer cells.
  41. Metabolic reprogramming in Nrf2-driven proliferation of normal rat hepatocytes.
  42. Paired microbiome and metabolome analyses associate bile acid changes with colorectal cancer progression.
  43. Mitochondrial function and phenotype are defined by bioenergetics.
  44. The HuMet Repository: Watching human metabolism at work.
  45. Golgi retention and oncogenic KIT signaling via PLCγ2-PKD2-PI4KIIIβ activation in gastrointestinal stromal tumor cells.
  46. Epigenetic control of cancer inflammation.
  47. A cell cycle centric view of tumour dormancy.
  48. Gluconeogenesis Flux in Metabolic Disease.
  49. Tissue Biology: In Search of a New Paradigm.
  50. Cellular Origins and Lineage Plasticity in Cancer.
  1. Nat Metab. 2023 Aug 21.
    Glutarate regulates T cell metabolism and anti-tumour immunity.
    Eleanor Minogue, Pedro P Cunha, Brennan J Wadsworth, Guinevere L Grice, Shiv K Sah-Teli, Rob Hughes, David Bargiela, Alessandro Quaranta, Javier Zurita, Robin Antrobus, Pedro Velica, Laura Barbieri, Craig E Wheelock, Peppi Koivunen, James A Nathan, Iosifina P Foskolou, Randall S Johnson.
      T cell function and fate can be influenced by several metabolites: in some cases, acting through enzymatic inhibition of α-ketoglutarate-dependent dioxygenases, in others, through post-translational modification of lysines in important targets. We show here that glutarate, a product of amino acid catabolism, has the capacity to do both, and has potent effects on T cell function and differentiation. We found that glutarate exerts those effects both through α-ketoglutarate-dependent dioxygenase inhibition, and through direct regulation of T cell metabolism via glutarylation of the pyruvate dehydrogenase E2 subunit. Administration of diethyl glutarate, a cell-permeable form of glutarate, alters CD8+ T cell differentiation and increases cytotoxicity against target cells. In vivo administration of the compound is correlated with increased levels of both peripheral and intratumoural cytotoxic CD8+ T cells. These results demonstrate that glutarate is an important regulator of T cell metabolism and differentiation with a potential role in the improvement of T cell immunotherapy.
    DOI:  https://doi.org/10.1038/s42255-023-00855-2
  2. Cell Chem Biol. 2023 Aug 11. pii: S2451-9456(23)00243-X. [Epub ahead of print]
    Succinylation of a KEAP1 sensor lysine promotes NRF2 activation.
    Lara Ibrahim, Caroline Stanton, Kayla Nutsch, Thu Nguyen, Chloris Li-Ma, Yeonjin Ko, Gabriel C Lander, R Luke Wiseman, Michael J Bollong.
      Cross talk between metabolism and stress-responsive signaling is essential for maintaining cellular homeostasis. This cross talk is often achieved through covalent modification of proteins by endogenous, reactive metabolites that regulate key stress-responsive transcription factors like NRF2. Metabolites including methylglyoxal, glyceraldehyde 3-phosphate, fumarate, and itaconate covalently modify sensor cysteines of the NRF2 repressor KEAP1, resulting in stabilization of NRF2 and activation of its cytoprotective transcriptional program. Here, we employed a shRNA-based screen targeting the enzymes of central carbon metabolism to identify additional regulatory nodes bridging metabolism to NRF2 activation. Succinic anhydride, increased by genetic depletion of the TCA cycle enzyme succinyl-CoA synthetase or by direct administration, results in N-succinylation of lysine 131 of KEAP1 to activate NRF2 signaling. This study identifies KEAP1 as capable of sensing reactive metabolites not only by several cysteine residues but also by a conserved lysine residue, indicating its potential to sense an expanded repertoire of reactive metabolic messengers.
    DOI:  https://doi.org/10.1016/j.chembiol.2023.07.014
  3. Cell Metab. 2023 Aug 15. pii: S1550-4131(23)00272-3. [Epub ahead of print]
    Comprehensive isotopomer analysis of glutamate and aspartate in small tissue samples.
    Feng Cai, Divya Bezwada, Ling Cai, Rohit Mahar, Zheng Wu, Mario C Chang, Panayotis Pachnis, Chendong Yang, Sherwin Kelekar, Wen Gu, Bailey Brooks, Bookyung Ko, Hieu S Vu, Thomas P Mathews, Lauren G Zacharias, Misty Martin-Sandoval, Duyen Do, K Celeste Oaxaca, Eunsook S Jin, Vitaly Margulis, Craig R Malloy, Matthew E Merritt, Ralph J DeBerardinis.
      Stable isotopes are powerful tools to assess metabolism. 13C labeling is detected using nuclear magnetic resonance (NMR) spectroscopy or mass spectrometry (MS). MS has excellent sensitivity but generally cannot discriminate among different 13C positions (isotopomers), whereas NMR is less sensitive but reports some isotopomers. Here, we develop an MS method that reports all 16 aspartate and 32 glutamate isotopomers while requiring less than 1% of the sample used for NMR. This method discriminates between pathways that result in the same number of 13C labels in aspartate and glutamate, providing enhanced specificity over conventional MS. We demonstrate regional metabolic heterogeneity within human tumors, document the impact of fumarate hydratase (FH) deficiency in human renal cancers, and investigate the contributions of tricarboxylic acid (TCA) cycle turnover and CO2 recycling to isotope labeling in vivo. This method can accompany NMR or standard MS to provide outstanding sensitivity in isotope-labeling experiments, particularly in vivo.
    Keywords:  aspartate; cancer; glutamate; isotopomer; mass spectrometry; nuclear magnetic resonance; pyruvate carboxylase; stable isotope; tricarboxylic acid cycle
    DOI:  https://doi.org/10.1016/j.cmet.2023.07.013
  4. Nat Metab. 2023 Aug 21.
    Glutarate tunes T cell fate.
    Francisco Yanqui-Rivera, Christiane A Opitz.
      
    DOI:  https://doi.org/10.1038/s42255-023-00878-9
  5. Nat Rev Mol Cell Biol. 2023 Aug 23.
    The molecular basis of nutrient sensing and signalling by mTORC1 in metabolism regulation and disease.
    Claire Goul, Roberta Peruzzo, Roberto Zoncu.
      The Ser/Thr kinase mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolism. As part of mTOR complex 1 (mTORC1), mTOR integrates signals such as the levels of nutrients, growth factors, energy sources and oxygen, and triggers responses that either boost anabolism or suppress catabolism. mTORC1 signalling has wide-ranging consequences for the growth and homeostasis of key tissues and organs, and its dysregulated activity promotes cancer, type 2 diabetes, neurodegeneration and other age-related disorders. How mTORC1 integrates numerous upstream cues and translates them into specific downstream responses is an outstanding question with major implications for our understanding of physiology and disease mechanisms. In this Review, we discuss recent structural and functional insights into the molecular architecture of mTORC1 and its lysosomal partners, which have greatly increased our mechanistic understanding of nutrient-dependent mTORC1 regulation. We also discuss the emerging involvement of aberrant nutrient-mTORC1 signalling in multiple diseases.
    DOI:  https://doi.org/10.1038/s41580-023-00641-8
  6. Mol Neurobiol. 2023 Aug 24.
    Pyruvate Dehydrogenase-Dependent Metabolic Programming Affects the Oligodendrocyte Maturation and Remyelination.
    M Sajad, Insha Zahoor, Faraz Rashid, Mirela Cerghet, Ramandeep Rattan, Shailendra Giri.
      The metabolic needs of the premature/premyelinating oligodendrocytes (pre-OLs) and mature oligodendrocytes (OLs) are distinct. The metabolic control of oligodendrocyte maturation from the pre-OLs to the OLs is not fully understood. Here, we show that the terminal maturation and higher mitochondrial respiration in the OLs is an integrated process controlled through pyruvate dehydrogenase complex (Pdh). Combined bioenergetics and metabolic studies show that OLs show elevated mitochondrial respiration than the pre-OLs. Our signaling studies show that the increased mitochondrial respiration activity in the OLs is mediated by the activation of Pdh due to inhibition of the pyruvate dehydrogenase kinase-1 (Pdhk1) that phosphorylates and inhibits Pdh activity. Accordingly, when Pdhk1 is directly expressed in the pre-OLs, they fail to mature into the OLs. While Pdh converts pyruvate into the acetyl-CoA by its oxidative decarboxylation, our study shows that Pdh-dependent acetyl-CoA generation from pyruvate contributes to the acetylation of the bHLH family transcription factor, oligodendrocyte transcription factor 1 (Olig1) which is known to be involved in the OL maturation. Pdh inhibition via direct expression of Pdhk1 in the pre-OLs blocks the Olig1-acetylation and OL maturation. Using the cuprizone model of demyelination, we show that Pdh is deactivated during the demyelination phase, which is however reversed in the remyelination phase upon cuprizone withdrawal. In addition, Pdh activity status correlates with the Olig1-acetylation status in the cuprizone model. Hence, the Pdh metabolic node activation allows a robust mitochondrial respiration and activation of a molecular program necessary for the terminal maturation of oligodendrocytes. Our findings open a new dialogue in the developmental biology that links cellular development and metabolism. These findings have far-reaching implications in the development of therapies for a variety of demyelinating disorders including multiple sclerosis.
