bims-camemi 2022-02-06 papers

bims-camemi

Biomed News

on Mitochondrial metabolism in cancer

Issue of 2022‒02‒06
forty-five papers selected by
Christian Frezza,

Leucine retention in lysosomes is regulated by starvation.
Unraveling and targeting RAS-driven metabolic signaling for therapeutic gain.
Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions.
Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis.
NRF2: KEAPing Tumors Protected.
Assembly-dependent translation of subunits 6 (Atp6) and 9 (Atp9) of ATP synthase in yeast mitochondria.
SETD2 loss perturbs the kidney cancer epigenetic landscape to promote metastasis and engenders actionable dependencies on histone chaperone complexes.
Forgetting in obesity: The pregnenolone link.
The interplay between BAX and BAK tunes apoptotic pore growth to control mitochondrial-DNA-mediated inflammation.
Protocols for analyzing metabolic derangements caused by increased NADH/NAD+ ratio in cell lines and in mice.
BMAL1 drives muscle repair through control of hypoxic NAD+ regeneration in satellite cells.
Macrophages, Metabolism and Heterophagy in the Heart.
Disrupted Liver Oxidative Metabolism in Glycine N-Methyltransferase-Deficient Mice is Mitigated by Dietary Methionine Restriction.
E3 ligase RNF167 and deubiquitinase STAMBPL1 modulate mTOR and cancer progression.
Mitochondrial respiratory chain dysfunction alters ER sterol sensing and mevalonate pathway activity.
miR-669a-5p promotes adipogenic differentiation and induces browning in preadipocytes.
Oxidative pentose phosphate pathway controls vascular mural cell coverage by regulating extracellular matrix composition.
Mapping transcriptomic vector fields of single cells.
Implications of IDH mutations on immunotherapeutic strategies for malignant glioma.
Lima1 mediates the pluripotency control of membrane dynamics and cellular metabolism.
Loss of glucose 6-phosphate dehydrogenase function increases oxidative stress and glutaminolysis in metastasizing melanoma cells.
Cancer metabolism challenges genomic instability and clonal evolution as therapeutic targets.
Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity.
Monitoring NAD(H) and NADP(H) dynamics during organismal development with genetically encoded fluorescent biosensors.
Cyanide as a primordial reductant enables a protometabolic reductive glyoxylate pathway.
Pegylated arginine deiminase drives arginine turnover and systemic autophagy to dictate energy metabolism.
A macrophage-hepatocyte glucocorticoid receptor axis coordinates fasting ketogenesis.
Regulation of Tumor Invasion by the Physical Microenvironment: Lessons from Breast and Brain Cancer.
IKKα-deficient lung adenocarcinomas generate an immunosuppressive microenvironment by overproducing Treg-inducing cytokines.
Complexities of Complex II: Sulfide metabolism in vivo.
ΔNp63 regulates a common landscape of enhancer associated genes in non-small cell lung cancer.
Selective vulnerabilities in the proteostasis network of castration-resistant prostate cancer.
Dangerous dynamic duo: Lactic acid and PD-1 blockade.
Epigenetic state determines inflammatory sensing in neuroblastoma.
Mutant Kras co-opts a proto-oncogenic enhancer network in inflammation-induced metaplastic progenitor cells to initiate pancreatic cancer.
Yme2, a putative RNA recognition motif and AAA+ domain containing protein, genetically interacts with the mitochondrial protein export machinery.
Targeting purine synthesis in ASS1-expressing tumors enhances the response to immune checkpoint inhibitors.
Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients.
Cancer-derived cholesterol sulfate is a key mediator to prevent tumor infiltration by effector T cells.
Investigating the importance of acylcarnitines in Alzheimer's disease.
The role of ROS in tumour development and progression.
Cancer research that matters.
Adipose-tissue plasticity in health and disease.
Interplay between K-RAS and miRNAs.
ASS1igning purine dependency to cancer.

Proc Natl Acad Sci U S A. 2022 Feb 08. pii: e2114912119. [Epub ahead of print]119(6):

Leucine retention in lysosomes is regulated by starvation.

Urmi Bandyopadhyay, Pavlina Todorova, Natalya N Pavlova, Yuma Tada, Craig B Thompson, Lydia W S Finley, Michael Overholtzer.

  Cells acquire essential nutrients from the environment and utilize adaptive mechanisms to survive when nutrients are scarce. How nutrients are trafficked and compartmentalized within cells and whether they are stored in response to stress remain poorly understood. Here, we investigate amino acid trafficking and uncover evidence for the lysosomal transit of numerous essential amino acids. We find that starvation induces the lysosomal retention of leucine in a manner requiring RAG-GTPases and the lysosomal protein complex Ragulator, but that this process occurs independently of mechanistic target of rapamycin complex 1 activity. We further find that stored leucine is utilized in protein synthesis and that inhibition of protein synthesis releases lysosomal stores. These findings identify a regulated starvation response that involves the lysosomal storage of leucine.

Keywords:  leucine; lysosome; mTOR

DOI:  https://doi.org/10.1073/pnas.2114912119
Adv Cancer Res. 2022 ;pii: S0065-230X(21)00081-6. [Epub ahead of print]153 267-304

Unraveling and targeting RAS-driven metabolic signaling for therapeutic gain.

Jonathan M DeLiberty, Ryan Robb, Claire E Gates, Kirsten L Bryant.

  RAS mutations are among the most frequent oncogenic drivers observed in human cancers. With a lack of available treatment options, RAS-mutant cancers account for many of the deadliest cancers in the United States. Recent studies established that altered metabolic requirements are a hallmark of cancer, and many of these alterations are driven by aberrant RAS signaling. Specifically, RAS-driven cancers are characterized by upregulated glycolysis, the differential channeling of glycolytic intermediates, upregulated nutrient scavenging pathways such as autophagy and macropinocytosis, and altered glutamine utilization and mitochondrial function. This unique metabolic landscape promotes tumorigenesis, proliferation, survival in nutrient deficient environments and confers resistance to conventional cytotoxic and targeted therapies. Emerging work demonstrates how these dependencies can be therapeutically exploited in vitro and in vivo with many metabolic inhibitors currently in clinical trials. This review aims to outline the unique metabolic requirements induced by aberrant RAS signaling and how these altered dependencies present opportunities for therapeutic intervention.

Keywords:  Autophagy; Glycolysis; Macropinocytosis; Metabolism; Mitochondria; RAS; Scavenging

DOI:  https://doi.org/10.1016/bs.acr.2021.07.010
Cell Rep. 2022 Feb 01. pii: S2211-1247(22)00031-6. [Epub ahead of print]38(5): 110320

Proline synthesis through PYCR1 is required to support cancer cell proliferation and survival in oxygen-limiting conditions.

Rebecca L Westbrook, Esther Bridges, Jennie Roberts, Cristina Escribano-Gonzalez, Katherine L Eales, Lisa A Vettore, Paul D Walker, Elias Vera-Siguenza, Himani Rana, Federica Cuozzo, Kattri-Liis Eskla, Hans Vellama, Abeer Shaaban, Colin Nixon, Hendrik Luuk, Gareth G Lavery, David J Hodson, Adrian L Harris, Daniel A Tennant.

  The demands of cancer cell proliferation alongside an inadequate angiogenic response lead to insufficient oxygen availability in the tumor microenvironment. Within the mitochondria, oxygen is the major electron acceptor for NADH, with the result that the reducing potential produced through tricarboxylic acid (TCA) cycle activity and mitochondrial respiration are functionally linked. As the oxidizing activity of the TCA cycle is required for efficient synthesis of anabolic precursors, tumoral hypoxia could lead to a cessation of proliferation without another means of correcting the redox imbalance. We show that in hypoxic conditions, mitochondrial pyrroline 5-carboxylate reductase 1 (PYCR1) activity is increased, oxidizing NADH with the synthesis of proline as a by-product. We further show that PYCR1 activity is required for the successful maintenance of hypoxic regions by permitting continued TCA cycle activity, and that its loss leads to significantly increased hypoxia in vivo and in 3D culture, resulting in widespread cell death.

Keywords:  NADH; PYCR1; cancer; hypoxia; mitochondria; proline; redox

DOI:  https://doi.org/10.1016/j.celrep.2022.110320
Nat Commun. 2022 Feb 03. 13(1): 651

Mitochondrial protein import determines lifespan through metabolic reprogramming and de novo serine biosynthesis.

Eirini Lionaki, Ilias Gkikas, Ioanna Daskalaki, Maria-Konstantina Ioannidi, Maria I Klapa, Nektarios Tavernarakis.

Sustained mitochondrial fitness relies on coordinated biogenesis and clearance. Both processes are regulated by constant targeting of proteins into the organelle. Thus, mitochondrial protein import sets the pace for mitochondrial abundance and function. However, our understanding of mitochondrial protein translocation as a regulator of longevity remains enigmatic. Here, we targeted the main protein import translocases and assessed their contribution to mitochondrial abundance and organismal physiology. We find that reduction in cellular mitochondrial load through mitochondrial protein import system suppression, referred to as MitoMISS, elicits a distinct longevity paradigm. We show that MitoMISS triggers the mitochondrial unfolded protein response, orchestrating an adaptive reprogramming of metabolism. Glycolysis and de novo serine biosynthesis are causatively linked to longevity, whilst mitochondrial chaperone induction is dispensable for lifespan extension. Our findings extent the pro-longevity role of UPRmt and provide insight, relevant to the metabolic alterations that promote or undermine survival and longevity.

