bims-camemi Biomed News
on Mitochondrial metabolism in cancer
Issue of 2022‒12‒18
47 papers selected by
Christian Frezza, Universität zu Köln



  1. Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01710-7. [Epub ahead of print]41(11): 111818
      Oncogenic KRas activates mitochondrial fission through Erk-mediated phosphorylation of the mitochondrial fission GTPase Drp1. Drp1 deletion inhibits tumorigenesis of KRas-driven pancreatic cancer, but the role of mitochondrial dynamics in other Ras-driven malignancies is poorly defined. Here we show that in vitro and in vivo growth of KRas-driven lung adenocarcinoma is unaffected by deletion of Drp1 but is inhibited by deletion of Opa1, the GTPase that regulates inner membrane fusion and proper cristae morphology. Mechanistically, Opa1 knockout disrupts cristae morphology and inhibits electron transport chain (ETC) assembly and activity, which inhibits tumor cell proliferation through loss of NAD+ regeneration. Simultaneous inactivation of Drp1 and Opa1 restores cristae morphology, ETC activity, and cell proliferation indicating that mitochondrial fission activity drives ETC dysfunction induced by Opa1 knockout. Our results support a model in which mitochondrial fission events disrupt cristae structure, and tumor cells with hyperactive fission activity require Opa1 activity to maintain ETC function.
    Keywords:  CP: Cancer; Drp1; ETC; KRas; NAD; Opa1; cancer; cristae; fission; fusion; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2022.111818
  2. Sci Adv. 2022 Dec 16. 8(50): eabp8293
      Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from VHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism. Genetic silencing of isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 impaired reductive labeling of tricarboxylic acid (TCA) cycle intermediates in vivo and suppressed growth of tumors generated from tumorgraft-derived cells. Glutaminase inhibition reduced the contribution of glutamine to the TCA cycle and resulted in modest suppression of tumorgraft growth. Infusions with [amide-15N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth in both immunocompromised and immunocompetent mice. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase.
    DOI:  https://doi.org/10.1126/sciadv.abp8293
  3. Cell Metab. 2022 Dec 08. pii: S1550-4131(22)00502-2. [Epub ahead of print]
      The mammalian succinate dehydrogenase (SDH) complex has recently been shown as capable of operating bidirectionally. Here, we develop a method (Q-Flux) capable of measuring absolute rates of both forward (VSDH(F)) and reverse (VSDH(R)) flux through SDH in vivo while also deconvoluting the amount of glucose derived from four discreet carbon sources in the liver. In validation studies, a mitochondrial uncoupler increased net SDH flux by >100% in awake rodents but also increased SDH cycling. During hyperglucagonemia, attenuated pyruvate cycling enhances phosphoenolpyruvate carboxykinase efficiency to drive increased gluconeogenesis, which is complemented by increased glutaminase (GLS) flux, methylmalonyl-CoA mutase (MUT) flux, and glycerol conversion to glucose. During hyperinsulinemic-euglycemic clamp, both pyruvate carboxylase and GLS are suppressed, while VSDH(R) is increased. Unstimulated MUT is a minor anaplerotic reaction but is readily induced by small amounts of propionate, which elicits glucagon-like metabolic rewiring. Taken together, Q-Flux yields a comprehensive picture of hepatic mitochondrial metabolism and should be broadly useful to researchers.
    Keywords:  anaplerosis; glucagon; glutaminase; insulin; mass spectrometry; metabolic flux analysis; methylmalonyl-CoA mutase; mitochondrial metabolism; propionate; succinate dehydrogenase
    DOI:  https://doi.org/10.1016/j.cmet.2022.11.011
  4. Mol Metab. 2022 Dec 10. pii: S2212-8778(22)00222-8. [Epub ahead of print] 101653
      BACKGROUND: Key cellular metabolites reflecting the immediate activity of metabolic enzymes as well as the functional metabolic state of intracellular organelles can act as powerful signal regulators to ensure the activation of homeostatic responses. The citrate/acetyl-CoA pathway, initially recognized for its role in intermediate metabolism, has emerged as a fundamental branch of this nutrient-sensing homeostatic response. Emerging studies indicate that fluctuations in acetyl-CoA availability within different cellular organelles and compartments provides substrate-level regulation of many biological functions. A fundamental aspect of these regulatory functions involves Nε-lysine acetylation.SCOPE OF REVIEW: Here, we will examine the emerging regulatory functions of the citrate/acetyl-CoA pathway and the specific role of the endoplasmic reticulum (ER) acetylation machinery in the maintenance of intracellular crosstalk and homeostasis. These functions will be analyzed in the context of associated human diseases and specific mouse models of dysfunctional ER acetylation and citrate/acetyl-CoA flux. A primary objective of this review is to highlight the complex yet integrated response of compartment- and organelle-specific Nε-lysine acetylation to the intracellular availability and flux of acetyl-CoA, linking this important post-translational modification to cellular metabolism.
    MAJOR CONCLUSIONS: The ER acetylation machinery regulates the proteostatic functions of the organelle as well as metabolic crosstalk between different intracellular organelles and compartments. This crosstalk enables the cell to impart adaptive responses within the ER and the secretory pathway. However, it also enables the ER to impart adaptive responses within different cellular organelles and compartments. Defects in the homeostatic balance of acetyl-CoA flux and ER acetylation reflect different but converging disease states in humans as well as converging phenotypes in relevant mouse models. In conclusion, citrate and acetyl-CoA should not only be seen as metabolic substrates of intermediate metabolism but also as signaling molecules that direct functional adaptation of the cell to both intracellular and extracellular messages. Future discoveries in CoA biology and acetylation are likely to yield novel therapeutic approaches.
    Keywords:  Acetyl-CoA; Acetylation; Citrate; CoA; Endoplasmic Reticulum
    DOI:  https://doi.org/10.1016/j.molmet.2022.101653
  5. Trends Cell Biol. 2022 Dec 12. pii: S0962-8924(22)00259-8. [Epub ahead of print]
      The mitochondrial calcium uniporter (MCU) controls mitochondrial bioenergetics, and its activity varies greatly between tissues. Here, we highlight a recently identified MCU-EMRE-UCP1 complex, named thermoporter, in the adaptive thermogenesis of brown adipose tissue (BAT). The thermoporter enhances MCU activity to promote thermogenic metabolism, demonstrating a BAT-specific regulation for MCU activity.