    Keywords:  Metabolism; Multiple sclerosis; OPC maturation; Oligodendrocytes; Pdh; Pdhk1
    DOI:  https://doi.org/10.1007/s12035-023-03546-x
  7. Biomolecules. 2023 Aug 07. pii: 1225. [Epub ahead of print]13(8):
    Mechanisms of Modulation of Mitochondrial Architecture.
    Juan Pablo Muñoz, Fernanda Luisa Basei, María Laura Rojas, David Galvis, Antonio Zorzano.
      Mitochondrial network architecture plays a critical role in cellular physiology. Indeed, alterations in the shape of mitochondria upon exposure to cellular stress can cause the dysfunction of these organelles. In this scenario, mitochondrial dynamics proteins and the phospholipid composition of the mitochondrial membrane are key for fine-tuning the modulation of mitochondrial architecture. In addition, several factors including post-translational modifications such as the phosphorylation, acetylation, SUMOylation, and o-GlcNAcylation of mitochondrial dynamics proteins contribute to shaping the plasticity of this architecture. In this regard, several studies have evidenced that, upon metabolic stress, mitochondrial dynamics proteins are post-translationally modified, leading to the alteration of mitochondrial architecture. Interestingly, several proteins that sustain the mitochondrial lipid composition also modulate mitochondrial morphology and organelle communication. In this context, pharmacological studies have revealed that the modulation of mitochondrial shape and function emerges as a potential therapeutic strategy for metabolic diseases. Here, we review the factors that modulate mitochondrial architecture.
    Keywords:  lipids; membrane contact sites (MCSs); metabolic disease; metabolism; mitochondria; mitochondrial dynamics; pharmacology; post-translational modification; tethers
    DOI:  https://doi.org/10.3390/biom13081225
  8. Nature. 2023 Aug 23.
    Structural mechanism of mitochondrial membrane remodelling by human OPA1.
    Alexander von der Malsburg, Gracie M Sapp, Kelly E Zuccaro, Alexander von Appen, Frank R Moss, Raghav Kalia, Jeremy A Bennett, Luciano A Abriata, Matteo Dal Peraro, Martin van der Laan, Adam Frost, Halil Aydin.
      Distinct morphologies of the mitochondrial network support divergent metabolic and regulatory processes that determine cell function and fate1-3. The mechanochemical GTPase optic atrophy 1 (OPA1) influences the architecture of cristae and catalyses the fusion of the mitochondrial inner membrane4,5. Despite its fundamental importance, the molecular mechanisms by which OPA1 modulates mitochondrial morphology are unclear. Here, using a combination of cellular and structural analyses, we illuminate the molecular mechanisms that are key to OPA1-dependent membrane remodelling and fusion. Human OPA1 embeds itself into cardiolipin-containing membranes through a lipid-binding paddle domain. A conserved loop within the paddle domain inserts deeply into the bilayer, further stabilizing the interactions with cardiolipin-enriched membranes. OPA1 dimerization through the paddle domain promotes the helical assembly of a flexible OPA1 lattice on the membrane, which drives mitochondrial fusion in cells. Moreover, the membrane-bending OPA1 oligomer undergoes conformational changes that pull the membrane-inserting loop out of the outer leaflet and contribute to the mechanics of membrane remodelling. Our findings provide a structural framework for understanding how human OPA1 shapes mitochondrial morphology and show us how human disease mutations compromise OPA1 functions.
    DOI:  https://doi.org/10.1038/s41586-023-06441-6
  9. Nat Metab. 2023 Aug;5(8): 1275-1289
    The pentose phosphate pathway in health and disease.
    Tara TeSlaa, Markus Ralser, Jing Fan, Joshua D Rabinowitz.
      The pentose phosphate pathway (PPP) is a glucose-oxidizing pathway that runs in parallel to upper glycolysis to produce ribose 5-phosphate and nicotinamide adenine dinucleotide phosphate (NADPH). Ribose 5-phosphate is used for nucleotide synthesis, while NADPH is involved in redox homoeostasis as well as in promoting biosynthetic processes, such as the synthesis of tetrahydrofolate, deoxyribonucleotides, proline, fatty acids and cholesterol. Through NADPH, the PPP plays a critical role in suppressing oxidative stress, including in certain cancers, in which PPP inhibition may be therapeutically useful. Conversely, PPP-derived NADPH also supports purposeful cellular generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) for signalling and pathogen killing. Genetic deficiencies in the PPP occur relatively commonly in the committed pathway enzyme glucose-6-phosphate dehydrogenase (G6PD). G6PD deficiency typically manifests as haemolytic anaemia due to red cell oxidative damage but, in severe cases, also results in infections due to lack of leucocyte oxidative burst, highlighting the dual redox roles of the pathway in free radical production and detoxification. This Review discusses the PPP in mammals, covering its roles in biochemistry, physiology and disease.
    DOI:  https://doi.org/10.1038/s42255-023-00863-2
  10. Curr Opin Biotechnol. 2023 Aug 21. pii: S0958-1669(23)00101-5. [Epub ahead of print]83 102991
    Strategies for uncovering stable isotope tracing patterns between cell populations.
    Sarah MacPherson, Kyle D Duncan, David R Goodlett, Julian J Lum.
      Despite practical complexities, isotope tracing studies in humans are becoming increasingly feasible. However, several technological challenges need to be addressed in order to take full advantage of human tracing studies. First, absolute metabolic flux measurements in mice are not so easily applied to human models, given that tissue resection is restricted to a single surgical time point. Second, isotope tracing has yet to be employed to detect metabolic differences between cells types in vivo. Here, we discuss the current models and propose an alternative, liquid tumor environment, that could overcome these limitations. Furthermore, we highlight current strategies used to maintain isotopolog enrichment following cell isolation techniques to facilitate cell-type-specific analysis.
    DOI:  https://doi.org/10.1016/j.copbio.2023.102991
  11. Nature. 2023 Aug 23.
    Non-cell-autonomous cancer progression from chromosomal instability.
    Jun Li, Melissa J Hubisz, Ethan M Earlie, Mercedes A Duran, Christy Hong, Austin A Varela, Emanuele Lettera, Matthew Deyell, Bernardo Tavora, Jonathan J Havel, Su M Phyu, Amit Dipak Amin, Karolina Budre, Erina Kamiya, Julie-Ann Cavallo, Christopher Garris, Simon Powell, Jorge S Reis-Filho, Hannah Wen, Sarah Bettigole, Atif J Khan, Benjamin Izar, Eileen E Parkes, Ashley M Laughney, Samuel F Bakhoum.
      Chromosomal instability (CIN) is a driver of cancer metastasis1-4, yet the extent to which this effect depends on the immune system remains unknown. Using ContactTracing-a newly developed, validated and benchmarked tool to infer the nature and conditional dependence of cell-cell interactions from single-cell transcriptomic data-we show that CIN-induced chronic activation of the cGAS-STING pathway promotes downstream signal re-wiring in cancer cells, leading to a pro-metastatic tumour microenvironment. This re-wiring is manifested by type I interferon tachyphylaxis selectively downstream of STING and a corresponding increase in cancer cell-derived endoplasmic reticulum (ER) stress response. Reversal of CIN, depletion of cancer cell STING or inhibition of ER stress response signalling abrogates CIN-dependent effects on the tumour microenvironment and suppresses metastasis in immune competent, but not severely immune compromised, settings. Treatment with STING inhibitors reduces CIN-driven metastasis in melanoma, breast and colorectal cancers in a manner dependent on tumour cell-intrinsic STING. Finally, we show that CIN and pervasive cGAS activation in micronuclei are associated with ER stress signalling, immune suppression and metastasis in human triple-negative breast cancer, highlighting a viable strategy to identify and therapeutically intervene in tumours spurred by CIN-induced inflammation.
    DOI:  https://doi.org/10.1038/s41586-023-06464-z
  12. J Biol Chem. 2023 Aug 21. pii: S0021-9258(23)02213-5. [Epub ahead of print] 105185
    The Transcription Factor ChREBP Links Mitochondrial Lipidomes to Mitochondrial Morphology and Progression of Diabetic Kidney Disease.
    Li Li, Jianyin Long, Koki Mise, Naravat Poungavrin, Philip L Lorenzi, Iqbal Mahmud, Lin Tan, Pradip K Saha, Yashpal S Kanwar, Benny H Chang, Farhad R Danesh.