DOI: https://doi.org/10.1038/s41467-022-28272-1
Cancer Discov. 2022 Jan 31.

NRF2: KEAPing Tumors Protected.

Ray Pillai, Makiko Hayashi, Anastasia-Maria Zavitsanou, Thales Papagiannakopoulos.

The Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway plays a physiologic protective role against xenobiotics and reactive oxygen species. However, activation of NRF2 provides a powerful selective advantage for tumors by rewiring metabolism to enhance proliferation, suppress various forms of stress, and promote immune evasion. Genetic, epigenetic, and posttranslational alterations that activate the KEAP1/NRF2 pathway are found in multiple solid tumors. Emerging clinical data highlight that alterations in this pathway result in resistance to multiple therapies. Here, we provide an overview of how dysregulation of the KEAP1/NRF2 pathway in cancer contributes to several hallmarks of cancer that promote tumorigenesis and lead to treatment resistance. SIGNIFICANCE: Alterations in the KEAP1/NRF2 pathway are found in multiple cancer types. Activation of NRF2 leads to metabolic rewiring of tumors that promote tumor initiation and progression. Here we present the known alterations that lead to NRF2 activation in cancer, the mechanisms in which NRF2 activation promotes tumors, and the therapeutic implications of NRF2 activation.

DOI: https://doi.org/10.1158/2159-8290.CD-21-0922
Genetics. 2022 Jan 20. pii: iyac007. [Epub ahead of print]

Assembly-dependent translation of subunits 6 (Atp6) and 9 (Atp9) of ATP synthase in yeast mitochondria.

Anna M Kabala, Krishia Binko, François Godard, Camille Charles, Alain Dautant, Emilia Baranowska, Natalia Skoczen, Kewin Gombeau, Marine Bouhier, Hubert D Becker, Sharon H Ackerman, Lars M Steinmetz, Déborah Tribouillard-Tanvier, Rosa Kucharczyk, Jean-Paul di Rago.

  The yeast mitochondrial ATP synthase is an assembly of 28 subunits of 17 types of which 3 (subunits 6, 8, and 9) are encoded by mitochondrial genes while the 14 others have a nuclear genetic origin. Within the membrane domain (FO) of this enzyme, the subunit 6 and a ring of 10 identical subunits 9 transport protons across the mitochondrial inner membrane coupled to ATP synthesis in the extra-membrane structure (F1) of ATP synthase. As a result of their dual genetic origin, the ATP synthase subunits are synthesized in the cytosol and inside the mitochondrion. How they are produced in the proper stoichiometry from two different cellular compartments is still poorly understood. The experiments herein reported show that the rate of translation of the subunits 9 and 6 is enhanced in strains with mutations leading to specific defects in the assembly of these proteins. These translation modifications involve assembly intermediates interacting with subunits 6 and 9 within the final enzyme and cis-regulatory sequences that control gene expression in the organelle. In addition to enabling a balanced output of the ATP synthase subunits, these assembly-dependent feedback loops are presumably important to limit the accumulation of harmful assembly intermediates that have the potential to dissipate the mitochondrial membrane electrical potential and the main source of chemical energy of the cell.

Keywords:  ATP synthase; Mitochondria; Mitochondria DNA; Mitochondrial biogenesis; Mitochondrial gene expression; yeast

DOI:  https://doi.org/10.1093/genetics/iyac007
Nat Cancer. 2022 Feb 03.

SETD2 loss perturbs the kidney cancer epigenetic landscape to promote metastasis and engenders actionable dependencies on histone chaperone complexes.

Yuchen Xie, Merve Sahin, Sonali Sinha, Yufeng Wang, Amrita M Nargund, Yang Lyu, Song Han, Yiyu Dong, James J Hsieh, Christina S Leslie, Emily H Cheng.

SETD2 is a histone H3 lysine 36 (H3K36) trimethyltransferase that is mutated with high prevalence (13%) in clear cell renal cell carcinoma (ccRCC). Genomic profiling of primary ccRCC tumors reveals a positive correlation between SETD2 mutations and metastasis. However, whether and how SETD2 loss promotes metastasis remains unclear. In this study, we used a SETD2-mutant (SETD2MT) metastatic ccRCC human-derived cell line and xenograft models and showed that H3K36me3 restoration greatly reduced distant metastases of ccRCC in mice in a matrix metalloproteinase 1 (MMP1)-dependent manner. An integrated multiomics analysis using assay for transposase-accessible chromatin using sequencing (ATAC-seq), chromatin immunoprecipitation-sequencing (ChIP-seq) and RNA sequencing (RNA-seq) established a tumor suppressor model in which loss of SETD2-mediated H3K36me3 activates enhancers to drive oncogenic transcriptional output through regulation of chromatin accessibility. Furthermore, we uncovered mechanism-based therapeutic strategies for SETD2-deficient cancer through the targeting of specific histone chaperone complexes, including ASF1A/ASF1B and SPT16. Overall, SETD2 loss creates a permissive epigenetic landscape for cooperating oncogenic drivers to amplify transcriptional output, providing unique therapeutic opportunities.

DOI: https://doi.org/10.1038/s43018-021-00316-3
Cell Metab. 2022 Feb 01. pii: S1550-4131(22)00006-7. [Epub ahead of print]34(2): 187-188

Forgetting in obesity: The pregnenolone link.

Luigi Bellocchio, Giovanni Marsicano.

Cognitive dysfunction is often diagnosed in people with obesity and associated metabolic disorders. In the latest issue of Cell Metabolism, Ramírez et al. highlight an impaired production of the neurosteroid pregnenolone in the hypothalamus as a mechanism for obesity-induced cognitive impairment in both rodent models and patients with obesity.

DOI: https://doi.org/10.1016/j.cmet.2022.01.006
Mol Cell. 2022 Jan 28. pii: S1097-2765(22)00008-9. [Epub ahead of print]

The interplay between BAX and BAK tunes apoptotic pore growth to control mitochondrial-DNA-mediated inflammation.

Katia Cosentino, Vanessa Hertlein, Andreas Jenner, Timo Dellmann, Milos Gojkovic, Aida Peña-Blanco, Shashank Dadsena, Noel Wajngarten, John S H Danial, Jervis Vermal Thevathasan, Markus Mund, Jonas Ries, Ana J Garcia-Saez.

  BAX and BAK are key apoptosis regulators that mediate the decisive step of mitochondrial outer membrane permeabilization. However, the mechanism by which they assemble the apoptotic pore remains obscure. Here, we report that BAX and BAK present distinct oligomerization properties, with BAK organizing into smaller structures with faster kinetics than BAX. BAK recruits and accelerates BAX assembly into oligomers that continue to grow during apoptosis. As a result, BAX and BAK regulate each other as they co-assemble into the same apoptotic pores, which we visualize. The relative availability of BAX and BAK molecules thereby determines the growth rate of the apoptotic pore and the relative kinetics by which mitochondrial contents, most notably mtDNA, are released. This feature of BAX and BAK results in distinct activation kinetics of the cGAS/STING pathway with implications for mtDNA-mediated paracrine inflammatory signaling.

Keywords:  AFM; BAK; BAX; BCL-2; inflammatory cell death; membrane pore; mitochondria; pore-forming protein; single-molecule imaging; super-resolution microscopy

DOI:  https://doi.org/10.1016/j.molcel.2022.01.008
STAR Protoc. 2022 Mar 18. 3(1): 101120

Protocols for analyzing metabolic derangements caused by increased NADH/NAD+ ratio in cell lines and in mice.

Shanshan Liu, Yan Ma, Hui Jiang.

  Mitochondrial electron transport chain (ETC) dysfunction elevates the NADH/NAD+ ratio to cause metabolic derangements. Here we describe a protocol to measure the NADH/NAD+ ratio and analyze the rewiring of glucose metabolism using [4-2H]-glucose, [3-2H]-glucose, and [U-13C]-glucose in ETC-inhibited human cancer cells. We also describe a protocol to analyze the NADH/NAD+ ratio-sensitive metabolites in mouse plasma and mouse liver following phenformin treatment. These protocols comprehensively analyze the metabolic derangements resulting from increased NADH/NAD+ ratio in in vitro and in vivo models. For complete details on the use and execution of this profile, please refer to Liu et al. (2021).

Keywords:  Cell Biology; Cell culture; Cell-based Assays; Mass Spectrometry; Metabolism; Model Organisms

DOI:  https://doi.org/10.1016/j.xpro.2021.101120
Genes Dev. 2022 Feb 03.

BMAL1 drives muscle repair through control of hypoxic NAD+ regeneration in satellite cells.

Pei Zhu, Noah X Hamlish, Abhishek Vijay Thakkar, Adam W T Steffeck, Emily J Rendleman, Nabiha H Khan, Nathan J Waldeck, Andrew W DeVilbiss, Misty S Martin-Sandoval, Thomas P Mathews, Navdeep S Chandel, Clara B Peek.