    DOI:  https://doi.org/10.1016/j.tcb.2022.11.008
  6. Cancers (Basel). 2022 Nov 24. pii: 5779. [Epub ahead of print]14(23):
      The human isocitrate dehydrogenase (IDH) gene encodes for the isoenzymes IDH1, 2, and 3, which catalyze the conversion of isocitrate and α-ketoglutarate (α-KG) and are required for normal mammalian metabolism. Isocitrate dehydrogenase 1 and 2 catalyze the reversible conversion of isocitrate to α-KG. Isocitrate dehydrogenase 3 is the key enzyme that mediates the production of α-KG from isocitrate in the tricarboxylic acid (TCA) cycle. In the TCA cycle, the decarboxylation reaction catalyzed by isocitrate dehydrogenase mediates the conversion of isocitrate to α-KG accompanied by dehydrogenation, a process commonly known as oxidative decarboxylation. The formation of 6-C isocitrate from α-KG and CO2 catalyzed by IDH is termed reductive carboxylation. This IDH-mediated reversible reaction is of great importance in tumor cells. We outline the role of the various isocitrate dehydrogenase isoforms in cancer, discuss the metabolic implications of interference with IDH, summarize therapeutic interventions targeting changes in IDH expression, and highlight areas for future research.
    Keywords:  cancer metabolism; isocitrate dehydrogenase (IDH); nicotinamide adenine dinucleotide phosphate (NADPH); oxidative decarboxylation; reductive carboxylation; α-ketoglutarate (α-KG)
    DOI:  https://doi.org/10.3390/cancers14235779
  7. Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01677-1. [Epub ahead of print]41(11): 111789
      Organisms use several strategies to mitigate mitochondrial stress, including the activation of the mitochondrial unfolded protein response (UPRmt). The UPRmt in Caenorhabditis elegans, regulated by the transcription factor ATFS-1, expands on this recovery program by inducing an antimicrobial response against pathogens that target mitochondrial function. Here, we show that the mammalian ortholog of ATFS-1, ATF5, protects the host during infection with enteric pathogens but, unexpectedly, by maintaining the integrity of the intestinal barrier. Intriguingly, ATF5 supports intestinal barrier function by promoting a satiety response that prevents obesity and associated hyperglycemia. This consequently averts dysregulated glucose metabolism that is detrimental to barrier function. Mechanistically, we show that intestinal ATF5 stimulates the satiety response by transcriptionally regulating the gastrointestinal peptide hormone cholecystokinin, which promotes the secretion of the hormone leptin. We propose that ATF5 protects the host from enteric pathogens by promoting intestinal barrier function through a satiety-response-mediated metabolic control mechanism.
    Keywords:  ATF5; CP: Metabolism; CP: Molecular biology; UPR(mt); cholecystokinin; colitis; epithelial barrier; host-pathogen interaction; hyperglycemia; leptin; mitochondria; satiety
    DOI:  https://doi.org/10.1016/j.celrep.2022.111789
  8. Cells. 2022 Nov 30. pii: 3863. [Epub ahead of print]11(23):
      Targeting cancer metabolism has become one of the strategies for a rational anti-tumor therapy. However, cellular plasticity, driven by a major regulator of cellular growth and metabolism, mTORC1, often leads toward treatment resistance. Sestrin2, a stress-inducible protein, has been described as an mTORC1 inhibitor upon various types of stress signals. Immune assays and online measurements of cellular bioenergetics were employed to investigate the nature of Sestrin2 regulation, and finally, by silencing the SESN2 gene, to identify the role of induced Sestrin2 upon a single amino acid deprivation in cancer cells of various origins. Our data suggest that a complex interplay of either oxidative, energetic, nutritional stress, or in combination, play a role in Sestrin2 regulation upon single amino acid deprivation. Therefore, cellular metabolic background and sequential metabolic response dictate Sestrin2 expression in the absence of an amino acid. While deprivations of essential amino acids uniformly induce Sestrin2 levels, non-essential amino acids regulate Sestrin2 differently, drawing a characteristic Sestrin2 expression fingerprint, which could serve as a first indication of the underlying cellular vulnerability. Finally, we show that canonical GCN2-ATF4-mediated Sestrin2 induction leads to mTORC1 inhibition only in amino acid auxotroph cells, where the amino acid cannot be replenished by metabolic reprogramming.
    Keywords:  Sestrin2; amino acid deprivation; mTORC1; metabolic adaptation; nutritional stress
    DOI:  https://doi.org/10.3390/cells11233863
  9. Nat Cancer. 2022 Dec 12.
      The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has emerged as a critical innate immune pathway that, following engagement by DNA, promotes distinct immune effector responses that can impact virtually all aspects of tumorigenesis, from malignant cell transformation to metastasis. Here we address how natural tumor-associated processes and traditional cancer therapies are shaped by cGAS-STING signaling, and how this contributes to beneficial or detrimental outcomes of cancer. We consider current efforts to target the cGAS-STING axis in tumors and highlight new frontiers in cGAS-STING biology to inspire thinking about their connection to cancer.
    DOI:  https://doi.org/10.1038/s43018-022-00468-w
  10. Cell Chem Biol. 2022 Dec 01. pii: S2451-9456(22)00415-9. [Epub ahead of print]
      While it is well known that expression levels of metabolic enzymes regulate the metabolic state of the cell, there is mounting evidence that the converse is also true, that metabolite levels themselves can modulate gene expression via epigenetic modifications and transcriptional regulation. Here we focus on the one-carbon metabolic pathway, which provides the essential building blocks of many classes of biomolecules, including purine nucleotides, thymidylate, serine, and methionine. We review the epigenetic roles of one-carbon metabolic enzymes and their associated metabolites and introduce an interactive computational resource that places enzyme essentiality in the context of metabolic pathway topology. Therefore, we briefly discuss examples of metabolic condensates and higher-order complexes of metabolic enzymes downstream of one-carbon metabolism. We speculate that they may be required to the formation of transcriptional condensates and gene expression control. Finally, we discuss new ways to exploit metabolic pathway compartmentalization to selectively target these enzymes in cancer.
    Keywords:  cancer; chromatin; epigenetics; folate metabolism; metabolic condensates; nuclear condensates; nuclear metabolism; nucleotides; one-carbon metabolism; phase separation; purinergic signaling; transcription regulation; transcriptional condensates
    DOI:  https://doi.org/10.1016/j.chembiol.2022.11.009
  11. FEBS J. 2022 Dec 14.
      Advances in cancer biology over the past decades have revealed that metabolic adaptation of cancer cells is an essential aspect of tumorigenesis. However, recent insights into tumor metabolism in vivo have revealed dissimilarities with results obtained in vitro. This is partly due to the reductionism of in vitro cancer models that struggle to reproduce the complexity of tumor tissues. This review describes some of the discrepancies in cancer cell metabolism between in vitro and in vivo conditions, and presents current methodological approaches and tools used to bridge the gap with the clinically relevant microenvironment. As such, these approaches should generate new knowledge that could be more effectively translated into therapeutic opportunities.