      A substantial body of evidence has established the contributions of both mitochondrial dynamics and lipid metabolism to the pathogenesis of diabetic kidney disease (DKD). However, the precise interplay between these two key metabolic regulators of DKD is not fully understood. Here, we uncover a link between mitochondrial dynamics and lipid metabolism by investigating the role of carbohydrate-response element-binding protein (ChREBP), a glucose-responsive transcription factor and a master regulator of lipogenesis, in kidney podocytes. We find that inducible podocyte-specific knockdown of ChREBP in diabetic db/db mice improves key biochemical and histological features of DKD in addition to significantly reducing mitochondrial fragmentation. Because of the critical role of ChREBP in lipid metabolism, we interrogated whether and how mitochondrial lipidomes play a role in ChREBP-mediated mitochondrial fission. Our findings suggest a key role for a family of ether phospholipids in ChREBP-induced mitochondrial remodeling. We find that overexpression of glyceronephosphate O-acyltransferase (GNPAT), a critical enzyme in the biosynthesis of plasmalogens, reverses the protective phenotype of ChREBP deficiency on mitochondrial fragmentation. Finally, our data also points to Gnpat as a direct transcriptional target of ChREBP. Taken together, our results uncover a distinct mitochondrial lipid signature as the link between ChREBP-induced mitochondrial dynamics and progression of DKD.
    Keywords:  diabetic nephropathy; kidney metabolism; lipid metabolism; mitochondria; phospholipid
    DOI:  https://doi.org/10.1016/j.jbc.2023.105185
  13. Autophagy. 2023 Aug 24. 1-3
    The CTNS-MTORC1 axis couples lysosomal cystine to epithelial cell fate decisions and is a targetable pathway in cystinosis.
    Alessandro Luciani, Olivier Devuyst.
      Differentiation and fate decisions are critical for the epithelial cells lining the proximal tubule (PT) of the kidney, but the signals involved remain unknown. Defective cystine mobilization from lysosomes through CTNS (cystinosin, lysosomal cystine transporter), which is mutated in cystinosis, triggers the dedifferentiation and dysfunction of the PT cells, causing kidney disease and severe metabolic complications. Using preclinical models and physiologically relevant cellular systems, along with functional assays and a generative artificial intelligence (AI)-powered engine, we found that cystine storage imparted by CTNS deficiency stimulates Ragulator-RRAG GTPase-dependent recruitment of MTORC1 and its constitutive activation. In turn, this diverts the catabolic trajectories and differentiating states of PT cells toward growth and proliferation, disrupting homeostasis and their specialized functions. Therapeutic MTORC1 inhibition by using low doses of rapamycin corrects lysosome function and differentiation downstream of cystine storage and ameliorates PT dysfunction in preclinical models of cystinosis. These discoveries suggest that cystine may act as a lysosomal fasting signal that tailors MTORC1 signaling to direct fate decisions in the kidney PT epithelium, highlighting novel therapeutic paradigms for cystinosis and other lysosome-related disorders.
    Keywords:  autophagy; chronic kidney disease; cystinosis; drug repurposing; lysosome; nutrient sensing
    DOI:  https://doi.org/10.1080/15548627.2023.2250165
  14. Mol Genet Metab. 2023 Aug 15. pii: S1096-7192(23)00316-5. [Epub ahead of print]140(3): 107686
    A Caenorhabditis elegans model of adenylosuccinate lyase deficiency reveals neuromuscular and reproductive phenotypes of distinct etiology.
    Adam R Fenton, Haley N Janowitz, Latisha P Franklin, Riley G Young, Corinna A Moro, Michael V DeGennaro, Melanie R McReynolds, Wenqing Wang, Wendy Hanna-Rose.
      Inborn errors of purine metabolism are rare syndromes with an array of complex phenotypes in humans. One such disorder, adenylosuccinate lyase deficiency (ASLD), is caused by a decrease in the activity of the bi-functional purine biosynthetic enzyme adenylosuccinate lyase (ADSL). Mutations in human ADSL cause epilepsy, muscle ataxia, and autistic-like symptoms. Although the genetic basis of ASLD is known, the molecular mechanisms driving phenotypic outcome are not. Here, we characterize neuromuscular and reproductive phenotypes associated with a deficiency of adsl-1 in Caenorhabditis elegans. We demonstrate that adsl-1 function contributes to regulation of spontaneous locomotion, that adsl-1 functions acutely for proper mobility, and that aspects of adsl-1-related dysfunction are reversible. Using pharmacological supplementation, we correlate phenotypes with distinct metabolic perturbations. The neuromuscular defect correlates with accumulation of a purine biosynthetic intermediate whereas reproductive deficiencies can be ameliorated by purine supplementation, indicating differing molecular mechanisms behind the phenotypes. Because purine metabolism is highly conserved in metazoans, we suggest that similar separable metabolic perturbations result in the varied symptoms in the human disorder and that a dual-approach therapeutic strategy may be beneficial.
    Keywords:  C. elegans; Locomotion; Purine metabolism; Reproduction; adsl-1
    DOI:  https://doi.org/10.1016/j.ymgme.2023.107686
  15. Cell Rep. 2023 Aug 24. pii: S2211-1247(23)01043-4. [Epub ahead of print]42(9): 113032
    Lipocalin-2 induces mitochondrial dysfunction in renal tubular cells via mTOR pathway activation.
    Eloïse Marques, Maraiza Alves Teixeira, Clément Nguyen, Fabiola Terzi, Morgan Gallazzini.
      Mitochondrial dysfunction is a critical process in renal epithelial cells upon kidney injury. While its implication in kidney disease progression is established, the mechanisms modulating it remain unclear. Here, we describe the role of Lipocalin-2 (LCN2), a protein expressed in injured tubular cells, in mitochondrial dysfunction. We show that LCN2 expression decreases mitochondrial mass and function and induces mitochondrial fragmentation. Importantly, while LCN2 expression favors DRP1 mitochondrial recruitment, DRP1 inhibition antagonizes LCN2's effect on mitochondrial shape. Remarkably, LCN2 promotes mitochondrial fragmentation independently of its secretion or transport iron activity. Mechanistically, intracellular LCN2 expression increases mTOR activity, and rapamycin inhibits LCN2's effect on mitochondrial shape. In vivo, Lcn2 gene inactivation prevents mTOR activation and mitochondrial length decrease observed upon ischemia-reperfusion-induced kidney injury (IRI) in Lcn2+/+ mice. Our data identify LCN2 as a key regulator of mitochondrial dynamics and further elucidate the mechanisms leading to mitochondrial dysfunction.
    Keywords:  CP: Metabolism; Lipocalin-2; kidney; mTOR pathway; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.celrep.2023.113032
  16. Cell Metab. 2023 Aug 18. pii: S1550-4131(23)00296-6. [Epub ahead of print]
    Deciphering the decline of metabolic elasticity in aging and obesity.
    Qiuzhong Zhou, Lexiang Yu, Joshua R Cook, Li Qiang, Lei Sun.
      Organisms must adapt to fluctuating nutrient availability to maintain energy homeostasis. Here, we term the capacity for such adaptation and restoration "metabolic elasticity" and model it through ad libitum-fasting-refeeding cycles. Metabolic elasticity is achieved by coordinate versatility in gene expression, which we call "gene elasticity." We have developed the gene elasticity score as a systematic method to quantify the elasticity of the transcriptome across metabolically active tissues in mice and non-human primates. Genes involved in lipid and carbohydrate metabolism show high gene elasticity, and their elasticity declines with age, particularly with PPARγ dysregulation in adipose tissue. Synchronizing PPARγ activity with nutrient conditions through feeding-timed agonism optimizes their metabolic benefits and safety. We further broaden the conceptual scope of metabolic and gene elasticity to dietary challenges, revealing declines in diet-induced obesity similar to those in aging. Altogether, our findings provide a dynamic perspective on the dysmetabolic consequences of aging and obesity.
    Keywords:  adipocyte; adipose tissue; aging; gene elasticity; liver; metabolic decline; metabolic elasticity; muscle; nutrient challenge; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2023.08.001
  17. Proc Natl Acad Sci U S A. 2023 Aug 29. 120(35): e2208117120
    Hypoxia induces a glycolytic complex in intestinal epithelial cells independent of HIF-1-driven glycolytic gene expression.
    Sarah J Kierans, Raphael R Fagundes, Mykyta I Malkov, Ríona Sparkes, Eugène T Dillon, Albert Smolenski, Klaas Nico Faber, Cormac T Taylor.
      The metabolic adaptation of eukaryotic cells to hypoxia involves increasing dependence upon glycolytic adenosine triphosphate (ATP) production, an event with consequences for cellular bioenergetics and cell fate. This response is regulated at the transcriptional level by the hypoxia-inducible factor-1(HIF-1)-dependent transcriptional upregulation of glycolytic enzymes (GEs) and glucose transporters. However, this transcriptional upregulation alone is unlikely to account fully for the levels of glycolytic ATP produced during hypoxia. Here, we investigated additional mechanisms regulating glycolysis in hypoxia. We observed that intestinal epithelial cells treated with inhibitors of transcription or translation and human platelets (which lack nuclei and the capacity for canonical transcriptional activity) maintained the capacity for hypoxia-induced glycolysis, a finding which suggests the involvement of a nontranscriptional component to the hypoxia-induced metabolic switch to a highly glycolytic phenotype. In our investigations into potential nontranscriptional mechanisms for glycolytic induction, we identified a hypoxia-sensitive formation of complexes comprising GEs and glucose transporters in intestinal epithelial cells. Surprisingly, the formation of such glycolytic complexes occurs independent of HIF-1-driven transcription. Finally, we provide evidence for the presence of HIF-1α in cytosolic fractions of hypoxic cells which physically interacts with the glucose transporter GLUT1 and the GEs in a hypoxia-sensitive manner. In conclusion, we provide insights into the nontranscriptional regulation of hypoxia-induced glycolysis in intestinal epithelial cells.