  The process of tissue regeneration occurs in a developmentally timed manner, yet the role of circadian timing is not understood. Here, we identify a role for the adult muscle stem cell (MuSC)-autonomous clock in the control of muscle regeneration following acute ischemic injury. We observed greater muscle repair capacity following injury during the active/wake period as compared with the inactive/rest period in mice, and loss of Bmal1 within MuSCs leads to impaired muscle regeneration. We demonstrate that Bmal1 loss in MuSCs leads to reduced activated MuSC number at day 3 postinjury, indicating a failure to properly expand the myogenic precursor pool. In cultured primary myoblasts, we observed that loss of Bmal1 impairs cell proliferation in hypoxia (a condition that occurs in the first 1-3 d following tissue injury in vivo), as well as subsequent myofiber differentiation. Loss of Bmal1 in both cultured myoblasts and in vivo activated MuSCs leads to reduced glycolysis and premature activation of prodifferentiation gene transcription and epigenetic remodeling. Finally, hypoxic cell proliferation and myofiber formation in Bmal1-deficient myoblasts are restored by increasing cytosolic NAD+ Together, we identify the MuSC clock as a pivotal regulator of oxygen-dependent myoblast cell fate and muscle repair through the control of the NAD+-driven response to injury.

Keywords:  NAD+; circadian rhythm; hypoxia; muscle regeneration; muscle stem cell

DOI:  https://doi.org/10.1101/gad.349066.121
Circ Res. 2022 Feb 04. 130(3): 418-431

Macrophages, Metabolism and Heterophagy in the Heart.

José A Nicolás-Ávila, Laura Pena-Couso, Pura Muñoz-Cánoves, Andrés Hidalgo.

  The heart is a never-stopping engine that relies on a formidable pool of mitochondria to generate energy and propel pumping. Because dying cardiomyocytes cannot be replaced, this high metabolic rate creates the challenge of preserving organelle fitness and cell function for life. Here, we provide an immunologist's perspective on how the heart solves this challenge, which is in part by incorporating macrophages as an integral component of the myocardium. Cardiac macrophages surround cardiomyocytes and capture dysfunctional mitochondria that these cells eject to the milieu, effectively establishing a client cell-support cell interaction. We refer to this heterologous partnership as heterophagy. Notably, this process shares analogies with other biological systems, is essential for proteostasis and metabolic fitness of cardiomyocytes, and unveils a remarkable degree of dependence of the healthy heart on immune cells for everyday function.

Keywords:  exopher; heart; heterophagy; macrophages; myocardium

DOI:  https://doi.org/10.1161/CIRCRESAHA.121.319812
Mol Metab. 2022 Feb 01. pii: S2212-8778(22)00021-7. [Epub ahead of print] 101452

Disrupted Liver Oxidative Metabolism in Glycine N-Methyltransferase-Deficient Mice is Mitigated by Dietary Methionine Restriction.

Ferrol I Rome, Curtis C Hughey.

  OBJECTIVE: One-carbon metabolism is routinely dysregulated in nonalcoholic fatty liver disease. This includes decreased glycine N-methyltransferase (GNMT), a critical regulator of s-adenosylmethionine (SAM). Deletion of GNMT in mice increases SAM and promotes liver steatosis. Lower liver oxidative metabolism as indicated by a decline in gluconeogenesis, citric acid cycle flux, and oxidative phosphorylation contributes to liver steatosis in GNMT-null mice, however, the extent to which this phenotype is mediated by higher SAM remains unclear. Here, we determined the SAM-dependent impairment in liver oxidative metabolism by loss of GNMT.METHODS: GNMT knockout (KO) mice were fed a methionine-restricted diet to prevent increased SAM. 2H/13C metabolic flux analysis was performed in conscious, unrestrained mice to quantify liver nutrient fluxes. Metabolomics and high-resolution respirometry was used to quantify liver nutrient pool sizes and mitochondrial oxidative phosphorylation, respectively. Folic acid-supplemented and serine/glycine-deficient diets were used independently to further define the metabolic implications of perturbed one-carbon donor availability.
RESULTS: Dietary methionine restriction prevented a 75-fold increase in SAM and 53% rise in triacylglycerides in livers of KO mice. Dietary methionine restriction increased gluconeogenesis independent of genotype and restored cytochrome c oxidase respiratory function in KO mice. Citric acid cycle fluxes remained lower in KO mice irrespective of diet. Restricting dietary methionine abrogated markers of increased lipogenesis and folate cycle dysfunction in KO mice.
CONCLUSION: The impaired liver oxidative metabolism following loss of GNMT is both dependent and independent of greater SAM availability. Lower in vivo citric acid cycle flux is independent of increased SAM. In contrast, gluconeogenesis and oxidative phosphorylation are negatively regulated by excess SAM. Lipid accumulation in livers of mice lacking GNMT is also linked to the higher SAM.

Keywords:  citric acid cycle; gluconeogenesis; lipogenesis; nonalcoholic fatty liver disease; one-carbon metabolism; oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.molmet.2022.101452
Mol Cell. 2022 Jan 25. pii: S1097-2765(22)00002-8. [Epub ahead of print]

E3 ligase RNF167 and deubiquitinase STAMBPL1 modulate mTOR and cancer progression.

Dong Wang, Chenchen Xu, Wenyu Yang, Jie Chen, Yuhui Ou, Yuanyuan Guan, Jialiang Guan, Ying Liu.

  The mTOR complex 1 (mTORC1) is an essential metabolic hub that coordinates cellular metabolism with the availability of nutrients, including amino acids. Sestrin2 has been identified as a cytosolic leucine sensor that transmits leucine status signals to mTORC1. In this study, we identify an E3 ubiquitin ligase RING finger protein 167 (RNF167) and a deubiquitinase STAMBPL1 that function in concert to control the polyubiquitination level of Sestrin2 in response to leucine availability. Ubiquitination of Sestrin2 promotes its interaction with GATOR2 and inhibits mTORC1 signaling. Bioinformatic analysis reveals decreased RNF167 expression and increased STAMBPL1 expression in gastric and colorectal tumors. Knockout of STAMBPL1 or correction of the heterozygous STAMBPL1 mutation in a human colon cancer cell line suppresses xenograft tumor growth. Lastly, a cell-permeable peptide that blocks the STAMBPL1-Sestrin2 interaction inhibits mTORC1 and provides a potential option for cancer therapy.

Keywords:  Sestrin2; amino acid sensing; colorectal cancer; mTOR; tumorigenesis; ubiquitination

DOI:  https://doi.org/10.1016/j.molcel.2022.01.002
J Biol Chem. 2022 Jan 28. pii: S0021-9258(22)00092-8. [Epub ahead of print] 101652

Mitochondrial respiratory chain dysfunction alters ER sterol sensing and mevalonate pathway activity.

Christopher Tadhg James Wall, Gregory Lefebvre, Sylviane Metairon, Patrick Descombes, Andreas Wiederkehr, Jaime Santo Domingo.

  Mitochondrial dysfunction induces a strong adaptive retrograde signaling response; however, many of the down-stream effectors of this response remain to be discovered. Here, we studied the shared transcriptional responses to three different mitochondrial respiratory chain inhibitors in human primary skin fibroblasts using QuantSeq 3'-RNA-sequencing. We found that genes involved in the mevalonate pathway were concurrently downregulated, irrespective of the respiratory chain complex affected. Targeted metabolomics demonstrated that impaired mitochondrial respiration at any of the three affected complexes also had functional consequences on the mevalonate pathway, reducing levels of cholesterol precursor metabolites. A deeper study of complex I inhibition showed a reduced activity of ER-bound sterol-sensing enzymes through impaired processing of the transcription factor SREBP2 and accelerated degradation of the ER cholesterol-sensors SQLE and HMGCR. These adaptations of mevalonate pathway activity affected neither total intracellular cholesterol levels nor the cellular free (non-esterified) cholesterol pool. Finally, measurement of intracellular cholesterol using the fluorescent cholesterol binding dye filipin revealed that complex I inhibition elevated cholesterol on intracellular compartments. Taken together, our study shows that mitochondrial respiratory chain dysfunction elevates intracellular free cholesterol levels and therefore attenuates the expression of mevalonate pathway enzymes, which lowers endogenous cholesterol biosynthesis, disrupting the metabolic output of the mevalonate pathway. We conclude that intracellular disturbances in cholesterol homeostasis may alter systemic cholesterol management in diseases associated with declining mitochondrial function.

Keywords:  Cholesterol; CoQ; HMGCR; SQLE; SREBP2; farnesyl pyrophosphate; geranyl pyrophosphate; mevalonate pathway; mitochondria; retrograde signaling; sterol; ubiquinol

DOI:  https://doi.org/10.1016/j.jbc.2022.101652
Adipocyte. 2022 Dec;11(1): 120-132

miR-669a-5p promotes adipogenic differentiation and induces browning in preadipocytes.

Xiaoqiong Tan, Tingting Zhu, Linqiang Zhang, Lin Fu, Ying Hu, Huiqin Li, Chengbin Li, Jingjing Zhang, Bin Liang, Jing Liu.