    Keywords:  3D models; metabolic heterogeneity; metabolic sensors; tissue culture media; tumor cell metabolism
    DOI:  https://doi.org/10.1111/febs.16704
  12. Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01697-7. [Epub ahead of print]41(11): 111809
      The gut microbiota influences acetylation on host histones by fermenting dietary fiber into butyrate. Although butyrate could promote histone acetylation by inhibiting histone deacetylases, it may also undergo oxidation to acetyl-coenzyme A (CoA), a necessary cofactor for histone acetyltransferases. Here, we find that epithelial cells from germ-free mice harbor a loss of histone H4 acetylation across the genome except at promoter regions. Using stable isotope tracing in vivo with 13C-labeled fiber, we demonstrate that the microbiota supplies carbon for histone acetylation. Subsequent metabolomic profiling revealed hundreds of labeled molecules and supported a microbial contribution to host fatty acid metabolism, which declined in response to colitis and correlated with reduced expression of genes involved in fatty acid oxidation. These results illuminate the flow of carbon from the diet to the host via the microbiota, disruptions to which may affect energy homeostasis in the distal gut and contribute to the development of colitis.
    Keywords:  CP: Microbiology; colitis; epigenetics; fatty acid metabolism; histone acetylation; host-microbiota interactions
    DOI:  https://doi.org/10.1016/j.celrep.2022.111809
  13. Cells. 2022 Nov 30. pii: 3866. [Epub ahead of print]11(23):
      The mitochondrial permeability transition (PT) is a phenomenon that can be broadly defined as an increase in the permeability of the mitochondrial inner membrane [...].
    DOI:  https://doi.org/10.3390/cells11233866
  14. J Cell Sci. 2022 Dec 01. pii: jcs259748. [Epub ahead of print]135(23):
      Mitochondria are crucial organelles that play a central role in various cell signaling and metabolic pathways. A healthy mitochondrial population is maintained through a series of quality control pathways and requires a fine-tuned balance between mitochondrial biogenesis and degradation. Defective targeting of dysfunctional mitochondria to lysosomes through mitophagy has been linked to several diseases, but the underlying mechanisms and the relative importance of distinct mitophagy pathways in vivo are largely unknown. In this Cell Science at a Glance and the accompanying poster, we describe our current understanding of how parts of, or whole, mitochondria are recognized by the autophagic machinery and targeted to lysosomes for degradation. We also discuss how this might be regulated under different physiological conditions to maintain mitochondrial and cellular health.
    Keywords:  BNIP3; HIF1; Mitochondria; Mitophagy; NIX; PINK1; Parkin; SLR; Selective autophagy
    DOI:  https://doi.org/10.1242/jcs.259748
  15. Sci Adv. 2022 Dec 16. 8(50): eade1516
      The mitochondrial calcium uniporter, which regulates aerobic metabolism by catalyzing mitochondrial Ca2+ influx, is arguably the most selective ion channel known. The mechanisms for this exquisite Ca2+ selectivity have not been defined. Here, using a reconstituted system, we study the electrical properties of the channel's minimal Ca2+-conducting complex, MCU-EMRE, from Tribolium castaneum to probe ion selectivity mechanisms. The wild-type TcMCU-EMRE complex recapitulates hallmark electrophysiological properties of endogenous Uniporter channels. Through interrogation of pore-lining mutants, we find that a ring of glutamate residues, the "E-locus," serves as the channel's selectivity filter. Unexpectedly, a nearby "D-locus" at the mouth of the pore has diminutive influence on selectivity. Anomalous mole fraction effects indicate that multiple Ca2+ ions are accommodated within the E-locus. By facilitating ion-ion interactions, the E-locus engenders both exquisite Ca2+ selectivity and high ion throughput. Direct comparison with structural information yields the basis for selective Ca2+ conduction by the channel.
    DOI:  https://doi.org/10.1126/sciadv.ade1516
  16. Cancer Res. 2022 Dec 13. pii: CAN-22-2145. [Epub ahead of print]
      Metabolic reprogramming can contribute to colorectal cancer (CRC) progression and therapy resistance. Identification of key regulators of CRC metabolism could provide new approaches to improve treatment and reduce recurrence. Here, we demonstrate a critical role for the COP9 signalosome subunit CSN6 in rewiring nucleotide metabolism in CRC. Transcriptomic analysis of CRC patient samples revealed a correlation between CSN6 expression and purine and pyrimidine metabolism. A colitis-associated colorectal cancer model established that Csn6 intestinal conditional deletion decreased tumor development and altered nucleotide metabolism. CSN6 knockdown increased the chemosensitivity of CRC cells in vitro and in vivo, which could be partially reversed with nucleoside supplementation. Isotope metabolite tracing showed that CSN6 loss reduced de novo nucleotide synthesis. Mechanistically, CSN6 upregulated purine and pyrimidine biosynthesis by increasing expression of PHGDH, a key enzyme in the serine synthesis pathway. CSN6 inhibited β-Trcp-mediated DDX5 polyubiquitination and degradation, which in turn promoted DDX5-mediated PHGDH mRNA stabilization, leading to metabolic reprogramming and CRC progression. Butyrate treatment decreased CSN6 expression and improved chemotherapy efficacy. These findings unravel the oncogenic role of CSN6 in regulating nucleotide metabolism and chemosensitivity in CRC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-2145
  17. Nature. 2022 Dec 14.
      Diffuse gliomas, particularly glioblastomas, are incurable brain tumours1. They are characterized by networks of interconnected brain tumour cells that communicate via Ca2+ transients2-6. However, the networks' architecture and communication strategy and how these influence tumour biology remain unknown. Here we describe how glioblastoma cell networks include a small, plastic population of highly active glioblastoma cells that display rhythmic Ca2+ oscillations and are particularly connected to others. Their autonomous periodic Ca2+ transients preceded Ca2+ transients of other network-connected cells, activating the frequency-dependent MAPK and NF-κB pathways. Mathematical network analysis revealed that glioblastoma network topology follows scale-free and small-world properties, with periodic tumour cells frequently located in network hubs. This network design enabled resistance against random damage but was vulnerable to losing its key hubs. Targeting of autonomous rhythmic activity by selective physical ablation of periodic tumour cells or by genetic or pharmacological interference with the potassium channel KCa3.1 (also known as IK1, SK4 or KCNN4) strongly compromised global network communication. This led to a marked reduction of tumour cell viability within the entire network, reduced tumour growth in mice and extended animal survival. The dependency of glioblastoma networks on periodic Ca2+ activity generates a vulnerability7 that can be exploited for the development of novel therapies, such as with KCa3.1-inhibiting drugs.
    DOI:  https://doi.org/10.1038/s41586-022-05520-4
  18. Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01719-3. [Epub ahead of print]41(11): 111827
      The cancer metastasis process involves dysregulated oncogenic kinase signaling, but how this orchestrates metabolic networks and signal cascades to promote metastasis is largely unclear. Here we report that inhibition of glutamate dehydrogenase 1 (GDH1) and ribosomal S6 kinase 2 (RSK2) synergistically attenuates cell invasion, anoikis resistance, and immune escape in lung cancer and more evidently in tumors harboring epidermal growth factor receptor (EGFR)-activating or EGFR inhibitor-resistant mutations. Mechanistically, GDH1 is activated by EGFR through phosphorylation at tyrosine 135 and, together with RSK2, enhances the cAMP response element-binding protein (CREB) activity via CaMKIV signaling, thereby promoting metastasis. Co-targeting RSK2 and GDH1 leads to enhanced intratumoral CD8 T cell infiltration. Moreover, GDH1, RSK2, and CREB phosphorylation positively correlate with EGFR mutation and activation in lung cancer patient tumors. Our findings reveal a crosstalk between kinase, metabolic, and transcription machinery in metastasis and offer an alternative combinatorial therapeutic strategy to target metastatic cancers with activated EGFRs that are often EGFR therapy resistant.