    Keywords:  HIF; glycolysis; hypoxia; metabolism
    DOI:  https://doi.org/10.1073/pnas.2208117120
  18. Front Cell Dev Biol. 2023 ;11 1196466
    Post-translational modifications and protein quality control of mitochondrial channels and transporters.
    Ashlesha Kadam, Pooja Jadiya, Dhanendra Tomar.
      Mitochondria play a critical role in energy metabolism and signal transduction, which is tightly regulated by proteins, metabolites, and ion fluxes. Metabolites and ion homeostasis are mainly mediated by channels and transporters present on mitochondrial membranes. Mitochondria comprise two distinct compartments, the outer mitochondrial membrane (OMM) and the inner mitochondrial membrane (IMM), which have differing permeabilities to ions and metabolites. The OMM is semipermeable due to the presence of non-selective molecular pores, while the IMM is highly selective and impermeable due to the presence of specialized channels and transporters which regulate ion and metabolite fluxes. These channels and transporters are modulated by various post-translational modifications (PTMs), including phosphorylation, oxidative modifications, ions, and metabolites binding, glycosylation, acetylation, and others. Additionally, the mitochondrial protein quality control (MPQC) system plays a crucial role in ensuring efficient molecular flux through the mitochondrial membranes by selectively removing mistargeted or defective proteins. Inefficient functioning of the transporters and channels in mitochondria can disrupt cellular homeostasis, leading to the onset of various pathological conditions. In this review, we provide a comprehensive overview of the current understanding of mitochondrial channels and transporters in terms of their functions, PTMs, and quality control mechanisms.
    Keywords:  MCU; MPQC; MPTP; SLCs; VDAC; mitochondrial channels; mitochondrial transporters; posttranslational modifications
    DOI:  https://doi.org/10.3389/fcell.2023.1196466
  19. Nat Commun. 2023 Aug 25. 14(1): 5206
    A transcriptional response to replication stress selectively expands a subset of Brca2-mutant mammary epithelial cells.
    Maryam Ghaderi Najafabadi, G Kenneth Gray, Li Ren Kong, Komal Gupta, David Perera, Huw Naylor, Joan S Brugge, Ashok R Venkitaraman, Mona Shehata.
      Germline BRCA2 mutation carriers frequently develop luminal-like breast cancers, but it remains unclear how BRCA2 mutations affect mammary epithelial subpopulations. Here, we report that monoallelic Brca2mut/WT mammary organoids subjected to replication stress activate a transcriptional response that selectively expands Brca2mut/WT luminal cells lacking hormone receptor expression (HR-). While CyTOF analyses reveal comparable epithelial compositions among wildtype and Brca2mut/WT mammary glands, Brca2mut/WT HR- luminal cells exhibit greater organoid formation and preferentially survive and expand under replication stress. ScRNA-seq analysis corroborates the expansion of HR- luminal cells which express elevated transcript levels of Tetraspanin-8 (Tspan8) and Thrsp, plus pathways implicated in replication stress survival including Type I interferon responses. Notably, CRISPR/Cas9-mediated deletion of Tspan8 or Thrsp prevents Brca2mut/WT HR- luminal cell expansion. Our findings indicate that Brca2mut/WT cells activate a transcriptional response after replication stress that preferentially favours outgrowth of HR- luminal cells through the expression of interferon-responsive and mammary alveolar genes.
    DOI:  https://doi.org/10.1038/s41467-023-40956-w
  20. Aging Cell. 2023 Aug 23. e13954
    Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects.
    Natalia Oleinik, Onder Albayram, Mohamed Faisal Kassir, F Cansu Atilgan, Chase Walton, Eda Karakaya, John Kurtz, Alexander Alekseyenko, Habeeb Alsudani, Megan Sheridan, Zdzislaw M Szulc, Besim Ogretmen.
      The metabolic consequences of mitophagy alterations due to age-related stress in healthy aging brains versus neurodegeneration remain unknown. Here, we demonstrate that ceramide synthase 1 (CerS1) is transported to the outer mitochondrial membrane by the p17/PERMIT transporter that recognizes mislocalized mitochondrial ribosomes (mitoribosomes) via 39-FLRN-42 residues, inducing ceramide-mediated mitophagy. P17/PERMIT-CerS1-mediated mitophagy attenuated the argininosuccinate/fumarate/malate axis and induced d-glucose and fructose accumulation in neurons in culture and brain tissues (primarily in the cerebellum) of wild-type mice in vivo. These metabolic changes in response to sodium-selenite were nullified in the cerebellum of CerS1to/to (catalytically inactive for C18-ceramide production CerS1 mutant), PARKIN-/- or p17/PERMIT-/- mice that have dysfunctional mitophagy. Whereas sodium selenite induced mitophagy in the cerebellum and improved motor-neuron deficits in aged wild-type mice, exogenous fumarate or malate prevented mitophagy. Attenuating ceramide-mediated mitophagy enhanced damaged mitochondria accumulation and age-dependent sensorimotor abnormalities in p17/PERMIT-/- mice. Reinstituting mitophagy using a ceramide analog drug with selenium conjugate, LCL768, restored mitophagy and reduced malate/fumarate metabolism, improving sensorimotor deficits in old p17/PERMIT-/- mice. Thus, these data describe the metabolic consequences of alterations to p17/PERMIT/ceramide-mediated mitophagy associated with the loss of mitochondrial quality control in neurons and provide therapeutic options to overcome age-dependent sensorimotor deficits and related disorders like amyotrophic lateral sclerosis (ALS).
    Keywords:  CerS1; Drp1; aging; ceramide; mitochondrial metabolism; mitophagy; neurodegeneration; sensorimotor defects
    DOI:  https://doi.org/10.1111/acel.13954
  21. Cell Rep. 2023 Aug 18. pii: S2211-1247(23)00976-2. [Epub ahead of print]42(8): 112965
    Distinct mutational processes shape selection of MHC class I and class II mutations across primary and metastatic tumors.
    Michael B Mumphrey, Noshad Hosseini, Abhijit Parolia, Jie Geng, Weiping Zou, Malini Raghavan, Arul Chinnaiyan, Marcin Cieslik.
      Disruption of antigen presentation via loss of major histocompatibility complex (MHC) expression is a strategy whereby cancer cells escape immune surveillance and develop resistance to immunotherapy. Here, we develop the personalized genomics algorithm Hapster and accurately call somatic mutations within the MHC genes of 10,001 primary and 2,199 metastatic tumors, creating a catalog of 1,663 non-synonymous mutations that provide key insights into MHC mutagenesis. We find that MHC class I genes are among the most frequently mutated genes in both primary and metastatic tumors, while MHC class II mutations are more restricted. Recurrent deleterious mutations are found within haplotype- and cancer-type-specific hotspots associated with distinct mutational processes. Functional classification of MHC residues reveals significant positive selection for mutations disruptive to the B2M, peptide, and T cell binding interfaces, as well as to MHC chaperones.
    Keywords:  CP: Cancer; CP: Immunology; HLA; MHC; cancer; evolution; genomics; immunogenetics; selection; somatic mutations
    DOI:  https://doi.org/10.1016/j.celrep.2023.112965
  22. Cell Rep. 2023 Aug 24. pii: S2211-1247(23)01051-3. [Epub ahead of print]42(9): 113040
    4-Octyl itaconate restricts STING activation by blocking its palmitoylation.
    Chaofei Su, Tian Cheng, Jian Huang, Tuan Zhang, Hang Yin.
      The cyclic guanosine monophosphate adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) axis plays a vital role in defending foreign pathogens and maintaining immune homeostasis. While substantial advances have been made in understanding the metabolic changes that occur during macrophage activation, little is known about how these metabolic changes affect the cGAS-STING axis. In this study, we identify that 4-octyl itaconate (4-OI), a derivative of itaconate, inhibits the activation of cGAS-STING. Furthermore, we show that 4-OI inhibits cGAS-STING-related antiviral immune responses and autoimmune inflammation. However, we find that endogenous itaconate does not affect cGAS-STING activation, indicating that 4-OI and itaconate function differently. Mechanistically, we find that 4-OI directly alkylates STING at Cys91, blocking STING palmitoylation and oligomerization. The alkylation of STING by 4-OI represents another type of post-translational modifications (PTMs) of STING. Our findings reveal a mechanism by which cGAS-STING function is regulated through 4-OI alkylation and provide insights into the crosstalk between different kinds of PTMs.
    Keywords:  4-OI; CP: Immunology; CP: Molecular biology; PTM; alkylation; cGAS-STING; palmitoylation
    DOI:  https://doi.org/10.1016/j.celrep.2023.113040
  23. Signal Transduct Target Ther. 2023 Aug 23. 8(1): 311
    Mitochondrial heterogeneity in diseases.
    Long Chen, Mengnan Zhou, Hao Li, Delin Liu, Peng Liao, Yao Zong, Changqing Zhang, Weiguo Zou, Junjie Gao.