  Obesity is a major global health issue that contributes to the occurrence of metabolic disorders. Based on this fact, understanding the underlying mechanisms and to uncover promising therapeutic approaches for obesity have attracted intense investigation. Brown adipose tissue (BAT) can help burns excess calories. Therefore, promoting White adipose tissue (WAT) browning and BAT activation is an attractive strategy for obesity treatment. MicroRNAs (miRNAs) are small, non-coding RNAs, which are involved in regulation of adipogenic processes and metabolic functions. Evidence is accumulating that miRNAs are important regulators for both brown adipocyte differentiation and white adipocyte browning. Here we report that the expression of miR-669a-5p increases during the adipogenic differentiation of 3T3-L1 and C3H10T1/2 adipocytes. miR-669a-5p supplementation promotes adipogenic differentiation and causes browning of 3T3-L1 and C3H10T1/2 cells. Moreover, the expression of miR-669a-5p is upregulated in iWAT of mice exposed to cold. These data demonstrate that miR-669a-5p plays a role in regulating adipocyte differentiation and fat browning.Abbreviations: Acadl: long-chain acyl-Coenzyme A dehydrogenase; Acadm: medium-chain acyl-Coenzyme A dehydrogenase; Acadvl: very long-chain acyl-Coenzyme A dehydrogenase, very long chain; Aco2: mitochondrial aconitase 2; BAT: brown adipose tissue; Bmper: BMP-binding endothelial regulator; Cpt1-b:carnitine palmitoyltransferase 1b; Cpt2: carnitine palmitoyltransferase 2; Crat: carnitine acetyltransferase; Cs: citrate synthase; C2MC: Chromosome 2 miRNA cluster; DMEM: Dulbecco's modified Eagle medium; eWAT: epididymal white adipose tissue; ETC: electron transport chain; FAO: fatty acid oxidation; Fabp4:fatty acid binding protein 4; FBS: fetal bovine serum; Hadha: hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha; Hadhb: hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta; HFD: high fat diet; Idh3a: isocitrate dehydrogenase 3 alpha; iWAT: inguinal subcutaneous white adipose tissue; Lpl: lipoprotein lipase; Mdh2: malate dehydrogenase 2; NBCS: NewBorn Calf Serum; mt-Nd1: mitochondrial NADH dehydrogenase 1; Ndufb8:ubiquinone oxidoreductase subunit B8; Nrf1: nuclear respiratory factor 1; Pgc1α: peroxisome proliferative activated receptor gamma coactivator 1 alpha; Pgc1b: peroxisome proliferative activated receptor, gamma, coactivator 1 beta; Pparγ: peroxisome proliferator activated receptor gamma; Prdm16: PR domain containing 16; Rgs4: regulator of G-protein signaling 4; Sdhb: succinate dehydrogenase complex, subunit B; Sdhc: succinate dehydrogenase complex, subunit C; Sdhd: succinate dehydrogenase complex, subunit D; Sh3d21: SH3 domain containing 21; Sfmbt2: Scm-like with four mbt domains 2; TG: triglyceride; TCA: tricarboxylic acid cycle; Tfam: transcription factor A, mitochondrial; TMRE: tetramethylrhodamine, methyl ester; Ucp1: uncoupling protein 1; Uqcrc2: ubiquinol cytochrome c reductase core protein 2; WAT: White adipose tissue.

Keywords:  3T3-L1; C3H10T1/2; adipocyte browning; adipocyte differentiation; miR-669a-5p; microRNA

DOI:  https://doi.org/10.1080/21623945.2022.2030570
Nat Metab. 2022 Jan;4(1): 123-140

Oxidative pentose phosphate pathway controls vascular mural cell coverage by regulating extracellular matrix composition.

Nicola Facchinello, Matteo Astone, Matteo Audano, Roxana E Oberkersch, Marianna Spizzotin, Enrica Calura, Madalena Marques, Mihaela Crisan, Nico Mitro, Massimo M Santoro.

Vascular mural cells (vMCs) play an essential role in the development and maturation of the vasculature by promoting vessel stabilization through their interactions with endothelial cells. Whether endothelial metabolism influences mural cell recruitment and differentiation is unknown. Here, we show that the oxidative pentose phosphate pathway (oxPPP) in endothelial cells is required for establishing vMC coverage of the dorsal aorta during early vertebrate development in zebrafish and mice. We demonstrate that laminar shear stress and blood flow maintain oxPPP activity, which in turn, promotes elastin expression in blood vessels through production of ribose-5-phosphate. Elastin is both necessary and sufficient to drive vMC recruitment and maintenance when the oxPPP is active. In summary, our work demonstrates that endothelial cell metabolism regulates blood vessel maturation by controlling vascular matrix composition and vMC recruitment.

DOI: https://doi.org/10.1038/s42255-021-00514-4
Cell. 2022 Feb 01. pii: S0092-8674(21)01577-4. [Epub ahead of print]

Mapping transcriptomic vector fields of single cells.

Xiaojie Qiu, Yan Zhang, Jorge D Martin-Rufino, Chen Weng, Shayan Hosseinzadeh, Dian Yang, Angela N Pogson, Marco Y Hein, Kyung Hoi Joseph Min, Li Wang, Emanuelle I Grody, Matthew J Shurtleff, Ruoshi Yuan, Song Xu, Yian Ma, Joseph M Replogle, Eric S Lander, Spyros Darmanis, Ivet Bahar, Vijay G Sankaran, Jianhua Xing, Jonathan S Weissman.

  Single-cell (sc)RNA-seq, together with RNA velocity and metabolic labeling, reveals cellular states and transitions at unprecedented resolution. Fully exploiting these data, however, requires kinetic models capable of unveiling governing regulatory functions. Here, we introduce an analytical framework dynamo (https://github.com/aristoteleo/dynamo-release), which infers absolute RNA velocity, reconstructs continuous vector fields that predict cell fates, employs differential geometry to extract underlying regulations, and ultimately predicts optimal reprogramming paths and perturbation outcomes. We highlight dynamo's power to overcome fundamental limitations of conventional splicing-based RNA velocity analyses to enable accurate velocity estimations on a metabolically labeled human hematopoiesis scRNA-seq dataset. Furthermore, differential geometry analyses reveal mechanisms driving early megakaryocyte appearance and elucidate asymmetrical regulation within the PU.1-GATA1 circuit. Leveraging the least-action-path method, dynamo accurately predicts drivers of numerous hematopoietic transitions. Finally, in silico perturbations predict cell-fate diversions induced by gene perturbations. Dynamo, thus, represents an important step in advancing quantitative and predictive theories of cell-state transitions.

Keywords:  RNA Jacobian; RNA metabolic labeling; cell-fate transitions; differential geometry analysis; dynamical systems theory; dynamo; hematopoiesis; in silico perturbation; least action path; vector field reconstruction

DOI:  https://doi.org/10.1016/j.cell.2021.12.045
Neurosurg Focus. 2022 Feb;pii: 2021.11.FOCUS21604. [Epub ahead of print]52(2): E6

Implications of IDH mutations on immunotherapeutic strategies for malignant glioma.

Leland G Richardson, Julie J Miller, Yosuke Kitagawa, Hiroaki Wakimoto, Bryan D Choi, William T Curry.

  Immunotherapy has emerged as a promising approach for treating aggressive solid tumors, even within the CNS. Mutation in the metabolic gene isocitrate dehydrogenase 1 (IDH1) represents not only a major glioma defining biomarker but also an attractive therapeutic neoantigen. As patients with IDH-mutant glioma enter early-phase vaccine and immune checkpoint inhibitor clinical trials, there is emerging evidence that implicates the oncometabolite, 2-hydroxyglutarate (2HG), generated by the neomorphic activity of mutant IDH, as a potential barrier to current immunotherapeutic approaches. Here, the authors review the immunomodulatory and immunosuppressive roles of 2HG within the unique IDH-mutant glioma tumor immune microenvironment and discuss promising immunotherapeutic approaches currently being investigated in preclinical models.

Keywords:  2-hydroxyglutarate; IDH; glioma; immunology; immunosuppression; isocitrate dehydrogenase; tumor immune microenvironment

DOI:  https://doi.org/10.3171/2021.11.FOCUS21604
Nat Commun. 2022 Feb 01. 13(1): 610

Lima1 mediates the pluripotency control of membrane dynamics and cellular metabolism.

Binyamin Duethorn, Fabian Groll, Bettina Rieger, Hannes C A Drexler, Heike Brinkmann, Ludmila Kremer, Martin Stehling, Marie-Theres Borowski, Karina Mildner, Dagmar Zeuschner, Magdalena Zernicka-Goetz, Marc P Stemmler, Karin B Busch, Juan M Vaquerizas, Ivan Bedzhov.

Lima1 is an extensively studied prognostic marker of malignancy and is also considered to be a tumour suppressor, but its role in a developmental context of non-transformed cells is poorly understood. Here, we characterise the expression pattern and examined the function of Lima1 in mouse embryos and pluripotent stem cell lines. We identify that Lima1 expression is controlled by the naïve pluripotency circuit and is required for the suppression of membrane blebbing, as well as for proper mitochondrial energetics in embryonic stem cells. Moreover, forcing Lima1 expression enables primed mouse and human pluripotent stem cells to be incorporated into murine pre-implantation embryos. Thus, Lima1 is a key effector molecule that mediates the pluripotency control of membrane dynamics and cellular metabolism.