    Keywords:  CP: Cancer; CREB; EGFR; EGFR mutations; GDH1; RSK2; cAMP response element-binding protein; epidermal growth factor receptor 1; glutamate dehydrogenase 1; metastasis; non-small cell lung carcinoma; oncogenic kinase signaling; ribosomal S6 kinase 2; tumor; tyrosine phosphorylation
    DOI:  https://doi.org/10.1016/j.celrep.2022.111827
  19. Redox Biol. 2022 Dec 05. pii: S2213-2317(22)00333-0. [Epub ahead of print]59 102561
      Nicotinamide adenine dinucleotide (NAD+) kinase (NADK) phosphorylates NAD+, thereby producing nicotinamide adenine dinucleotide phosphate (NADP). Both NADK genes and the NADP(H)-producing mechanism are evolutionarily conserved among archaea, bacteria, plants and mammals. In mammals, NADK is activated by phosphorylation and protein-protein interaction. Recent studies conducted using genetically altered models validate the essential role of NADK in cellular redox homeostasis and metabolism in multicellular organisms. Here, we describe the evolutionary conservation, molecular properties, and signaling mechanisms and discuss the pathophysiological significance of NADK.
    Keywords:  NAD(+); NADK; NADK2; NADPH; Nampt; Thioredoxin
    DOI:  https://doi.org/10.1016/j.redox.2022.102561
  20. Cancer Cell. 2022 Dec 06. pii: S1535-6108(22)00563-3. [Epub ahead of print]
      Mesenchymal colorectal cancer (mCRC) is microsatellite stable (MSS), highly desmoplastic, with CD8+ T cells excluded to the stromal periphery, resistant to immunotherapy, and driven by low levels of the atypical protein kinase Cs (aPKCs) in the intestinal epithelium. We show here that a salient feature of these tumors is the accumulation of hyaluronan (HA) which, along with reduced aPKC levels, predicts poor survival. HA promotes epithelial heterogeneity and the emergence of a tumor fetal metaplastic cell (TFMC) population endowed with invasive cancer features through a network of interactions with activated fibroblasts. TFMCs are sensitive to HA deposition, and their metaplastic markers have prognostic value. We demonstrate that in vivo HA degradation with a clinical dose of hyaluronidase impairs mCRC tumorigenesis and liver metastasis and enables immune checkpoint blockade therapy by promoting the recruitment of B and CD8+ T cells, including a proportion with resident memory features, and by blocking immunosuppression.
    Keywords:  aPKC; colorectal cancer; hyaluronan; immune checkpoint therapy; immunosuppression; inflammation; liver metastasis; mesenchymal; stroma; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2022.11.016
  21. Mol Cell. 2022 Dec 08. pii: S1097-2765(22)01130-3. [Epub ahead of print]
      Cell cycle (CC) facilitates cell division via robust, cyclical gene expression. Protective immunity requires the expansion of pathogen-responsive cell types, but whether CC confers unique gene expression programs that direct the subsequent immunological response remains unclear. Here, we demonstrate that single macrophages (MFs) adopt different plasticity states in CC, which leads to heterogeneous cytokine-induced polarization, priming, and repolarization programs. Specifically, MF plasticity to interferon gamma (IFNG) is substantially reduced during S-G2/M, whereas interleukin 4 (IL-4) induces S-G2/M-biased gene expression, mediated by CC-biased enhancers. Additionally, IL-4 polarization shifts the CC-phase distribution of MFs toward the G2/M phase, providing a subpopulation-specific mechanism for IL-4-induced, dampened IFNG responsiveness. Finally, we demonstrate CC-dependent MF responses in murine and human disease settings in vivo, including Th2-driven airway inflammation and pulmonary fibrosis, where MFs express an S-G2/M-biased tissue remodeling gene program. Therefore, MF inflammatory and regenerative responses are gated by CC in a cyclical, phase-dependent manner.
    Keywords:  cell cycle; macrophage plasticity; macrophage polarization; single-cell epigenomics
    DOI:  https://doi.org/10.1016/j.molcel.2022.11.017
  22. EMBO J. 2022 Dec 14. e111372
      Mitophagy, the elimination of mitochondria via the autophagy-lysosome pathway, is essential for the maintenance of cellular homeostasis. The best characterised mitophagy pathway is mediated by stabilisation of the protein kinase PINK1 and recruitment of the ubiquitin ligase Parkin to damaged mitochondria. Ubiquitinated mitochondrial surface proteins are recognised by autophagy receptors including NDP52 which initiate the formation of an autophagic vesicle around the mitochondria. Damaged mitochondria also generate reactive oxygen species (ROS) which have been proposed to act as a signal for mitophagy, however the mechanism of ROS sensing is unknown. Here we found that oxidation of NDP52 is essential for the efficient PINK1/Parkin-dependent mitophagy. We identified redox-sensitive cysteine residues involved in disulphide bond formation and oligomerisation of NDP52 on damaged mitochondria. Oligomerisation of NDP52 facilitates the recruitment of autophagy machinery for rapid mitochondrial degradation. We propose that redox sensing by NDP52 allows mitophagy to function as a mechanism of oxidative stress response.
    Keywords:  NDP52; autophagy; mitophagy; p62; redox
    DOI:  https://doi.org/10.15252/embj.2022111372
  23. Nat Cancer. 2022 Dec 12.
      The human genome contains 61 codons encoding 20 amino acids. Synonymous codons representing a given amino acid are decoded by a set of transfer RNAs (tRNAs) called isoacceptors. We report the surprising observation that two isoacceptor tRNAs that decode synonymous codons become modulated in opposing directions during breast cancer progression. Specifically, tRNAIleUAU became upregulated, whereas tRNAIleGAU became repressed as breast cancer cells attained enhanced metastatic capacity. Functionally, tRNAIleUAU promoted and tRNAIleGAU suppressed metastatic colonization in mouse xenograft models. These tRNAs mediated opposing effects on codon-dependent translation of growth-promoting genes, consistent with genomic enrichment or depletion of their cognate codons in mitotic genes. Our findings uncover a specific isoacceptor tRNA pair that act in opposition, divergently impacting growth-regulating genes and a disease phenotype. Degeneracy of the genetic code can thus be biologically exploited by human cancer cells via tRNA isoacceptor shifts that causally facilitate the transition toward a growth-promoting state.