      As key organelles involved in cellular metabolism, mitochondria frequently undergo adaptive changes in morphology, components and functions in response to various environmental stresses and cellular demands. Previous studies of mitochondria research have gradually evolved, from focusing on morphological change analysis to systematic multiomics, thereby revealing the mitochondrial variation between cells or within the mitochondrial population within a single cell. The phenomenon of mitochondrial variation features is defined as mitochondrial heterogeneity. Moreover, mitochondrial heterogeneity has been reported to influence a variety of physiological processes, including tissue homeostasis, tissue repair, immunoregulation, and tumor progression. Here, we comprehensively review the mitochondrial heterogeneity in different tissues under pathological states, involving variant features of mitochondrial DNA, RNA, protein and lipid components. Then, the mechanisms that contribute to mitochondrial heterogeneity are also summarized, such as the mutation of the mitochondrial genome and the import of mitochondrial proteins that result in the heterogeneity of mitochondrial DNA and protein components. Additionally, multiple perspectives are investigated to better comprehend the mysteries of mitochondrial heterogeneity between cells. Finally, we summarize the prospective mitochondrial heterogeneity-targeting therapies in terms of alleviating mitochondrial oxidative damage, reducing mitochondrial carbon stress and enhancing mitochondrial biogenesis to relieve various pathological conditions. The possibility of recent technological advances in targeted mitochondrial gene editing is also discussed.
    DOI:  https://doi.org/10.1038/s41392-023-01546-w
  24. Antioxidants (Basel). 2023 Jul 28. pii: 1517. [Epub ahead of print]12(8):
    Mitochondrial Volume Regulation and Swelling Mechanisms in Cardiomyocytes.
    Xavier R Chapa-Dubocq, Keishla M Rodríguez-Graciani, Nelson Escobales, Sabzali Javadov.
      Mitochondrion, known as the "powerhouse" of the cell, regulates ion homeostasis, redox state, cell proliferation and differentiation, and lipid synthesis. The inner mitochondrial membrane (IMM) controls mitochondrial metabolism and function. It possesses high levels of proteins that account for ~70% of the membrane mass and are involved in the electron transport chain, oxidative phosphorylation, energy transfer, and ion transport, among others. The mitochondrial matrix volume plays a crucial role in IMM remodeling. Several ion transport mechanisms, particularly K+ and Ca2+, regulate matrix volume. Small increases in matrix volume through IMM alterations can activate mitochondrial respiration, whereas excessive swelling can impair the IMM topology and initiates mitochondria-mediated cell death. The opening of mitochondrial permeability transition pores, the well-characterized phenomenon with unknown molecular identity, in low- and high-conductance modes are involved in physiological and pathological increases of matrix volume. Despite extensive studies, the precise mechanisms underlying changes in matrix volume and IMM structural remodeling in response to energy and oxidative stressors remain unknown. This review summarizes and discusses previous studies on the mechanisms involved in regulating mitochondrial matrix volume, IMM remodeling, and the crosstalk between these processes.
    Keywords:  heart; ions; ischemia-reperfusion; mitochondria; permeability transition pore
    DOI:  https://doi.org/10.3390/antiox12081517
  25. bioRxiv. 2023 Aug 11. pii: 2023.08.11.552890. [Epub ahead of print]
    An adult clock component links circadian rhythms to pancreatic β-cell maturation.
    Ana P Montalvo, Zoe L Gruskin, Andrew Leduc, Mai Liu, Zihan Gao, June H Ahn, Juerg R Straubhaar, Nikolai Slavov, Juan R Alvarez-Dominguez.
      How ubiquitous circadian clocks orchestrate tissue-specific outputs is not well understood. Pancreatic β cell-autonomous clocks attune insulin secretion to daily energy cycles, and desynchrony from genetic or behavioral disruptions raises type 2 diabetes risk. We show that the transcription factor DEC1, a clock component induced in adult β cells, coordinates their glucose responsiveness by synchronizing energy metabolism and secretory gene oscillations. Dec1 -ablated mice develop lifelong hypo-insulinemic diabetes, despite normal islet formation and intact circadian Clock and Bmal1 activators. DEC1, but not CLOCK/BMAL1, binds maturity-linked genes that mediate respiratory metabolism and insulin exocytosis, and Dec1 loss disrupts their transcription synchrony. Accordingly, β-cell Dec1 ablation causes hypo-insulinemia due to immature glucose responsiveness, dampening insulin rhythms. Thus, Dec1 links circadian clockwork to the β-cell maturation process, aligning metabolism to diurnal energy cycles.
    DOI:  https://doi.org/10.1101/2023.08.11.552890
  26. Proc Natl Acad Sci U S A. 2023 Aug 29. 120(35): e2302147120
    Principles of metabolome conservation in animals.
    Orsolya Liska, Gábor Boross, Charles Rocabert, Balázs Szappanos, Roland Tengölics, Balázs Papp.
      Metabolite levels shape cellular physiology and disease susceptibility, yet the general principles governing metabolome evolution are largely unknown. Here, we introduce a measure of conservation of individual metabolite levels among related species. By analyzing multispecies tissue metabolome datasets in phylogenetically diverse mammals and fruit flies, we show that conservation varies extensively across metabolites. Three major functional properties, metabolite abundance, essentiality, and association with human diseases predict conservation, highlighting a striking parallel between the evolutionary forces driving metabolome and protein sequence conservation. Metabolic network simulations recapitulated these general patterns and revealed that abundant metabolites are highly conserved due to their strong coupling to key metabolic fluxes in the network. Finally, we show that biomarkers of metabolic diseases can be distinguished from other metabolites simply based on evolutionary conservation, without requiring any prior clinical knowledge. Overall, this study uncovers simple rules that govern metabolic evolution in animals and implies that most tissue metabolome differences between species are permitted, rather than favored by natural selection. More broadly, our work paves the way toward using evolutionary information to identify biomarkers, as well as to detect pathogenic metabolome alterations in individual patients.
    Keywords:  metabolic networks; molecular evolution; neutral evolution; phylogenetic comparative method; systems biology
    DOI:  https://doi.org/10.1073/pnas.2302147120
  27. Nat Commun. 2023 Aug 22. 14(1): 5114
    Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming.
    Erika M Palmieri, Ronald Holewinski, Christopher L McGinity, Ciro L Pierri, Nunziata Maio, Jonathan M Weiss, Vincenzo Tragni, Katrina M Miranda, Tracey A Rouault, Thorkell Andresson, David A Wink, Daniel W McVicar.
      M1 macrophages enter a glycolytic state when endogenous nitric oxide (NO) reprograms mitochondrial metabolism by limiting aconitase 2 and pyruvate dehydrogenase (PDH) activity. Here, we provide evidence that NO targets the PDH complex by using lipoate to generate nitroxyl (HNO). PDH E2-associated lipoate is modified in NO-rich macrophages while the PDH E3 enzyme, also known as dihydrolipoamide dehydrogenase (DLD), is irreversibly inhibited. Mechanistically, we show that lipoate facilitates NO-mediated production of HNO, which interacts with thiols forming irreversible modifications including sulfinamide. In addition, we reveal a macrophage signature of proteins with reduction-resistant modifications, including in DLD, and identify potential HNO targets. Consistently, DLD enzyme is modified in an HNO-dependent manner at Cys477 and Cys484, and molecular modeling and mutagenesis show these modifications impair the formation of DLD homodimers. In conclusion, our work demonstrates that HNO is produced physiologically. Moreover, the production of HNO is dependent on the lipoate-rich PDH complex facilitating irreversible modifications that are critical to NO-dependent metabolic rewiring.
    DOI:  https://doi.org/10.1038/s41467-023-40738-4
  28. Trends Plant Sci. 2023 Aug 18. pii: S1360-1385(23)00238-8. [Epub ahead of print]
    Promotion of oxidative phosphorylation by complex I-anchored carbonic anhydrases?
    Hans-Peter Braun, Niklas Klusch.
      The mitochondrial NADH-dehydrogenase complex of the respiratory chain, known as complex I, includes a carbonic anhydrase (CA) module attached to its membrane arm on the matrix side in protozoans, algae, and plants. Its physiological role is so far unclear. Recent electron cryo-microscopy (cryo-EM) structures show that the CA module may directly provide protons for translocation across the inner mitochondrial membrane at complex I. CAs can have a central role in adjusting the proton concentration in the mitochondrial matrix. We suggest that CA anchoring in complex I represents the original configuration to secure oxidative phosphorylation (OXPHOS) in the context of early endosymbiosis. After development of 'modern mitochondria' with pronounced cristae structures, this anchoring became dispensable, but has been retained in protozoans, algae, and plants.
    Keywords:  NADH dehydrogenase complex (complex I); Oxidative Phosphorylation (OXPHOS); carbonic anhydrase; endosymbiotic theory; mitochondria; mitochondrial evolution
    DOI:  https://doi.org/10.1016/j.tplants.2023.07.007
  29. Nat Cancer. 2023 Aug;4(8): 1060-1062
    A single inhibitor for all KRAS mutations.
    Ryan B Corcoran.
      
    DOI:  https://doi.org/10.1038/s43018-023-00615-x
  30. Curr Opin Cell Biol. 2023 Aug 17. pii: S0955-0674(23)00067-4. [Epub ahead of print]84 102218
    Dynamic links between mechanical forces and metabolism shape the tumor milieu.
