bims-medica 2024-05-19 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024‒05‒19
twenty-one papers selected by
Brett Chrest, East Carolina University

The potential of triplet combination therapies for patients with FLT3-ITD -mutated acute myeloid leukemia.
Metabolic dependencies of acute myeloid leukemia stem cells.
NADPH composite index analysis quantifies the relationship between compartmentalized NADPH dynamics and growth rates in cancer cells.
Olutasidenib: a novel mutant IDH1 inhibitor for the treatment of relapsed or refractory acute myeloid leukemia.
Quantitative Optical Redox Imaging of Melanoma Xenografts with Different Metastatic Potentials.
AMPK as a mediator of tissue preservation: time for a shift in dogma?
Integration of proteomic and metabolomic analysis reveal distinct metabolic alterations of prostate cancer-associated fibroblasts compared to normal fibroblasts from patient's stroma samples.
Skeletal muscle hypertrophy rewires glucose metabolism: An experimental investigation and systematic review.
Mitochondrial fatty acid beta-oxidation: a possible therapeutic target for skeletal muscle lipotoxicity in peripheral artery disease myopathy.
Lactate regulates respiratory efficiency and mitochondrial dynamics in primary rat podocytes.
Ketogenic Diet Protects from Experimental Colitis in a Mouse Model Regardless of Dietary Fat Source.
iATPSnFR2: A high-dynamic-range fluorescent sensor for monitoring intracellular ATP.
Spatial hepatocyte plasticity of gluconeogenesis during the metabolic transitions between fed, fasted and starvation states.
Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.
IDH inhibition in gliomas: from preclinical models to clinical trials.
Misspellings or "miscellings"-Non-verifiable and unknown cell lines in cancer research publications.
Ketogenic diet induces p53-dependent cellular senescence in multiple organs.
Exploring dietitians' practice and perspectives on the role of dietary patterns during cancer treatment: A qualitative study.
A PET-Surrogate Signature for the Interrogation of the Metabolic Status of Breast Cancers.
Residual OXPHOS is required to drive primary and metastatic lung tumours in an orthotopic breast cancer model.
Steady-State Delivery and Chemical Modification of Food Nutrients to Improve Cancer Intervention Ability.

Expert Rev Hematol. 2024 May 15.

The potential of triplet combination therapies for patients with FLT3-ITD -mutated acute myeloid leukemia.

Antonella Bruzzese, Ernesto Vigna, Enrica Antonia Martino, Caterina Labanca, Francesco Mendicino, Eugenio Lucia, Virginia Olivito, Gaia Stanzione, Annamaria Zimbo, Elisabetta Lugli, Antonino Neri, Fortunato Morabito, Massimo Gentile.

  INTRODUCTION: Acute myeloid leukemia (AML) encompasses a heterogeneous group of aggressive myeloid malignancies, where FMS-like tyrosine kinase 3 (FLT3) mutations are prevalent, accounting for approximately 25-30% of adult patients. The presence of this mutation is related to a dismal prognosis and high relapse rates. In the lasts years many FLT3 inhibitors have been developed.AREAS COVERED: This review provides a comprehensive overview of FLT3mut AML, summarizing the state of art of current treatment and available data about combination strategies including an FLT3 inhibitor.
EXPERT OPINION: In addition, the review discusses the emergence of drug resistance and the need for a nuanced approaches in treating patients who are ineligible for or resistant to intensive chemotherapy. Specifically, it explores the historical context of FLT3 inhibitors (FLT3Is) and their impact on treatment outcomes, emphasizing the pivotal role of midostaurin, as well as gilteritinib and quizartinib, and providing detailed insights into ongoing trials exploring the safety and efficacy of novel triplet combinations involving FLT3Is in different AML settings.

Keywords:  Acute myeloid leukemia; FLT3 inhibition; FLT3 mutation; FLT3-ITD; triplet therapy in AML

DOI:  https://doi.org/10.1080/17474086.2024.2356258
Int J Hematol. 2024 May 15.