DOI: https://doi.org/10.1038/s41467-022-28139-5
Proc Natl Acad Sci U S A. 2022 Feb 08. pii: e2120617119. [Epub ahead of print]119(6):

Loss of glucose 6-phosphate dehydrogenase function increases oxidative stress and glutaminolysis in metastasizing melanoma cells.

Arin B Aurora, Vishal Khivansara, Ashley Leach, Jennifer G Gill, Misty Martin-Sandoval, Chendong Yang, Stacy Y Kasitinon, Divya Bezwada, Alpaslan Tasdogan, Wen Gu, Thomas P Mathews, Zhiyu Zhao, Ralph J DeBerardinis, Sean J Morrison.

  The pentose phosphate pathway is a major source of NADPH for oxidative stress resistance in cancer cells but there is limited insight into its role in metastasis, when some cancer cells experience high levels of oxidative stress. To address this, we mutated the substrate binding site of glucose 6-phosphate dehydrogenase (G6PD), which catalyzes the first step of the pentose phosphate pathway, in patient-derived melanomas. G6PD mutant melanomas had significantly decreased G6PD enzymatic activity and depletion of intermediates in the oxidative pentose phosphate pathway. Reduced G6PD function had little effect on the formation of primary subcutaneous tumors, but when these tumors spontaneously metastasized, the frequency of circulating melanoma cells in the blood and metastatic disease burden were significantly reduced. G6PD mutant melanomas exhibited increased levels of reactive oxygen species, decreased NADPH levels, and depleted glutathione as compared to control melanomas. G6PD mutant melanomas compensated for this increase in oxidative stress by increasing malic enzyme activity and glutamine consumption. This generated a new metabolic vulnerability as G6PD mutant melanomas were more dependent upon glutaminase than control melanomas, both for oxidative stress management and anaplerosis. The oxidative pentose phosphate pathway, malic enzyme, and glutaminolysis thus confer layered protection against oxidative stress during metastasis.

Keywords:  glutaminolysis; melanoma; metastasis; oxidative stress; pentose phosphate pathway

DOI:  https://doi.org/10.1073/pnas.2120617119
Cancer Sci. 2022 Feb 03.

Cancer metabolism challenges genomic instability and clonal evolution as therapeutic targets.

Yu Takeda, Ryota Chijimatsu, Ken Ofusa, Shogo Kobayashi, Yuichiro Doki, Hidetoshi Eguchi, Hideshi Ishii.

  Although cancer precision medicine has improved diagnosis and therapy, refractory cancers such as pancreatic cancer remain to be challenging targets. Clinical sequencing has identified the significant alterations in driver genes and traced their clonal evolutions. Recent studies indicated that the tumor microenvironment elicits alterations in cancer metabolism, although its involvement in the cause and development of genomic alterations have not been established. Genomic abnormalities can contribute to the survival of selected subpopulations, recently recognized as clonal evolution, and dysfunction can lead to DNA mutations. Here, we present the most recent studies on the mechanisms of cancer metabolism involved in the maintenance of genomic stability to update current understanding of such processes. Sirtuins, which are NAD+-dependent protein deacetylases, appear to be involved in the control of genomic stability. Alterations of deleterious subpopulations would be exposed to selective pressure for cell survival. Recent studies indicated that a new type of cell death, ferroptosis, determines the survival of clones and exert cancer-restricting or -promoting effects to surrounding cells in the tumor microenvironment. Suppressing genomic instability and eliminating deleterious clones by cell death will contribute to the improvement of cancer medicine. Furthermore, the elucidation of the mechanisms involved is seen as a bridgehead to the pharmacologic suppression of such refractory cancers as pancreatic cancer.

Keywords:  ferroptosis; metabolism; oxidative stress; pancreatic cancer; sirtuins

DOI:  https://doi.org/10.1111/cas.15279
Nat Commun. 2022 Feb 01. 13(1): 608

Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity.

Aparajita Madhavan, Bernard P Kok, Bibiana Rius, Julia M D Grandjean, Adekunle Alabi, Verena Albert, Ara Sukiasyan, Evan T Powers, Andrea Galmozzi, Enrique Saez, R Luke Wiseman.

In obesity, signaling through the IRE1 arm of the unfolded protein response exerts both protective and harmful effects. Overexpression of the IRE1-regulated transcription factor XBP1s in liver or fat protects against obesity-linked metabolic deterioration. However, hyperactivation of IRE1 engages regulated IRE1-dependent decay (RIDD) and TRAF2/JNK pro-inflammatory signaling, which accelerate metabolic dysfunction. These pathologic IRE1-regulated processes have hindered efforts to pharmacologically harness the protective benefits of IRE1/XBP1s signaling in obesity-linked conditions. Here, we report the effects of a XBP1s-selective pharmacological IRE1 activator, IXA4, in diet-induced obese (DIO) mice. IXA4 transiently activates protective IRE1/XBP1s signaling in liver without inducing RIDD or TRAF2/JNK signaling. IXA4 treatment improves systemic glucose metabolism and liver insulin action through IRE1-dependent remodeling of the hepatic transcriptome that reduces glucose production and steatosis. IXA4-stimulated IRE1 activation also enhances pancreatic function. Our findings indicate that systemic, transient activation of IRE1/XBP1s signaling engenders multi-tissue benefits that integrate to mitigate obesity-driven metabolic dysfunction.

DOI: https://doi.org/10.1038/s41467-022-28271-2
Cell Regen. 2022 Feb 01. 11(1): 5

Monitoring NAD(H) and NADP(H) dynamics during organismal development with genetically encoded fluorescent biosensors.

Ting Li, Yejun Zou, Shuning Liu, Yi Yang, Zhuo Zhang, Yuzheng Zhao.

  Cell metabolism plays vital roles in organismal development, but it has been much less studied than transcriptional and epigenetic control of developmental programs. The difficulty might be largely attributed to the lack of in situ metabolite assays. Genetically encoded fluorescent sensors are powerful tools for noninvasive metabolic monitoring in living cells and in vivo by highly spatiotemporal visualization. Among all living organisms, the NAD(H) and NADP(H) pools are essential for maintaining redox homeostasis and for modulating cellular metabolism. Here, we introduce NAD(H) and NADP(H) biosensors, present example assays in developing organisms, and describe promising prospects for how sensors contribute to developmental biology research.

Keywords:  Cell metabolism; Genetically encoded fluorescent sensors; NAD(H) and NADP(H); Organismal development; Real-time monitoring

DOI:  https://doi.org/10.1186/s13619-021-00105-4
Nat Chem. 2022 Feb;14(2): 170-178

Cyanide as a primordial reductant enables a protometabolic reductive glyoxylate pathway.

Mahipal Yadav, Sunil Pulletikurti, Jayasudhan R Yerabolu, Ramanarayanan Krishnamurthy.

Investigation of prebiotic metabolic pathways is predominantly based on abiotically replicating the reductive citric acid cycle. While attractive from a parsimony point of view, attempts using metal/mineral-mediated reductions have produced complex mixtures with inefficient and uncontrolled reactions. Here we show that cyanide acts as a mild and efficient reducing agent mediating abiotic transformations of tricarboxylic acid intermediates and derivatives. The hydrolysis of the cyanide adducts followed by their decarboxylation enables the reduction of oxaloacetate to malate and of fumarate to succinate, whereas pyruvate and α-ketoglutarate themselves are not reduced. In the presence of glyoxylate, malonate and malononitrile, alternative pathways emerge that bypass the challenging reductive carboxylation steps to produce metabolic intermediates and compounds found in meteorites. These results suggest a simpler prebiotic forerunner of today's metabolism, involving a reductive glyoxylate pathway without oxaloacetate and α-ketoglutarate-implying that the extant metabolic reductive carboxylation chemistries are an evolutionary invention mediated by complex metalloproteins.

DOI: https://doi.org/10.1038/s41557-021-00878-w
Cell Rep Med. 2022 Jan 18. 3(1): 100498

Pegylated arginine deiminase drives arginine turnover and systemic autophagy to dictate energy metabolism.

Yiming Zhang, Cassandra B Higgins, Brian A Van Tine, John S Bomalaski, Brian J DeBosch.

  Obesity is a multi-systemic disorder of energy balance. Despite intense investigation, the determinants of energy homeostasis remain incompletely understood, and efficacious treatments against obesity and its complications are lacking. Here, we demonstrate that conferred arginine iminohydrolysis by the bacterial virulence factor and arginine deiminase, arcA, promotes mammalian energy expenditure and insulin sensitivity and reverses dyslipidemia, hepatic steatosis, and inflammation in obese mice. Extending this, pharmacological arginine catabolism via pegylated arginine deiminase (ADI-PEG 20) recapitulates these metabolic effects in dietary and genetically obese models. These effects require hepatic and whole-body expression of the autophagy complex protein BECN1 and hepatocyte-specific FGF21 secretion. Single-cell ATAC sequencing further reveals BECN1-dependent hepatocyte chromatin accessibility changes in response to ADI-PEG 20. The data thus reveal an unexpected therapeutic utility for arginine catabolism in modulating energy metabolism by activating systemic autophagy, which is now exploitable through readily available pharmacotherapy.