    DOI:  https://doi.org/10.1038/s43018-022-00469-9
  24. J Cell Physiol. 2022 Dec 11.
      Recent developments in lysosome biology have transformed our view of lysosomes from static garbage disposals that can also act as suicide bags to decidedly dynamic multirole adaptive operators of cellular homeostasis. Lysosome-governed signaling pathways, proteins, and transcription factors equilibrate the rate of catabolism and anabolism (autophagy to lysosomal biogenesis and metabolite pool maintenance) by sensing cellular metabolic status. Lysosomes also interact with other organelles by establishing contact sites through which they exchange cellular contents. Lysosomal function is critically assessed by lysosomal positioning and motility for cellular adaptation. In this setting, mechanistic target of rapamycin kinase (MTOR) is the chief architect of lysosomal signaling to control cellular homeostasis. Notably, lysosomes can orchestrate explicit cell death mechanisms, such as autophagic cell death and lysosomal membrane permeabilization-associated regulated necrotic cell death, to maintain cellular homeostasis. These lines of evidence emphasize that the lysosomes serve as a central signaling hub for cellular homeostasis.
    Keywords:  autophagy; lysosomal biogenesis; lysosomal membrane permeabilization; lysosome; mechanistic target of rapamycin kinase
    DOI:  https://doi.org/10.1002/jcp.30928
  25. Technol Cancer Res Treat. 2022 Jan-Dec;21:21 15330338221144446
      Cancer cells are characterized by accelerated proliferation and an outstanding adaptation of their metabolic pathways to meet energy demands. The folate cycle, also known as folate metabolism or one-carbon metabolism, through enzymatic interconversions, provides metabolites necessary for nucleotide synthesis, methylation, and reduction power, helping to maintain the high rate of proliferation; therefore, the study of this metabolic pathway is of great importance in the study of cancer. Moreover, multiple enzymes involved in this cycle have been implicated in different types of cancer, corroborating the cell's adaptations under this pathology. During the last decade, nonalcoholic fatty liver disease has emerged as the leading etiology related to the rise in the incidence and deaths of hepatocellular carcinoma. Specifically, cholesterol accumulation has been a determinant promoter of tumor formation, with solid evidence that an enriched-cholesterol diet plays a crucial role in accelerating the development of an aggressive subtype of hepatocellular carcinoma compared to other models. In this review, we will discuss the most recent findings to understand the contribution of folate metabolism to cancer cells and tumor microenvironment while creating a link between the dynamics given by cholesterol and methylenetetrahydrofolate dehydrogenase 1-like, a key enzyme of the cycle located in the mitochondrial compartment.
    Keywords:  MTHFD1L; cholesterol; folate cycle; hepatocellular carcinoma
    DOI:  https://doi.org/10.1177/15330338221144446
  26. Semin Cancer Biol. 2022 Dec 07. pii: S1044-579X(22)00255-3. [Epub ahead of print]88 32-45
      Immune checkpoint inhibitors and adoptive T cell therapies have been valuable additions to the toolbox in the fight against cancer. These treatments have profoundly increased the number of patients with a realistic perspective toward a return to a cancer-free life. Yet, in a number of patients and tumor entities, cancer immunotherapies have been ineffective so far. In solid tumors, immune exclusion and the immunosuppressive tumor microenvironment represent substantial roadblocks to successful therapeutic outcomes. A major contributing factor to the depressed anti-tumor activity of immune cells in tumors is the harsh metabolic environment. Hypoxia, nutrient competition with tumor and stromal cells, and accumulating noxious waste products, including lactic acid, pose massive constraints to anti-tumor immune cells. Numerous strategies are being developed to exploit the metabolic vulnerabilities of tumor cells in the hope that these would also alleviate metabolism-inflicted immune suppression. While promising in principle, especially in combination with immunotherapies, these strategies need to be scrutinized for their effect on tumor-fighting immune cells, which share some of their key metabolic properties with tumor cells. Here, we provide an overview of strategies that seek to tackle lactate metabolism in tumor or immune cells to unleash anti-tumor immune responses, thereby opening therapeutic options for patients whose tumors are currently not treatable.
    Keywords:  Acidification; Adoptive cell transfer; Checkpoint inhibition; Glycolysis; Immunotherapy; Lactate; Metabolism
    DOI:  https://doi.org/10.1016/j.semcancer.2022.12.001
  27. Int J Mol Sci. 2022 Nov 29. pii: 14945. [Epub ahead of print]23(23):
      Glucose is a direct energy source for eukaryotic cells, and its deficiency elicits complex stress responses and diverse cellular outcomes. Although several signaling pathways involved have been identified, how they coordinately dictate the cell fate remains obscure. We propose a minimal network model for the cellular response to glucose restriction, characterizing the glucose uptake and signaling of the AMPK, Akt, mTOR, and p53 pathways. We demonstrate that in the presence of sufficient growth factors and amino acids, cells may undergo proliferation, senescence, or apoptosis, depending on the extracellular glucose level. AMPK is first activated upon glucose limitation, activating p53 to induce cell-cycle arrest; possibly, cells resume proliferation after timely glucose restoration. For long-term energy stress, cell senescence is maintained by low/intermediate levels of p53 and persistent activation of mTOR and Akt, or cells commit apoptosis when the proteins undergo biphasic dynamics, e.g., p53 switches from intermediate levels to high levels while mTOR and Akt become inactivated in the later phase. The biphasic dynamics of p53 are associated with flipping of two bistable switches. Appropriate mTOR levels are required for optimal cell-fate decision. This work suggests that senescence and apoptosis occur sequentially in glucose-depleted cells, and a theoretical framework is provided for exploring the cellular response to energy stress.
    Keywords:  apoptosis; biphasic dynamics; cell-fate decision; glucose starvation; network modeling; senescence
    DOI:  https://doi.org/10.3390/ijms232314945
  28. Acta Biochim Biophys Sin (Shanghai). 2022 Nov 25. 54(11): 1-9
      In pancreatic cancer, KRAS G12D can trigger pancreatic cancer initiation and development. Rapid tumor growth is often accompanied by excess intracellular reactive oxygen species (ROS) production, which is unfavorable to tumor. However, the regulation of intracellular ROS levels in KRAS mutant pancreatic cancer remains unclear. In this study, we establish BxPC3 stable cell strains expressing KRAS wild type (WT) and G12D mutation and find unchanged ROS levels despite higher glycolysis and proliferation viability in KRAS mutant cells than KRAS WT cells. The key hydrogen sulfide (H 2S)-generating enzyme cystathionine-γ-lyase (CSE) is upregulated in KRAS mutant BxPC3 cells, and its knockdown significantly increases intracellular ROS levels and decreases cell glycolysis and proliferation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is activated by KRAS mutation to promote CSE transcription. An Nrf2 binding site (‒47/‒39 bp) in the CSE promoter is verified. CSE overexpression and the addition of NaHS after Nrf2 knockdown or inhibition by brusatol decreases ROS levels and rescues cell proliferation. Our study reveals the regulatory mechanism of intracellular ROS levels in KRAS mutant pancreatic cancer cells, which provides a potential target for pancreatic cancer therapy.