    Rebecca Bertolio, Francesco Napoletano, Giannino Del Sal.
      Cell function relies on the spatiotemporal dynamics of metabolic reactions. In all physiopathological processes of tissues, mechanical forces impact the structure and function of membranes, enzymes, organelles and regulators of metabolic gene programs, thus regulating cell metabolism. In turn, metabolic pathways feedback impacts the physical properties of cell and tissues. Hence, metabolism and tissue mechanics are dynamically intertwined and continuously interact. Cancer is akin to an ecosystem, comprising tumor cells and various subpopulations of stromal cells embedded in an altered extracellular matrix. The progression of cancer, from initiation to advanced stage and metastasis, is driven by genetic mutations and crucially influenced by physical and metabolic alterations in the tumor microenvironment. These alterations also play a pivotal role in cancer cells evasion from immune surveillance and in developing resistance to treatments. Here, we highlight emerging evidence showing that mechano-metabolic circuits in cancer and stromal cells regulate multiple processes crucial for tumor progression and discuss potential approaches to improve therapeutic treatments by interfering with these circuits.
    DOI:  https://doi.org/10.1016/j.ceb.2023.102218
  31. Cancer Discov. 2023 Aug 25. OF1
    Pan-Cancer Proteogenomics Uncovers Phenotypes of Cancer Driver Events.
      Large-scale proteogenomic analyses of human tumors revealed cellular phenotypes of cancer drivers.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-136
  32. Nat Commun. 2023 Aug 25. 14(1): 5211
    Driver gene combinations dictate cutaneous squamous cell carcinoma disease continuum progression.
    Peter Bailey, Rachel A Ridgway, Patrizia Cammareri, Mairi Treanor-Taylor, Ulla-Maja Bailey, Christina Schoenherr, Max Bone, Daniel Schreyer, Karin Purdie, Jason Thomson, William Rickaby, Rene Jackstadt, Andrew D Campbell, Emmanouil Dimonitsas, Alexander J Stratigos, Sarah T Arron, Jun Wang, Karen Blyth, Charlotte M Proby, Catherine A Harwood, Owen J Sansom, Irene M Leigh, Gareth J Inman.
      The molecular basis of disease progression from UV-induced precancerous actinic keratosis (AK) to malignant invasive cutaneous squamous cell carcinoma (cSCC) and potentially lethal metastatic disease remains unclear. DNA sequencing studies have revealed a massive mutational burden but have yet to illuminate mechanisms of disease progression. Here we perform RNAseq transcriptomic profiling of 110 patient samples representing normal sun-exposed skin, AK, primary and metastatic cSCC and reveal a disease continuum from a differentiated to a progenitor-like state. This is accompanied by the orchestrated suppression of master regulators of epidermal differentiation, dynamic modulation of the epidermal differentiation complex, remodelling of the immune landscape and an increase in the preponderance of tumour specific keratinocytes. Comparative systems analysis of human cSCC coupled with the generation of genetically engineered murine models reveal that combinatorial sequential inactivation of the tumour suppressor genes Tgfbr2, Trp53, and Notch1 coupled with activation of Ras signalling progressively drives cSCC progression along a differentiated to progenitor axis. Taken together we provide a comprehensive map of the cSCC disease continuum and reveal potentially actionable events that promote and accompany disease progression.
    DOI:  https://doi.org/10.1038/s41467-023-40822-9
  33. Nat Immunol. 2023 Sep;24(9): 1405-1406
    cDC1 craves glutamine for its glory.
    Stefania Vilbois, Jaeoh Park, Ping-Chih Ho.
      
    DOI:  https://doi.org/10.1038/s41590-023-01598-8
  34. Mol Biol Evol. 2023 Aug 24. pii: msad187. [Epub ahead of print]
    The architecture of metabolic networks constrains the evolution of microbial resource hierarchies.
    Sotaro Takano, Jean C C Vila, Ryo Miyazaki, Alvaro Sanchez, Djordje Bajic.
      Microbial strategies for resource use are an essential determinant of their fitness in complex habitats. When facing environments with multiple nutrients, microbes often use them sequentially according to a preference hierarchy, resulting in well-known patterns of diauxic growth. In theory, the evolutionary diversification of metabolic hierarchies could represent a mechanism supporting coexistence and biodiversity by enabling temporal segregation of niches. Despite this ecologically critical role, the extent to which substrate preference hierarchies can evolve and diversify remains largely unexplored. Here we used genome-scale metabolic modeling to systematically explore the evolution of metabolic hierarchies across a vast space of metabolic network genotypes. We find that only a limited number of metabolic hierarchies can readily evolve, corresponding to the most commonly observed hierarchies in genome-derived models. We further show how the evolution of novel hierarchies is constrained by the architecture of central metabolism, which determines both the propensity to change ranks between pairs of substrates and the effect of specific reactions on hierarchy evolution. Our analysis sheds light on the genetic and mechanistic determinants of microbial metabolic hierarchies, opening new research avenues to understand their evolution, evolvability, and ecology.
    DOI:  https://doi.org/10.1093/molbev/msad187
  35. Biochem Biophys Res Commun. 2023 Aug 20. pii: S0006-291X(23)00978-6. [Epub ahead of print]678 45-61
    A big picture of the mitochondria-mediated signals: From mitochondria to organism.
    Neşe Vardar Acar, R Köksal Özgül.
      Mitochondria, well-known for years as the powerhouse and biosynthetic center of the cell, are dynamic signaling organelles beyond their energy production and biosynthesis functions. The metabolic functions of mitochondria, playing an important role in various biological events both in physiological and stress conditions, transform them into important cellular stress sensors. Mitochondria constantly communicate with the rest of the cell and even from other cells to the organism, transmitting stress signals including oxidative and reductive stress or adaptive signals such as mitohormesis. Mitochondrial signal transduction has a vital function in regulating integrity of human genome, organelles, cells, and ultimately organism.
    Keywords:  Cellular stress; Mitochondrial crosstalk; Mitochondrial functions; Mitochondrial signaling transduction
    DOI:  https://doi.org/10.1016/j.bbrc.2023.08.032
  36. JCI Insight. 2023 Aug 22. pii: e167007. [Epub ahead of print]8(16):
    Metabolic heterogeneity in adrenocortical carcinoma impacts patient outcomes.
    Qian Wang, Na Sun, Raphael Meixner, Ronan Le Gleut, Thomas Kunzke, Annette Feuchtinger, Jun Wang, Jian Shen, Stefan Kircher, Ulrich Dischinger, Isabel Weigand, Felix Beuschlein, Martin Fassnacht, Matthias Kroiss, Axel Walch.
      Spatially resolved metabolomics enables the investigation of tumoral metabolites in situ. Inter- and intratumor heterogeneity are key factors associated with patient outcomes. Adrenocortical carcinoma (ACC) is an exceedingly rare tumor associated with poor survival. Its clinical prognosis is highly variable, but the contributions of tumor metabolic heterogeneity have not been investigated thus far to our knowledge. An in-depth understanding of tumor heterogeneity requires molecular feature-based identification of tumor subpopulations associated with tumor aggressiveness. Here, using spatial metabolomics by high-mass resolution MALDI Fourier transform ion cyclotron resonance mass spectrometry imaging, we assessed metabolic heterogeneity by de novo discovery of metabolic subpopulations and Simpson's diversity index. After identification of tumor subpopulations in 72 patients with ACC, we additionally performed a comparison with 25 tissue sections of normal adrenal cortex to identify their common and unique metabolic subpopulations. We observed variability of ACC tumor heterogeneity and correlation of high metabolic heterogeneity with worse clinical outcome. Moreover, we identified tumor subpopulations that served as independent prognostic factors and, furthermore, discovered 4 associated anticancer drug action pathways. Our research may facilitate comprehensive understanding of the biological implications of tumor subpopulations in ACC and showed that metabolic heterogeneity might impact chemotherapy.
    Keywords:  Bioinformatics; Cancer; Metabolism; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.167007
  37. Dev Cell. 2023 Aug 22. pii: S1534-5807(23)00394-5. [Epub ahead of print]
    Elimination of oncogenic KRAS in genetic mouse models eradicates pancreatic cancer by inducing FAS-dependent apoptosis by CD8+ T cells.
    Krishnan K Mahadevan, Valerie S LeBleu, Elena V Ramirez, Yang Chen, Bingrui Li, Amari M Sockwell, Mihai Gagea, Hikaru Sugimoto, Lakshmi Kavitha Sthanam, Desiree Tampe, Michael Zeisberg, Haoqiang Ying, Abhinav K Jain, Ronald A DePinho, Anirban Maitra, Kathleen M McAndrews, Raghu Kalluri.