Keywords:  ADI-PEG 20; Beclin-1; FGF21; GLUT; arcA; arginase; arginine; arginine deiminase; autophagy; caloric restriction; diabetes; energy metabolism; fasting; glucose transport; insulin resistance; liver; non-alcoholic fatty liver disease; obesity; thermogenesis

DOI:  https://doi.org/10.1016/j.xcrm.2021.100498
Cell Metab. 2022 Jan 31. pii: S1550-4131(22)00004-3. [Epub ahead of print]

A macrophage-hepatocyte glucocorticoid receptor axis coordinates fasting ketogenesis.

Anne Loft, Søren Fisker Schmidt, Giorgio Caratti, Ulrich Stifel, Jesper Havelund, Revathi Sekar, Yun Kwon, Alba Sulaj, Kan Kau Chow, Ana Jimena Alfaro, Thomas Schwarzmayr, Nikolaj Rittig, Mads Svart, Foivos-Filippos Tsokanos, Adriano Maida, Andreas Blutke, Annette Feuchtinger, Niels Møller, Matthias Blüher, Peter Nawroth, Julia Szendrödi, Nils J Færgeman, Anja Zeigerer, Jan Tuckermann, Stephan Herzig.

  Fasting metabolism and immunity are tightly linked; however, it is largely unknown how immune cells contribute to metabolic homeostasis during fasting in healthy subjects. Here, we combined cell-type-resolved genomics and computational approaches to map crosstalk between hepatocytes and liver macrophages during fasting. We identified the glucocorticoid receptor (GR) as a key driver of fasting-induced reprogramming of the macrophage secretome including fasting-suppressed cytokines and showed that lack of macrophage GR impaired induction of ketogenesis during fasting as well as endotoxemia. Mechanistically, macrophage GR suppressed the expression of tumor necrosis factor (TNF) and promoted nuclear translocation of hepatocyte GR to activate a fat oxidation/ketogenesis-related gene program, cooperatively induced by GR and peroxisome proliferator-activated receptor alpha (PPARα) in hepatocytes. Together, our results demonstrate how resident liver macrophages directly influence ketogenesis in hepatocytes, thereby also outlining a strategy by which the immune system can set the metabolic tone during inflammatory disease and infection.

Keywords:  fasting; genomics; glucocorticoid receptor; hepatocyte; ketogenesis; liver; macrophage; nuclear receptor; transcripional regulation; tumor necrosis factor

DOI:  https://doi.org/10.1016/j.cmet.2022.01.004
Annu Rev Biomed Eng. 2022 Feb 04.

Regulation of Tumor Invasion by the Physical Microenvironment: Lessons from Breast and Brain Cancer.

Garrett F Beeghly, Kwasi Y Amofa, Claudia Fischbach, Sanjay Kumar.

The success of anticancer therapies is often limited by heterogeneity within and between tumors. While much attention has been devoted to understanding the intrinsic molecular diversity of tumor cells, the surrounding tissue microenvironment is also highly complex and coevolves with tumor cells to drive clinical outcomes. Here, we propose that diverse types of solid tumors share common physical motifs that change in time and space, serving as universal regulators of malignancy. We use breast cancer and glioblastoma as instructive examples and highlight how invasion in both diseases is driven by the appropriation of structural guidance cues, contact-dependent heterotypic interactions with stromal cells, and elevated interstitial fluid pressure and flow. We discuss how engineering strategies show increasing value for measuring and modeling these physical properties for mechanistic studies. Moreover, engineered systems offer great promise for developing and testing novel therapies that improve patient prognosis by normalizing the physical tumor microenvironment. Expected final online publication date for the Annual Review of Biomedical Engineering, Volume 24 is June 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-bioeng-110220-115419
Proc Natl Acad Sci U S A. 2022 Feb 08. pii: e2120956119. [Epub ahead of print]119(6):

IKKα-deficient lung adenocarcinomas generate an immunosuppressive microenvironment by overproducing Treg-inducing cytokines.

Na-Young Song, Xin Li, Buyong Ma, Jami Willette-Brown, Feng Zhu, Chengfei Jiang, Ling Su, Jyoti Shetty, Yongmei Zhao, Gongping Shi, Sayantan Banerjee, Xiaolin Wu, Bao Tran, Ruth Nussinov, Michael Karin, Yinling Hu.

  The tumor microenvironment (TME) provides potential targets for cancer therapy. However, how signals originating in cancer cells affect tumor-directed immunity is largely unknown. Deletions in the CHUK locus, coding for IκB kinase α (IKKα), correlate with reduced lung adenocarcinoma (ADC) patient survival and promote KrasG12D-initiated ADC development in mice, but it is unknown how reduced IKKα expression affects the TME. Here, we report that low IKKα expression in human and mouse lung ADC cells correlates with increased monocyte-derived macrophage and regulatory T cell (Treg) scores and elevated transcription of genes coding for macrophage-recruiting and Treg-inducing cytokines (CSF1, CCL22, TNF, and IL-23A). By stimulating recruitment of monocyte-derived macrophages from the bone marrow and enforcing a TNF/TNFR2/c-Rel signaling cascade that stimulates Treg generation, these cytokines promote lung ADC progression. Depletion of TNFR2, c-Rel, or TNF in CD4+ T cells or monocyte-derived macrophages dampens Treg generation and lung tumorigenesis. Treg depletion also attenuates carcinogenesis. In conclusion, reduced cancer cell IKKα activity enhances formation of a protumorigenic TME through a pathway whose constituents may serve as therapeutic targets for KRAS-initiated lung ADC.

Keywords:  NK-κB signaling; Treg cells; immunosuppressive response; inflammation; lung cancer

DOI:  https://doi.org/10.1073/pnas.2120956119
J Biol Chem. 2022 Jan 28. pii: S0021-9258(22)00101-6. [Epub ahead of print] 101661

Complexities of Complex II: Sulfide metabolism in vivo.

Gary Cecchini.

DOI: https://doi.org/10.1016/j.jbc.2022.101661
Nat Commun. 2022 Feb 01. 13(1): 614

ΔNp63 regulates a common landscape of enhancer associated genes in non-small cell lung cancer.

Marco Napoli, Sarah J Wu, Bethanie L Gore, Hussein Abbas, Kyubum Lee, Rahul Checker, Shilpa Dhar, Kimal Rajapakshe, Aik Choon Tan, Min Gyu Lee, Cristian Coarfa, Elsa R Flores.

Distinct lung stem cells give rise to lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). ΔNp63, the p53 family member and p63 isoform, guides the maturation of these stem cells through the regulation of their self-renewal and terminal differentiation; however, the underlying mechanistic role regulated by ∆Np63 in lung cancer development has remained elusive. By utilizing a ΔNp63-specific conditional knockout mouse model and xenograft models of LUAD and LUSC, we found that ∆Np63 promotes non-small cell lung cancer by maintaining the lung stem cells necessary for lung cancer cell initiation and progression in quiescence. ChIP-seq analysis of lung basal cells, alveolar type 2 (AT2) cells, and LUAD reveals robust ∆Np63 regulation of a common landscape of enhancers of cell identity genes. Importantly, one of these genes, BCL9L, is among the enhancer associated genes regulated by ∆Np63 in Kras-driven LUAD and mediates the oncogenic effects of ∆Np63 in both LUAD and LUSC. Accordingly, high BCL9L levels correlate with poor prognosis in LUAD patients. Taken together, our findings provide a unifying oncogenic role for ∆Np63 in both LUAD and LUSC through the regulation of a common landscape of enhancer associated genes.

DOI: https://doi.org/10.1038/s41467-022-28202-1
Cell Chem Biol. 2022 Jan 27. pii: S2451-9456(22)00050-2. [Epub ahead of print]

Selective vulnerabilities in the proteostasis network of castration-resistant prostate cancer.

Arielle Shkedi, Isabelle R Taylor, Frank Echtenkamp, Poornima Ramkumar, Mohamed Alshalalfa, Génesis M Rivera-Márquez, Michael A Moses, Hao Shao, Robert Jeffrey Karnes, Len Neckers, Felix Feng, Martin Kampmann, Jason E Gestwicki.

  Castration-resistant prostate cancer (CRPC) is associated with an increased reliance on heat shock protein 70 (HSP70), but it is not clear what other protein homeostasis (proteostasis) factors might be involved. To address this question, we performed functional and synthetic lethal screens in four prostate cancer cell lines. These screens confirmed key roles for HSP70, HSP90, and their co-chaperones, but also suggested that the mitochondrial chaperone, HSP60/HSPD1, is selectively required in CRPC cell lines. Knockdown of HSP60 does not impact the stability of androgen receptor (AR) or its variants; rather, it is associated with loss of mitochondrial spare respiratory capacity, partly owing to increased proton leakage. Finally, transcriptional data revealed a correlation between HSP60 levels and poor survival of prostate cancer patients. These findings suggest that re-wiring of the proteostasis network is associated with CRPC, creating selective vulnerabilities that might be targeted to treat the disease.

Keywords:  chaperones; functional genomics; heat shock proteins; mitochondria; prostate cancer; proteostasis; shRNA

DOI:  https://doi.org/10.1016/j.chembiol.2022.01.008
Cancer Cell. 2022 Jan 28. pii: S1535-6108(22)00010-1. [Epub ahead of print]

Dangerous dynamic duo: Lactic acid and PD-1 blockade.