    Keywords:  CSE; KRAS mutation; Nrf2; ROS; pancreatic cancer
    DOI:  https://doi.org/10.3724/abbs.2022173
  29. Cells. 2022 Dec 06. pii: 3940. [Epub ahead of print]11(23):
      Lonp1 is a mitochondrial protease that degrades oxidized and damaged proteins, assists protein folding, and contributes to the maintenance of mitochondrial DNA. A higher expression of LonP1 has been associated with higher tumour aggressiveness. Besides the full-length isoform (ISO1), we identified two other isoforms of Lonp1 in humans, resulting from alternative splicing: Isoform-2 (ISO2) lacking aa 42-105 and isoform-3 (ISO3) lacking aa 1-196. An inspection of the public database TSVdb showed that ISO1 was upregulated in lung, bladder, prostate, and breast cancer, ISO2 in all the cancers analysed (including rectum, colon, cervical, bladder, prostate, breast, head, and neck), ISO3 did not show significant changes between cancer and normal tissue. We overexpressed ISO1, ISO2, and ISO3 in SW620 cells and found that the ISO1 isoform was exclusively mitochondrial, ISO2 was present in the organelle and in the cytoplasm, and ISO3 was exclusively cytoplasmatic. The overexpression of ISO1 and, at a letter extent, of ISO2 enhanced basal, ATP-linked, and maximal respiration without altering the mitochondria number or network, mtDNA amount. or mitochondrial dynamics. A higher extracellular acidification rate was observed in ISO1 and ISO2, overexpressing cells, suggesting an increase in glycolysis. Cells overexpressing the different isoforms did not show a difference in the proliferation rate but showed a great increase in anchorage-independent growth. ISO1 and ISO2, but not ISO3, determined an upregulation of EMT-related proteins, which appeared unrelated to higher mitochondrial ROS production, nor due to the activation of the MEK ERK pathway, but rather to global metabolic reprogramming of cells.
    Keywords:  Lon protease; SW620; mitochondria; mitochondrial DNA
    DOI:  https://doi.org/10.3390/cells11233940
  30. Trends Pharmacol Sci. 2022 Dec 07. pii: S0165-6147(22)00254-1. [Epub ahead of print]
      The importance of mitochondrial dynamics, the physiological process of mitochondrial fusion and fission, in regulating diverse cellular functions and cellular fitness has been well established. Several pathologies are associated with aberrant mitochondrial fusion or fission that is often a consequence of deregulated mitochondrial dynamics proteins; however, pharmacological targeting of these proteins has been lacking and is challenged by complex molecular mechanisms. Recent studies have advanced our understanding in this area and have enabled rational drug design and chemical screening strategies. We provide an updated overview of the regulatory mechanisms of fusion and fission proteins, their structure-function relationships, and the discovery of pharmacological modulators demonstrating their therapeutic potential. These advances provide exciting opportunities for the development of prototype therapeutics for various diseases.
    Keywords:  activators; fission; fusion; inhibitors; mitochondria; mitochondrial dynamics; mitochondrial structure
    DOI:  https://doi.org/10.1016/j.tips.2022.11.004
  31. Nat Commun. 2022 Dec 13. 13(1): 7732
      Chromosome segregation is initiated by cohesin degradation, which is driven by anaphase-promoting complex/cyclosome (APC/C). Chromosome cohesin is removed by activated separase, with the degradation of securin and cyclinB1. Dynamin-related protein 1 (DRP1), a component of the mitochondrial fission machinery, is related to cyclin dynamics in mitosis progression. Here, we show that DRP1 is recruited to the kinetochore by centromeric Centromere protein F (CENP-F) after nuclear envelope breakdown in mouse oocytes. Loss of DRP1 during prometaphase leads to premature cohesin degradation and chromosome segregation. Importantly, acute DRP1 depletion activates separase by initiating cyclinB1 and securin degradation during the metaphase-to-anaphase transition. Finally, we demonstrate that DRP1 is bound to APC2 to restrain the E3 ligase activity of APC/C. In conclusion, DRP1 is a CENP-F-dependent atypical spindle assembly checkpoint (SAC) protein that modulates metaphase-to-anaphase transition by controlling APC/C activity during meiosis I in oocytes.
    DOI:  https://doi.org/10.1038/s41467-022-35461-5
  32. Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01691-6. [Epub ahead of print]41(11): 111803
      Nonalcoholic fatty liver disease (NAFLD) can be ameliorated by calorie restriction, which leads to the suppressed somatotroph axis. Paradoxically, the suppressed somatotroph axis is associated with patients with NAFLD and is correlated with the severity of fibrosis. How the somatotroph axis becomes dysregulated and whether the repressed somatotroph axis impacts liver damage during the progression of NAFLD are unclear. Here, we identify a regulatory branch of the hepatic integrated stress response (ISR), which represses the somatotroph axis in hepatocytes through ATF3, resulting in enhanced cell survival and reduced cell proliferation. In mouse models of NAFLD, the ISR represses the somatotroph axis, leading to reduced apoptosis and inflammation but decreased hepatocyte proliferation and exacerbated fibrosis in the liver. NAD+ repletion reduces the ISR, rescues the dysregulated somatotroph axis, and alleviates NAFLD. These results establish that the hepatic ISR suppresses the somatotroph axis to control cell fate decisions and liver damage in NAFLD.
    Keywords:  ATF3; CP: Metabolism; ER stress; IGF-1; SIRT7; aging; integrated stress response; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; sirtuin; somatotroph axis
    DOI:  https://doi.org/10.1016/j.celrep.2022.111803
  33. Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01674-6. [Epub ahead of print]41(11): 111786
      24 h whole-body substrate metabolism and the circadian clock within skeletal muscle are both compromised upon metabolic disease in humans. Here, we assessed the 24 h muscle metabolome by serial muscle sampling performed under 24 h real-life conditions in young, healthy (YH) men versus older, metabolically compromised (OMC) men. We find that metabolites associated with the initial steps of glycolysis and hexosamine biosynthesis are higher in OMC men around the clock, whereas metabolites associated with glutamine-alpha-ketoglutarate, ketone, and redox metabolism are lower in OMC men. The night period shows the largest number of differently expressed metabolites. Both groups demonstrate 24 h rhythmicity in half of the metabolome, but rhythmic metabolites only partially overlap. Specific metabolites are only rhythmic in YH men (adenosine), phase shifted in OMC men (cis-aconitate, flavin adenine dinucleotide [FAD], and uridine diphosphate [UDP]), or have a reduced 24 h amplitude in OMC men (hydroxybutyrate and hippuric acid). Our data highlight the plasticity of the skeletal muscle metabolome over 24 h and large divergence across the metabolic health spectrum.