      Oncogenic KRASG12D (KRAS∗) is critical for the initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC) and is a known repressor of tumor immunity. Conditional elimination of KRAS∗ in genetic mouse models of PDAC leads to the reactivation of FAS, CD8+ T cell-mediated apoptosis, and complete eradication of tumors. KRAS∗ elimination recruits activated CD4+ and CD8+ T cells and promotes the activation of antigen-presenting cells. Mechanistically, KRAS∗-mediated immune evasion involves the epigenetic regulation of Fas death receptor in cancer cells, via methylation of its promoter region. Furthermore, analysis of human RNA sequencing identifies that high KRAS expression in PDAC tumors shows a lower proportion of CD8+ T cells and demonstrates shorter survival compared with tumors with low KRAS expression. This study highlights the role of CD8+ T cells in the eradication of PDAC following KRAS∗ elimination and provides a rationale for the combination of KRAS∗ targeting with immunotherapy to control PDAC.
    Keywords:  CD8(+) T cells; FAS-FASL; KRAS(G12D); oncogenic KRAS; pancreatic cancer
    DOI:  https://doi.org/10.1016/j.devcel.2023.07.025
  38. Nat Commun. 2023 Aug 22. 14(1): 5092
    Convergent somatic evolution commences in utero in a germline ribosomopathy.
    Heather E Machado, Nina F Øbro, Nicholas Williams, Shengjiang Tan, Ahmed Z Boukerrou, Megan Davies, Miriam Belmonte, Emily Mitchell, E Joanna Baxter, Nicole Mende, Anna Clay, Philip Ancliff, Jutta Köglmeier, Sally B Killick, Austin Kulasekararaj, Stefan Meyer, Elisa Laurenti, Peter J Campbell, David G Kent, Jyoti Nangalia, Alan J Warren.
      Clonal tracking of cells using somatic mutations permits exploration of clonal dynamics in human disease. Here, we perform whole genome sequencing of 323 haematopoietic colonies from 10 individuals with the inherited ribosomopathy Shwachman-Diamond syndrome to reconstruct haematopoietic phylogenies. In ~30% of colonies, we identify mutually exclusive mutations in TP53, EIF6, RPL5, RPL22, PRPF8, plus chromosome 7 and 15 aberrations that increase SBDS and EFL1 gene dosage, respectively. Target gene mutations commence in utero, resulting in a profusion of clonal expansions, with only a few haematopoietic stem cell lineages (mean 8, range 1-24) contributing ~50% of haematopoietic colonies across 8 individuals (range 4-100% clonality) by young adulthood. Rapid clonal expansion during disease transformation is associated with biallelic TP53 mutations and increased mutation burden. Our study highlights how convergent somatic mutation of the p53-dependent nucleolar surveillance pathway offsets the deleterious effects of germline ribosomopathy but increases opportunity for TP53-mutated cancer evolution.
    DOI:  https://doi.org/10.1038/s41467-023-40896-5
  39. Sci Adv. 2023 Aug 25. 9(34): eadg8364
    mTORC1 regulates phagosome digestion of symbiotic bacteria for intracellular nutritional symbiosis in a deep-sea mussel.
    Akihiro Tame, Tadashi Maruyama, Tetsuro Ikuta, Yoshihito Chikaraishi, Nanako O Ogawa, Masashi Tsuchiya, Kiyotaka Takishita, Miwako Tsuda, Miho Hirai, Yoshihiro Takaki, Naohiko Ohkouchi, Katsunori Fujikura, Takao Yoshida.
      Phagocytosis is one of the methods used to acquire symbiotic bacteria to establish intracellular symbiosis. A deep-sea mussel, Bathymodiolus japonicus, acquires its symbiont from the environment by phagocytosis of gill epithelial cells and receives nutrients from them. However, the manner by which mussels retain the symbiont without phagosome digestion remains unknown. Here, we show that controlling the mechanistic target of rapamycin complex 1 (mTORC1) in mussels leads to retaining symbionts in gill cells. The symbiont is essential for the host mussel nutrition; however, depleting the symbiont's energy source triggers the phagosome digestion of symbionts. Meanwhile, the inhibition of mTORC1 by rapamycin prevented the digestion of the resident symbionts and of the engulfed exogenous dead symbionts in gill cells. This indicates that mTORC1 promotes phagosome digestion of symbionts under reduced nutrient supply from the symbiont. The regulation mechanism of phagosome digestion by mTORC1 through nutrient signaling with symbionts is key for maintaining animal-microbe intracellular nutritional symbiosis.
    DOI:  https://doi.org/10.1126/sciadv.adg8364
  40. Chem Biol Drug Des. 2023 Aug 24.
    Folate trapping is lethal to cancer cells.
    Gulam Mohmad Rather.
      Regulation of formate flux by a key folate enzyme, MTHFD2 (methylene tetrahydrofolate dehydrogenase 2) in cancer cells remains poorly understood. Green et al. (Nature Metabolism, 2023; 5: 642-659) showed an interesting phenomenon of "folate trapping" toxicity leads to cancer cell kill using a potent inhibitor (TH9619) against the dehydrogenase and cyclohydrolase (DC) activities of cytosolic methylenetetrahydrofolate dehydrogenase 1 (cMTHFD1) and nuclear methylenetetrahydrofolate dehydrogenase 2 (nMTHFD2), but not the mitochondrial MTHFD2 (mTHFD2). But, mMTHFD2 is required for formate flow to cytosol which leads to the trapping of 10-formyl tetrahydrofolate and causes toxicity by TH9619 treatment, to kill cancer cells expressing mMTHFD2. This article opens new avenues to be evaluated for therapeutic benefits of cancer patients where MTHFD2 shows overexpression viz-a-viz breast, prostate, colorectal, acute myeloid leukemia, and other cancer types.
    Keywords:  MTHFD2; folate trapping; formate; metabolomics
    DOI:  https://doi.org/10.1111/cbdd.14329
  41. Hepatology. 2023 Aug 21.
    Metabolic reprogramming in Nrf2-driven proliferation of normal rat hepatocytes.
    Marta Anna Kowalik, Keiko Taguchi, Marina Serra, Andrea Caddeo, Elisabetta Puliga, Marina Bacci, Seizo Koshiba, Jin Inoue, Eiji Hishinuma, Andrea Morandi, Silvia Giordano, Andrea Perra, Masayuki Yamamoto, Amedeo Columbano.
       BACKGROUND AIMS: Cancer cells reprogram their metabolic pathways to support bioenergetic and biosynthetic needs and to maintain their redox balance. In several human tumors the Keap1-Nrf2 system controls proliferation and metabolic reprogramming by regulating the pentose phosphate pathway (PPP). However, whether this metabolic reprogramming also occurs in normal proliferating cells is unclear.
    APPROACH AND RESULTS: To define the metabolic phenotype in normal proliferating hepatocytes, we induced cell proliferation in the liver by three distinct stimuli: liver regeneration by partial hepatectomy (PH) and hepatic hyperplasia induced by two direct mitogens, lead nitrate (LN) or triiodothyronine (T3). Following LN treatment, well-established features of cancer metabolic reprogramming including enhanced glycolysis, oxidative PPP, nucleic acid synthesis, NAD+/NADH synthesis and altered amino acid content as well as downregulated oxidative phosphorylation (OXPHOS) occurred in normal proliferating hepatocytes displaying Nrf2 activation. Genetic deletion of Nrf2 blunted LN-induced PPP activation and suppressed hepatocyte proliferation. Moreover, Nrf2 activation and following metabolic reprogramming did not occur when hepatocyte proliferation was induced by PH or T3.
    CONCLUSION: Many metabolic changes in cancer cells are shared by proliferating normal hepatocytes in response to a hostile environment. Nrf2 activation is essential for bridging metabolic changes with crucial components of cancer metabolic reprogramming including the activation of oxidative PPP. Our study demonstrates that matured hepatocytes exposed to LN undergo a cancer-like metabolic reprogramming and offers a rapid and useful in vivo model to study the molecular alterations underpinning the differences/similarities of metabolic changes in normal and neoplastic hepatocytes.
    DOI:  https://doi.org/10.1097/HEP.0000000000000568
  42. Cell Rep. 2023 Aug 18. pii: S2211-1247(23)01008-2. [Epub ahead of print] 112997
    Paired microbiome and metabolome analyses associate bile acid changes with colorectal cancer progression.
    Ting Fu, Tao Huan, Gibraan Rahman, Hui Zhi, Zhenjiang Xu, Tae Gyu Oh, Jian Guo, Sally Coulter, Anupriya Tripathi, Cameron Martino, Justin L McCarville, Qiyun Zhu, Fritz Cayabyab, Brian Low, Mingxiao He, Shipei Xing, Fernando Vargas, Ruth T Yu, Annette Atkins, Christopher Liddle, Janelle Ayres, Manuela Raffatellu, Pieter C Dorrestein, Michael Downes, Rob Knight, Ronald M Evans.
      Colorectal cancer (CRC) is driven by genomic alterations in concert with dietary influences, with the gut microbiome implicated as an effector in disease development and progression. While meta-analyses have provided mechanistic insight into patients with CRC, study heterogeneity has limited causal associations. Using multi-omics studies on genetically controlled cohorts of mice, we identify diet as the major driver of microbial and metabolomic differences, with reductions in α diversity and widespread changes in cecal metabolites seen in high-fat diet (HFD)-fed mice. In addition, non-classic amino acid conjugation of the bile acid cholic acid (AA-CA) increased with HFD. We show that AA-CAs impact intestinal stem cell growth and demonstrate that Ileibacterium valens and Ruminococcus gnavus are able to synthesize these AA-CAs. This multi-omics dataset implicates diet-induced shifts in the microbiome and the metabolome in disease progression and has potential utility in future diagnostic and therapeutic developments.