Sheila Johnson, Marcia C Haigis, Stephanie K Dougan.

In this issue of Cancer Cell, Kumagai et al. reveal lactic acid as a mediator of checkpoint blockade resistance. Tumor-derived lactic acid promotes T regulatory cell (Treg) activity and impairs CD8+ T cell function. PD-1 blockade synergizes with lactic acid to enhance Treg suppression and impede antitumor immunity.

DOI: https://doi.org/10.1016/j.ccell.2022.01.008
Proc Natl Acad Sci U S A. 2022 Feb 08. pii: e2102358119. [Epub ahead of print]119(6):

Epigenetic state determines inflammatory sensing in neuroblastoma.

Adam J Wolpaw, Liron D Grossmann, Jessica L Dessau, May M Dong, Bailey J Aaron, Patricia A Brafford, Darya Volgina, Guillem Pascual-Pasto, Alba Rodriguez-Garcia, Yasin Uzun, Marie Arsenian-Henriksson, Daniel J Powell, Kristopher R Bosse, Andrew Kossenkov, Kai Tan, Michael D Hogarty, John M Maris, Chi V Dang.

  Immunotherapy has revolutionized cancer treatment, but many cancers are not impacted by currently available immunotherapeutic strategies. Here, we investigated inflammatory signaling pathways in neuroblastoma, a classically "cold" pediatric cancer. By testing the functional response of a panel of 20 diverse neuroblastoma cell lines to three different inflammatory stimuli, we found that all cell lines have intact interferon signaling, and all but one lack functional cytosolic DNA sensing via cGAS-STING. However, double-stranded RNA (dsRNA) sensing via Toll-like receptor 3 (TLR3) was heterogeneous, as was signaling through other dsRNA sensors and TLRs more broadly. Seven cell lines showed robust response to dsRNA, six of which are in the mesenchymal epigenetic state, while all unresponsive cell lines are in the adrenergic state. Genetically switching adrenergic cell lines toward the mesenchymal state fully restored responsiveness. In responsive cells, dsRNA sensing results in the secretion of proinflammatory cytokines, enrichment of inflammatory transcriptomic signatures, and increased tumor killing by T cells in vitro. Using single-cell RNA sequencing data, we show that human neuroblastoma cells with stronger mesenchymal signatures have a higher basal inflammatory state, demonstrating intratumoral heterogeneity in inflammatory signaling that has significant implications for immunotherapeutic strategies in this aggressive childhood cancer.

Keywords:  MYCN; Toll-like receptors; epigenetic states; immunotherapy; neuroblastoma

DOI:  https://doi.org/10.1073/pnas.2102358119
Nat Cancer. 2021 Jan;2(1): 49-65

Mutant Kras co-opts a proto-oncogenic enhancer network in inflammation-induced metaplastic progenitor cells to initiate pancreatic cancer.

Yong Li, Yi He, Junya Peng, Zhendong Su, Zeyao Li, Bingjie Zhang, Jing Ma, Meilian Zhuo, Di Zou, Xinde Liu, Xinhong Liu, Wenze Wang, Dan Huang, Mengyue Xu, Jianbin Wang, Haiteng Deng, Jing Xue, Wei Xie, Xun Lan, Mo Chen, Yupei Zhao, Wenming Wu, Charles J David.

Kras-activating mutations display the highest incidence in pancreatic ductal adenocarcinoma. Pancreatic inflammation accelerates mutant Kras-driven tumorigenesis in mice, suggesting high selectivity in the cells that oncogenic Kras transforms, although the mechanisms dictating this specificity are poorly understood. Here we show that pancreatic inflammation is coupled to the emergence of a transient progenitor cell population that is readily transformed in the presence of mutant KrasG12D. These progenitors harbor a proto-oncogenic transcriptional program driven by a transient enhancer network. KrasG12D mutations lock this enhancer network in place, providing a sustained Kras-dependent oncogenic program that drives tumors throughout progression. Enhancer co-option occurs through functional interactions between the Kras-activated transcription factors Junb and Fosl1 and pancreatic lineage transcription factors, potentially accounting for inter-tissue specificity of oncogene transformation. The pancreatic ductal adenocarcinoma cell of origin thus provides an oncogenic transcriptional program that fuels tumor progression beyond initiation, accounting for the intra-tissue selectivity of Kras transformation.

DOI: https://doi.org/10.1038/s43018-020-00134-z
Biol Chem. 2022 Jan 31.

Yme2, a putative RNA recognition motif and AAA+ domain containing protein, genetically interacts with the mitochondrial protein export machinery.

Nupur Sharma, Christof Osman.

  The mitochondrial respiratory chain is composed of nuclear as well as mitochondrial-encoded subunits. A variety of factors mediate co-translational integration of mtDNA-encoded proteins into the inner membrane. In Saccharomyces cerevisiae, Mdm38 and Mba1 are ribosome acceptors that recruit the mitochondrial ribosome to the inner membrane, where the insertase Oxa1, facilitates membrane integration of client proteins. The protein Yme2 has previously been shown to be localized in the inner mitochondrial membrane and has been implicated in mitochondrial protein biogenesis, but its mode of action remains unclear. Here, we show that multiple copies of Yme2 assemble into a high molecular weight complex. Using a combination of bioinformatics and mutational analyses, we find that Yme2 possesses an RNA recognition motif (RRM), which faces the mitochondrial matrix and a AAA+ domain that is located in the intermembrane space. We further show that YME2 genetically interacts with MDM38, MBA1 and OXA1, which links the function of Yme2 to the mitochondrial protein biogenesis machinery.

Keywords:  MBA1; MDM38; OXA1; RRM; Walker motifs; mitoribosome

DOI:  https://doi.org/10.1515/hsz-2021-0398
Nat Cancer. 2020 Sep;1(9): 894-908

Targeting purine synthesis in ASS1-expressing tumors enhances the response to immune checkpoint inhibitors.

Rom Keshet, Joo Sang Lee, Lital Adler, Muhammed Iraqi, Yarden Ariav, Lisha Qiu Jin Lim, Shaul Lerner, Shiran Rabinovich, Roni Oren, Rotem Katzir, Hila Weiss Tishler, Noa Stettner, Omer Goldman, Hadas Landesman, Sivan Galai, Yael Kuperman, Yuri Kuznetsov, Alexander Brandis, Tevi Mehlman, Sergey Malitsky, Maxim Itkin, S Eleonore Koehler, Yongmei Zhao, Keyur Talsania, Tsai-Wei Shen, Nir Peled, Igor Ulitsky, Angel Porgador, Eytan Ruppin, Ayelet Erez.

Argininosuccinate synthase (ASS1) downregulation in different tumors has been shown to support cell proliferation and yet, in several common cancer subsets ASS1 expression associates with poor patient prognosis. Here we demonstrate that ASS1 expression under glucose deprivation is induced by c-MYC, providing survival benefit by increasing nitric oxide synthesis and activating the gluconeogenic enzymes pyruvate carboxylase and phosphoenolpyruvate carboxykinase by S-nitrosylation. The resulting increased flux through gluconeogenesis enhances serine, glycine and subsequently purine synthesis. Notably, high ASS1-expressing breast cancer mice do not respond to immune checkpoint inhibitors and patients with breast cancer with high ASS1 have more metastases. We further find that inhibiting purine synthesis increases pyrimidine to purine ratio, elevates expression of the immunoproteasome and significantly enhances the response of autologous primary CD8+ T cells to anti-PD-1. These results suggest that treating patients with high-ASS1 cancers with purine synthesis inhibition is beneficial and may also sensitize them to immune checkpoint inhibition therapy.

DOI: https://doi.org/10.1038/s43018-020-0106-7
Cell. 2022 Feb 03. pii: S0092-8674(22)00003-4. [Epub ahead of print]185(3): 563-575.e11

Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients.

Bastien Nguyen, Christopher Fong, Anisha Luthra, Shaleigh A Smith, Renzo G DiNatale, Subhiksha Nandakumar, Henry Walch, Walid K Chatila, Ramyasree Madupuri, Ritika Kundra, Craig M Bielski, Brooke Mastrogiacomo, Mark T A Donoghue, Adrienne Boire, Sarat Chandarlapaty, Karuna Ganesh, James J Harding, Christine A Iacobuzio-Donahue, Pedram Razavi, Ed Reznik, Charles M Rudin, Dmitriy Zamarin, Wassim Abida, Ghassan K Abou-Alfa, Carol Aghajanian, Andrea Cercek, Ping Chi, Darren Feldman, Alan L Ho, Gopakumar Iyer, Yelena Y Janjigian, Michael Morris, Robert J Motzer, Eileen M O'Reilly, Michael A Postow, Nitya P Raj, Gregory J Riely, Mark E Robson, Jonathan E Rosenberg, Anton Safonov, Alexander N Shoushtari, William Tap, Min Yuen Teo, Anna M Varghese, Martin Voss, Rona Yaeger, Marjorie G Zauderer, Nadeem Abu-Rustum, Julio Garcia-Aguilar, Bernard Bochner, Abraham Hakimi, William R Jarnagin, David R Jones, Daniela Molena, Luc Morris, Eric Rios-Doria, Paul Russo, Samuel Singer, Vivian E Strong, Debyani Chakravarty, Lora H Ellenson, Anuradha Gopalan, Jorge S Reis-Filho, Britta Weigelt, Marc Ladanyi, Mithat Gonen, Sohrab P Shah, Joan Massague, Jianjiong Gao, Ahmet Zehir, Michael F Berger, David B Solit, Samuel F Bakhoum, Francisco Sanchez-Vega, Nikolaus Schultz.