    Keywords:  CP: Metabolism; FAD; PGK1; adenosine; circadian rhythm; glycolysis; hexosamine; hydroxybutyrate; insulin resistance; metabolomics; misalignment
    DOI:  https://doi.org/10.1016/j.celrep.2022.111786
  34. Science. 2022 Dec 16. 378(6625): eadf3971
      Peroxisomes are ubiquitous organelles whose dysfunction causes fatal human diseases. Most peroxisomal proteins are imported from the cytosol in a folded state by the soluble receptor PEX5. How folded cargo crosses the membrane is unknown. Here, we show that peroxisomal import is similar to nuclear transport. The peroxisomal membrane protein PEX13 contains a conserved tyrosine (Y)- and glycine (G)-rich YG domain, which forms a selective phase resembling that formed by phenylalanine-glycine (FG) repeats within nuclear pores. PEX13 resides in the membrane in two orientations that oligomerize and suspend the YG meshwork within the lipid bilayer. Purified YG domains form hydrogels into which PEX5 selectively partitions, by using conserved aromatic amino acid motifs, bringing cargo along. The YG meshwork thus forms an aqueous conduit through which PEX5 delivers folded proteins into peroxisomes.
    DOI:  https://doi.org/10.1126/science.adf3971
  35. Cancer Cell Int. 2022 Dec 12. 22(1): 402
      BACKGROUND: Metabolic reprogramming is an important issue in tumor biology. A recently-identified actor in this regard is the molecular chaperone TRAP1, that is considered an oncogene in several cancers for its high expression but an oncosuppressor in others with predominant oxidative metabolism. TRAP1 is mainly localized in mitochondria, where it interacts with respiratory complexes, although alternative localizations have been described, particularly on the endoplasmic reticulum, where it interacts with the translational machinery with relevant roles in protein synthesis regulation.RESULTS: Herein we show that, inside mitochondria, TRAP1 binds the complex III core component UQCRC2 and regulates complex III activity. This decreases respiration rate during basal conditions but allows sustained oxidative phosphorylation when glucose is limiting, a condition in which the direct TRAP1-UQCRC2 binding is disrupted, but not TRAP1-complex III binding. Interestingly, several complex III components and assembly factors show an inverse correlation with survival and response to platinum-based therapy in high grade serous ovarian cancers, where TRAP1 inversely correlates with stage and grade and directly correlates with survival. Accordingly, drug-resistant ovarian cancer cells show high levels of complex III components and high sensitivity to complex III inhibitory drug antimycin A.
    CONCLUSIONS: These results shed new light on the molecular mechanisms involved in TRAP1-dependent regulation of cancer cell metabolism and point out a potential novel target for metabolic therapy in ovarian cancer.
    Keywords:  Ovarian cancer; Platinum resistance; Respiratory complex III; TRAP1
    DOI:  https://doi.org/10.1186/s12935-022-02788-4
  36. Front Oncol. 2022 ;12 1018642
      Glutamine is a non-essential amino acid that can be synthesized by cells. It plays a vital role in the growth and proliferation of mammalian cells cultured in vitro. In the process of tumor cell proliferation, glutamine not only contributes to protein synthesis but also serves as the primary nitrogen donor for purine and pyrimidine synthesis. Studies have shown that glutamine-addicted tumor cells depend on glutamine for survival and reprogram glutamine utilization through the Krebs cycle. Potential therapeutic approaches for ovarian cancer including blocking the entry of glutamine into the tricarboxylic acid cycle in highly aggressive ovarian cancer cells or inhibiting glutamine synthesis in less aggressive ovarian cancer cells. Glutamine metabolism is associated with poor prognosis of ovarian cancer. Combining platinum-based chemotherapy with inhibition of glutamine metabolic pathways may be a new strategy for treating ovarian cancer, especially drug-resistant ovarian cancer. This article reviews the role of glutamine metabolism in the biological behaviors of ovarian cancer cells, such as proliferation, invasion, and drug resistance. Its potential use as a new target or biomarker for ovarian cancer diagnosis, treatment, and the prognosis is investigated.
    Keywords:  glutamine (Gln); mechanism; metabolism; ovarian cancer; resistance
    DOI:  https://doi.org/10.3389/fonc.2022.1018642
  37. Methods Mol Biol. 2023 ;2557 785-810
      Cancer cells utilize secretory pathways for paracrine signaling and extracellular matrix remodeling to facilitate directional cell migration, invasion, and metastasis. The Golgi apparatus is a central secretory signaling hub that is often deregulated in cancer. Here we described technologies that utilize microscopic, biochemical, and proteomic approaches to analyze Golgi secretory functions in genetically heterogeneous cancer cell lines.
    Keywords:  Cancer; Confocal microscopy; Golgi apparatus; Live-cell imaging; Proteomics; Quantitative image analysis; Secretion; Subcellular fractionation; Vesicle trafficking
    DOI:  https://doi.org/10.1007/978-1-0716-2639-9_47
  38. Science. 2022 Dec 16. 378(6625): eabq5209
      Cells respond to fluctuating nutrient supply by adaptive changes in organelle dynamics and in metabolism. How such changes are orchestrated on a cell-wide scale is unknown. We show that endosomal signaling lipid turnover by MTM1, a phosphatidylinositol 3-phosphate [PI(3)P] 3-phosphatase mutated in X-linked centronuclear myopathy in humans, controls mitochondrial morphology and function by reshaping the endoplasmic reticulum (ER). Starvation-induced endosomal recruitment of MTM1 impairs PI(3)P-dependent contact formation between tubular ER membranes and early endosomes, resulting in the conversion of ER tubules into sheets, the inhibition of mitochondrial fission, and sustained oxidative metabolism. Our results unravel an important role for early endosomal lipid signaling in controlling ER shape and, thereby, mitochondrial form and function to enable cells to adapt to fluctuating nutrient environments.
    DOI:  https://doi.org/10.1126/science.abq5209
  39. Br J Cancer. 2022 Dec 16.
      CONTEXT: Many cancer patients who initially respond to chemotherapy eventually develop chemoresistance, and to address this, we previously conducted a RNAi screen to identify genes contributing to resistance. One of the hits from the screen was branched-chain α-keto acid dehydrogenase kinase (BCKDK). BCKDK controls the metabolism of branched-chain amino acids (BCAAs) through phosphorylation and inactivation of the branched-chain α-keto acid dehydrogenase complex (BCKDH), thereby inhibiting catabolism of BCAAs.METHODS: We measured the impact on paclitaxel sensitivity of inhibiting BCKDK in ovarian and breast cancer cell lines.
    RESULTS: Inhibition of BCKDK using siRNA or two chemical inhibitors (BCKDKi) was synergistic with paclitaxel in both breast and ovarian cancer cells. BCKDKi reduced levels of BCAA and the addition of exogenous BCAA suppressed this synergy. BCKDKi inactivated the mTORC1-Aurora pathway, allowing cells to overcame M-phase arrest induced by paclitaxel. In some cases, cells almost completed cytokinesis, then reverted to a single cell, resulting in multinucleate cells.
    CONCLUSION: BCKDK is an attractive target to augment the sensitivity of cancer cells to paclitaxel.