    Keywords:  CP: Cancer; CP: Microbiology; bile acids; colorectal cancer; conjugated bile acids; high-fat diet; metabolome; microbiome
    DOI:  https://doi.org/10.1016/j.celrep.2023.112997
  43. Nat Metab. 2023 Aug 21.
    Mitochondrial function and phenotype are defined by bioenergetics.
    Ryan J Mailloux, Jason Treberg, Cathryn Grayson, Luis B Agellon, Helmut Sies.
      
    DOI:  https://doi.org/10.1038/s42255-023-00885-w
  44. bioRxiv. 2023 Aug 09. pii: 2023.08.08.550079. [Epub ahead of print]
    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.
      The human metabolism constantly responds to stimuli such as food intake, fasting, exercise, and stress, triggering adaptive biochemical processes across multiple metabolic pathways. To understand the role of these processes and disruptions thereof in health and disease, detailed documentation of healthy metabolic responses is needed but still scarce on a time-resolved metabolome-wide level. Here, we present the HuMet Repository, a web-based resource for exploring dynamic metabolic responses to six physiological challenges (exercise, 36 h fasting, oral glucose and lipid loads, mixed meal, cold stress) in healthy subjects. For building this resource, we integrated existing and newly derived metabolomics data measured in blood, urine, and breath samples of 15 young healthy men at up to 56 time points during the six highly standardized challenge tests conducted over four days. The data comprise 1.1 million data points acquired on multiple platforms with temporal profiles of 2,656 metabolites from a broad range of biochemical pathways. By embedding the dataset into an interactive web application, we enable users to easily access, search, filter, analyze, and visualize the time-resolved metabolomic readouts and derived results. Users can put metabolites into their larger context by identifying metabolites with similar trajectories or by visualizing metabolites within holistic metabolic networks to pinpoint pathways of interest. In three showcases, we outline the value of the repository for gaining biological insights and generating hypotheses by analyzing the wash-out of dietary markers, the complementarity of metabolomics platforms in dynamic versus cross-sectional data, and similarities and differences in systemic metabolic responses across challenges. With its comprehensive collection of time-resolved metabolomics data, the HuMet Repository, freely accessible at https://humet.org/ , is a reference for normal, healthy responses to metabolic challenges in young males. It will enable researchers with and without computational expertise, to flexibly query the data for their own research into the dynamics of human metabolism.
    DOI:  https://doi.org/10.1101/2023.08.08.550079
  45. Cell Rep. 2023 Aug 23. pii: S2211-1247(23)01046-X. [Epub ahead of print]42(9): 113035
    Golgi retention and oncogenic KIT signaling via PLCγ2-PKD2-PI4KIIIβ activation in gastrointestinal stromal tumor cells.
    Yuuki Obata, Kazuo Kurokawa, Takuro Tojima, Miyuki Natsume, Isamu Shiina, Tsuyoshi Takahashi, Ryo Abe, Akihiko Nakano, Toshirou Nishida.
      Most gastrointestinal stromal tumors (GISTs) develop due to gain-of-function mutations in the tyrosine kinase gene, KIT. We recently showed that mutant KIT mislocalizes to the Golgi area and initiates uncontrolled signaling. However, the molecular mechanisms underlying its Golgi retention remain unknown. Here, we show that protein kinase D2 (PKD2) is activated by the mutant, which causes Golgi retention of KIT. In PKD2-inhibited cells, KIT migrates from the Golgi region to lysosomes and subsequently undergoes degradation. Importantly, delocalized KIT cannot trigger downstream activation. In the Golgi/trans-Golgi network (TGN), KIT activates the PKD2-phosphatidylinositol 4-kinase IIIβ (PKD2-PI4KIIIβ) pathway through phospholipase Cγ2 (PLCγ2) to generate a PI4P-rich membrane domain, where the AP1-GGA1 complex is aberrantly recruited. Disruption of any factors in this cascade results in the release of KIT from the Golgi/TGN. Our findings show the molecular mechanisms underlying KIT mislocalization and provide evidence for a strategy for inhibition of oncogenic signaling.
    Keywords:  AP1; CP: Cancer; CP: Molecular biology; GGA1; GIST; Golgi/TGN; KIT; PI4KIIIβ; PKD2; PLCγ2; mislocalization; receptor tyrosine kinase
    DOI:  https://doi.org/10.1016/j.celrep.2023.113035
  46. Nat Cell Biol. 2023 Aug 21.
    Epigenetic control of cancer inflammation.
    David Corujo, Marcus Buschbeck.
      
    DOI:  https://doi.org/10.1038/s41556-023-01183-z
  47. Br J Cancer. 2023 Aug 22.
    A cell cycle centric view of tumour dormancy.
    William A Weston, Alexis R Barr.
      Tumour dormancy and recurrent metastatic cancer remain the greatest clinical challenge for cancer patients. Dormant tumour cells can evade treatment and detection, while retaining proliferative potential, often for years, before relapsing to tumour outgrowth. Cellular quiescence is one mechanism that promotes and maintains tumour dormancy due to its central role in reducing proliferation, elevating cyto-protective mechanisms, and retaining proliferative potential. Quiescence/proliferation decisions are dictated by intrinsic and extrinsic signals, which regulate the activity of cyclin-dependent kinases (CDKs) to modulate cell cycle gene expression. By clarifying the pathways regulating CDK activity and the signals which activate them, we can better understand how cancer cells enter, maintain, and escape from quiescence throughout the progression of dormancy and metastatic disease. Here we review how CDK activity is regulated to modulate cellular quiescence in the context of tumour dormancy and highlight the therapeutic challenges and opportunities it presents.
    DOI:  https://doi.org/10.1038/s41416-023-02401-z
  48. Annu Rev Nutr. 2023 08 21. 43 153-177
    Gluconeogenesis Flux in Metabolic Disease.
    Ankit Shah, Fredric E Wondisford.
      Gluconeogenesis is a critical biosynthetic process that helps maintain whole-body glucose homeostasis and becomes altered in certain medical diseases. We review gluconeogenic flux in various medical diseases, including common metabolic disorders, hormonal imbalances, specific inborn genetic errors, and cancer. We discuss how the altered gluconeogenic activity contributes to disease pathogenesis using data from experiments using isotopic tracer and spectroscopy methodologies. These in vitro, animal, and human studies provide insights into the changes in circulating levels of available gluconeogenesis substrates and the efficiency of converting those substrates to glucose by gluconeogenic organs. We highlight ongoing knowledge gaps, discuss emerging research areas, and suggest future investigations. A better understanding of altered gluconeogenesis flux may ultimately identify novel and targeted treatment strategies for such diseases.
    Keywords:  cancer; enzyme deficiency; gluconeogenesis; hormones; insulin resistance; metabolic flux
    DOI:  https://doi.org/10.1146/annurev-nutr-061121-091507
  49. Annu Rev Cell Dev Biol. 2023 Aug 22.
    Tissue Biology: In Search of a New Paradigm.
    Miri Adler, Arun R Chavan, Ruslan Medzhitov.
      Animal tissues are made up of multiple cell types that are increasingly well-characterized, yet our understanding of the core principles that govern tissue organization is still incomplete. This is in part because many observable tissue characteristics, such as cellular composition and spatial patterns, are emergent properties, and as such, they cannot be explained through the knowledge of individual cells alone. Here we propose a complex systems theory perspective to address this fundamental gap in our understanding of tissue biology. We introduce the concept of cell categories, which is based on cell relations rather than cell identity. Based on these notions we then discuss common principles of tissue modularity, introducing compositional, structural, and functional tissue modules. Cell diversity and cell relations provide a basis for a new perspective on the underlying principles of tissue organization in health and disease. Expected final online publication date for the Annual Review of Cell and Developmental Biology, Volume 39 is October 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-cellbio-120420-113830
  50. Cold Spring Harb Perspect Med. 2023 Aug 21. pii: a041389. [Epub ahead of print]
    Cellular Origins and Lineage Plasticity in Cancer.
    Jason R Pitarresi, Ben Z Stanger.
      All cancers arise from normal cells whose progeny acquire the cancer-initiating mutations and epigenetic modifications leading to frank tumorigenesis. The identity of those "cells-of-origin" has historically been a source of controversy across tumor types, as it has not been possible to witness the dynamic events giving rise to human tumors. Genetically engineered mouse models (GEMMs) of cancer provide an invaluable substitute, enabling researchers to interrogate the competence of various naive cellular compartments to initiate tumors in vivo. Researchers using these models have relied on lineage-specific promoters, knowledge of preneoplastic disease states in humans, and technical advances allowing more precise manipulations of the mouse germline. These approaches have given rise to the emerging view that multiple lineages within a given organ may generate tumors with similar histopathology. Here, we review some of the key studies leading to this conclusion in solid tumors and highlight the biological and clinical ramifications.
    DOI:  https://doi.org/10.1101/cshperspect.a041389
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