  Metastatic progression is the main cause of death in cancer patients, whereas the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we assembled MSK-MET, a pan-cancer cohort of over 25,000 patients with metastatic diseases. By analyzing genomic and clinical data from this cohort, we identified associations between genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma, and HR+/HER2+ breast ductal carcinoma, but not in others, including colorectal cancer and high-grade serous ovarian cancer, where copy-number alteration patterns may be established early in tumor development. We also identified somatic alterations associated with metastatic burden and specific target organs. Our data offer a valuable resource for the investigation of the biological basis for metastatic spread and highlight the complex role of chromosomal instability in cancer progression.

Keywords:  DNA sequencing; cancer; clinical sequencing; genomics; metastasis; molecular profiling; mutations; next-generation sequencing; organotropism; pan-cancer

DOI:  https://doi.org/10.1016/j.cell.2022.01.003
Int Immunol. 2022 Jan 30. pii: dxac002. [Epub ahead of print]

Cancer-derived cholesterol sulfate is a key mediator to prevent tumor infiltration by effector T cells.

Takaaki Tatsuguchi, Takehito Uruno, Yuki Sugiura, Daiji Sakata, Yoshihiro Izumi, Tetsuya Sakurai, Yuko Hattori, Eiji Oki, Naoto Kubota, Koshiro Nishimoto, Masafumi Oyama, Kazufumi Kunimura, Takuto Ohki, Takeshi Bamba, Hideaki Tahara, Michiie Sakamoto, Masafumi Nakamura, Makoto Suematsu, Yoshinori Fukui.

  The effective tumor immunotherapy requires physical contact of T cells with cancer cells. However, tumors often constitute a specialized microenvironment that excludes T cells from the vicinity of cancer cells, and its underlying mechanisms are still poorly understood. DOCK2 is a Rac activator critical for migration and activation of lymphocytes. We herein show that cancer-derived cholesterol sulfate (CS), a lipid product of the sulfotransferase SULT2B1b, acts as a DOCK2 inhibitor and prevents tumor infiltration by effector T cells. Using clinical samples, we found that CS was abundantly produced in certain types of human cancers such as colon cancers. Functionally, CS-producing cancer cells exhibited resistance to cancer-specific T cell transfer and immune checkpoint blockade. Although SULT2B1b is known to sulfate oxysterols and inactivate their tumor-promoting activity, the expression levels of cholesterol hydroxylases, which mediate oxysterol production, are low in SULT2B1b-expressing cancers. Therefore, SULT2B1b inhibition could be a therapeutic strategy to disrupt tumor immune evasion in oxysterol-non-producing cancers. Thus, our findings define a previously unknown mechanism for tumor immune evasion and provide a novel insight into the development of effective immunotherapies.

Keywords:  DOCK2; SULT2B1b; cholesterol sulfate; immune evasion

DOI:  https://doi.org/10.1093/intimm/dxac002
Alzheimers Dement. 2021 Dec;17 Suppl 3 e056647

Investigating the importance of acylcarnitines in Alzheimer's disease.

Priyanka Baloni, Kwangsik Nho, Matthias Arnold, Gregory Louie, Alexandra Kueider-Paisley, Andrew J Saykin, Kim Ekroos, Cory Funk, Leroy Hood, Nathan D Price, Rebecca Baillie, Gabi Kastenmüller, Xianlin Han, Rima F Kaddurah-Daouk.

BACKGROUND: L-carnitine is present in the mammalian cells as free carnitine (FC) and acylcarnitine and the adult human brain contains almost 10% of long chain acylcarnitine. Acylcarnitines are functionally involved in β-oxidation of fatty acids and are also known for their role in neuroprotection. Levels of plasma acylcarnitines are known to decreased on aging. It is important to understand the association of acylcarnitines with cognitive impairment in Alzheimer's disease (AD).METHOD: We integrated the transcriptome data from 1000 post-mortem brain samples from ROS/MAP, Mayo clinic and Mount Sinai Brain bank cohort with the brain region-specific metabolic networks. We calculated the metabolic fluxes for the reactions in the model and identified those that showed differential fluxes in AD samples. We filtered the reactions that are involved in acylcarnitine synthesis and transport namely carnitine transport, fatty acid oxidation, citric acid cycle, and glutathione metabolism.
RESULT: We found differences in metabolic fluxes for reactions involved in the acetylcarnitine transport to mitochondria (ACRNtm), carnitine palmitoyl transferase 1 and 2 (CPT1 and CPT2) as well as acyl-CoA dehydrogenase short and medium chain (ACADS, ACADM) located in mitochondria in AD samples. Using gene-based association analysis in participants of the AD Neuroimaging Initiative (ADNI) phases 1, GO and 2, we identified genetic variants linked to CPT1, CPT2, ACADM and ACADS genes suggested from the metabolic flux analysis.
CONCLUSION: Our findings suggest that acylcarnitine synthesis and transport is altered in AD. Altered metabolism of short and medium chain acylcarnitines can be used as metabolic features of AD.

DOI: https://doi.org/10.1002/alz.056647
Nat Rev Cancer. 2022 Jan 31.

The role of ROS in tumour development and progression.

Eric C Cheung, Karen H Vousden.

Eukaryotic cells have developed complex systems to regulate the production and response to reactive oxygen species (ROS). Different ROS control diverse aspects of cell behaviour from signalling to death, and deregulation of ROS production and ROS limitation pathways are common features of cancer cells. ROS also function to modulate the tumour environment, affecting the various stromal cells that provide metabolic support, a blood supply and immune responses to the tumour. Although it is clear that ROS play important roles during tumorigenesis, it has been difficult to reliably predict the effect of ROS modulating therapies. We now understand that the responses to ROS are highly complex and dependent on multiple factors, including the types, levels, localization and persistence of ROS, as well as the origin, environment and stage of the tumours themselves. This increasing understanding of the complexity of ROS in malignancies will be key to unlocking the potential of ROS-targeting therapies for cancer treatment.

DOI: https://doi.org/10.1038/s41568-021-00435-0
Nat Cancer. 2021 Dec;2(12): 1268-1270

Cancer research that matters.

Alexia-Ileana Zaromytidou.

DOI: https://doi.org/10.1038/s43018-021-00302-9
Cell. 2022 Feb 03. pii: S0092-8674(21)01454-9. [Epub ahead of print]185(3): 419-446

Adipose-tissue plasticity in health and disease.

Alexander Sakers, Mirian Krystel De Siqueira, Patrick Seale, Claudio J Villanueva.

  Adipose tissue, colloquially known as "fat," is an extraordinarily flexible and heterogeneous organ. While historically viewed as a passive site for energy storage, we now appreciate that adipose tissue regulates many aspects of whole-body physiology, including food intake, maintenance of energy levels, insulin sensitivity, body temperature, and immune responses. A crucial property of adipose tissue is its high degree of plasticity. Physiologic stimuli induce dramatic alterations in adipose-tissue metabolism, structure, and phenotype to meet the needs of the organism. Limitations to this plasticity cause diminished or aberrant responses to physiologic cues and drive the progression of cardiometabolic disease along with other pathological consequences of obesity.

Keywords:  adipocyte; adipocyte progenitor; adipose tissue; beige fat; brown fat; diabetes; obesity; thermogenesis

DOI:  https://doi.org/10.1016/j.cell.2021.12.016
Trends Cancer. 2022 Jan 26. pii: S2405-8033(22)00002-4. [Epub ahead of print]

Interplay between K-RAS and miRNAs.

Bing Shui, Gaspare La Rocca, Andrea Ventura, Kevin M Haigis.

  K-RAS is frequently mutated in cancers, and its overactivation can lead to oncogene-induced senescence (OIS), a barrier to cellular transformation. Feedback onto K-RAS limits its signaling to avoid senescence while achieving the appropriate level of activation that promotes proliferation and survival. Such regulation could be mediated by miRNAs, as aberrant RAS signaling and miRNA activity coexist in several cancers, with miRNAs acting both up- and downstream of K-RAS. Several miRNAs both regulate and are regulated by K-RAS, suggesting a noncoding RNA-based feedback mechanism. Functional interactions between K-RAS and the miRNA machinery have also begun to unfold. This review comprehensively surveys the state of knowledge connecting K-RAS to miRNA function and proposes a model for the regulation of K-RAS signaling by noncoding RNAs.

Keywords:  K-RAS; cancer; feedback regulation; miRNA

DOI:  https://doi.org/10.1016/j.trecan.2022.01.002
Nat Cancer. 2020 Sep;1(9): 862-863

ASS1igning purine dependency to cancer.

Elodie Villa, Issam Ben-Sahra.

DOI: https://doi.org/10.1038/s43018-020-00117-0