    DOI:  https://doi.org/10.1038/s41416-022-02095-9
  40. Eur J Epidemiol. 2022 Dec 13.
      
    Keywords:  Cancer epidemiology; Cancer prevention; Mutations and cancer risk; Tumour Promotion
    DOI:  https://doi.org/10.1007/s10654-022-00933-x
  41. Cancer Cell. 2022 Dec 07. pii: S1535-6108(22)00562-1. [Epub ahead of print]
      Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer with limited treatment options. KMT2D is one of the most frequently mutated genes in LUSC (>20%), and yet its role in LUSC oncogenesis remains unknown. Here, we identify KMT2D as a key regulator of LUSC tumorigenesis wherein Kmt2d deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partly through reprogramming the chromatin landscape to repress the expression of protein tyrosine phosphatases. These events provoke a robust elevation in the oncogenic RTK-RAS signaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor afatinib inhibits lung tumor growth in Kmt2d-deficient LUSC murine models and in patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study identifies KMT2D as a pivotal epigenetic modulator for LUSC oncogenesis and suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS inhibition.
    Keywords:  EGFR; ERBB2; KMT2D; SHP2; lung squamous cell carcinoma; organoids
    DOI:  https://doi.org/10.1016/j.ccell.2022.11.015
  42. Sci Adv. 2022 Dec 16. 8(50): eabm7902
      The contribution of nutrient availability to control epidermal cell proliferation, inflammation, and hyperproliferative diseases remains unknown. Here, we studied extracellular serine and serine/glycine metabolism using human keratinocytes, human skin biopsies, and a mouse model of psoriasis-like disease. We focused on a metabolic enzyme, serine hydroxymethyltransferase (SHMT), that converts serine into glycine and tetrahydrofolate-bound one‑carbon units to support cell growth. We found that keratinocytes are both serine and glycine auxotrophs. Metabolomic profiling and hypoxanthine supplementation indicated that SHMT silencing/inhibition reduced cell growth through purine depletion, leading to nucleotide loss. In addition, topical application of an SHMT inhibitor suppressed both keratinocyte proliferation and inflammation in the imiquimod model and resulted in a decrease in psoriasis-associated gene expression. In conclusion, our study highlights SHMT2 activity and serine/glycine availability as an important metabolic hub controlling both keratinocyte proliferation and inflammatory cell expansion in psoriasis and holds promise for additional approaches to treat skin diseases.
    DOI:  https://doi.org/10.1126/sciadv.abm7902
  43. Am J Cancer Res. 2022 ;12(11): 5004-5018
      The metabolism of tumor cells is characterized by the regulation of demand, nutrient supply and metabolic enzymes, which are different in cancer tissues from those in corresponding healthy tissues. There is growing evidence that dietary composition influences biological processes that contribute to tumor incidence and progression as much as genetic status. One possibility for specific dietary interventions in cancer patients is to limit methionine intake. The role of methionine metabolism in tumors suggests that interference with the methionine metabolism network by either drug or environmental effects may show substantial therapeutic effects, but the molecular mechanism is not completely clear. In this study, methionine deprivation was found to downregulate cathepsin L (CTSL) and induce proliferation inhibition in glioma cells. We also demonstrated that CTSL is a tumor-related gene, and promotes the proliferation and invasion of glioma. Our results showed that the treatment of methionine metabolism and CTSL related genes in glioma cells may be a novel strategy for glioma therapy in the future.
    Keywords:  CTSL; Tumor metabolism; cathepsin L; glioma; methionine deprivation
  44. Cancer Res. 2022 Dec 13. pii: CAN-22-1740. [Epub ahead of print]
      Contradictory characteristics of elevated mutational burden and a "cold" tumor microenvironment (TME) coexist in LKB1-mutant non-small cell lung cancers (NSCLC). The molecular basis underlying this paradox and strategies tailored to these historically difficult-to-treat cancers are lacking. Here, by mapping the single-cell transcriptomic landscape of genetically engineered mouse models with Kras versus Kras/Lkb1 driven lung tumors, we detected impaired tumor-intrinsic IFNγ signaling in Kras/Lkb1 driven tumors that explains the inert immune context. Mechanistic analysis showed that mutant LKB1 led to deficiency in the DNA damage repair process and abnormally activated PARP1. Hyperactivated PARP1 attenuated the IFNγ pathway by physically interacting with and enhancing the poly(ADP-ribosyl)ation of STAT1, compromising its phosphorylation and activation. Abrogation of the PARP1-driven program triggered synthetic lethality in NSCLC on the basis of the LKB1 mutation-mediated DNA repair defect, while also restoring phosphorylated STAT1 to favor an immunologically "hot" TME. Accordingly, PARP1 inhibition restored the disrupted IFN-γ signaling and thus mounted an adaptive immune response to synergize with PD-1 blockade in multiple LKB1-deficient murine tumor models. Overall, this study reveals an unexplored interplay between the DNA repair process and adaptive immune response, providing a molecular basis for dual PARP1 and PD-1 inhibition in treating LKB1-mutant NSCLC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1740
  45. Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01711-9. [Epub ahead of print]41(11): 111819
      The DNA damage response (DDR) and epithelial-to-mesenchymal transition (EMT) are two crucial cellular programs in cancer biology. While the DDR orchestrates cell-cycle progression, DNA repair, and cell death, EMT promotes invasiveness, cellular plasticity, and intratumor heterogeneity. Therapeutic targeting of EMT transcription factors, such as ZEB1, remains challenging, but tumor-promoting DDR alterations elicit specific vulnerabilities. Using multi-omics, inhibitors, and high-content microscopy, we discover a chemoresistant ZEB1-high-expressing sub-population (ZEB1hi) with co-rewired cell-cycle progression and proficient DDR across tumor entities. ZEB1 stimulates accelerated S-phase entry via CDK6, inflicting endogenous DNA replication stress. However, DDR buildups involving constitutive MRE11-dependent fork resection allow homeostatic cycling and enrichment of ZEB1hi cells during transforming growth factor β (TGF-β)-induced EMT and chemotherapy. Thus, ZEB1 promotes G1/S transition to launch a progressive DDR benefitting stress tolerance, which concurrently manifests a targetable vulnerability in chemoresistant ZEB1hi cells. Our study thus highlights the translationally relevant intercept of the DDR and EMT.
    Keywords:  CP: Cancer; DNA damage response; DNA replication stress; MRE11; ZEB1; cancer; cell cycle; chemoresistance; epithelial-to-mesenchymal transition; heterogeneity; plasticity
    DOI:  https://doi.org/10.1016/j.celrep.2022.111819
  46. Cell Host Microbe. 2022 Dec 14. pii: S1931-3128(22)00567-4. [Epub ahead of print]30(12): 1649-1650
      Recently in Cell Metabolism, Challapa et al. used isotope labeling to track NAD metabolism in host tissues and the gut microbiota. They describe a symbiotic relationship in which the gut microbiota uses host-derived nicotinamide to generate NAD and in return, produces nicotinic acid for host NAD biosynthesis.
    DOI:  https://doi.org/10.1016/j.chom.2022.11.011