Metabolic dependencies of acute myeloid leukemia stem cells.

Xiangguo Shi, Mengdie Feng, Daisuke Nakada.

  Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy primarily driven by an immature population of AML cells termed leukemia stem cells (LSCs) that are implicated in AML development, chemoresistance, and relapse. An emerging area of research in AML focuses on identifying and targeting the aberrant metabolism in LSCs. Dysregulated metabolism is involved in sustaining functional properties of LSCs, impeding myeloid differentiation, and evading programmed cell death, both in the process of leukemogenesis and in response to chemotherapy. This review discusses recent discoveries regarding the aberrant metabolic processes of AML LSCs that have begun to change the therapeutic landscape of AML.

Keywords:  Acute myeloid leukemia; Leukemia stem cell; Metabolic regulation

DOI:  https://doi.org/10.1007/s12185-024-03789-x
bioRxiv. 2024 Apr 29. pii: 2024.04.27.591477. [Epub ahead of print]

NADPH composite index analysis quantifies the relationship between compartmentalized NADPH dynamics and growth rates in cancer cells.

Sun Jin Moon, Anush Chiappino-Pepe, Wentao Dong, Joanne K Kelleher, Matthew Vander Heiden, Gregory Stephanopoulos, Hadley D Sikes.

NADPH, a highly compartmentalized electron donor in mammalian cells, plays essential roles in cell metabolism. However, little is known about how cytosolic and mitochondrial NADPH dynamics relate to cancer cell growth rates in response to varying nutrient conditions. To address this issue, we present NADPH composite index analysis, which quantifies the relationship between compartmentalized NADPH dynamics and growth rates using genetically encoded NADPH sensors, automated image analysis pipeline, and correlation analysis. Through this analysis, we demonstrated that compartmentalized NADPH dynamics patterns were cancer cell-type dependent. Specifically, cytosolic and mitochondrial NADPH dynamics of MDA-MB-231 decreased in response to serine deprivation, while those of HCT-116 increased in response to serine or glutamine deprivation. Furthermore, by introducing a fractional contribution parameter, we correlated cytosolic and mitochondrial NADPH dynamics to growth rates. Using this parameter, we identified cancer cell lines whose growth rates were selectively inhibited by targeting cytosolic or mitochondrial NADPH metabolism. Mechanistically, we identified citrate transporter as a key mitochondrial transporter that maintains compartmentalized NADPH dynamics and growth rates. Altogether, our results present a significant advance in quantifying the relationship between compartmentalized NADPH dynamics and cancer cell growth rates, highlighting a potential of targeting compartmentalized NADPH metabolism for selective cancer cell growth inhibitions.

DOI: https://doi.org/10.1101/2024.04.27.591477
Expert Rev Hematol. 2024 May 15.

Olutasidenib: a novel mutant IDH1 inhibitor for the treatment of relapsed or refractory acute myeloid leukemia.

Jorge E Cortes.

  INTRODUCTION: Recurrent mutations in isocitrate dehydrogenase 1 (mIDH1) occur in about 7% to 14% of all cases of acute myeloid leukemia (AML). The discovery of targetable mutations in AML, including IDH mutations, expanded the therapeutic landscape of AML and led to the development of targeted agents. Despite significant advances in current treatment options, remission and overall survival rates remain suboptimal. The IDH1 inhibitor, olutasidenib, demonstrated encouraging safety and clinical benefits as monotherapy in patients with relapsed or refractory (R/R) mIDH1-AML.AREAS COVERED: This review outlines the olutasidenib drug profile and summarizes key safety and efficacy data, focusing on the 150 mg twice daily dose from the pivotal registrational cohort of the phase 2 trial that formed the basis for the US Food and Drug Administration approval of olutasidenib in patients with R/R AML with a susceptible IDH1 mutation.
EXPERT OPINION: Olutasidenib offers patients with R/R mIDH1-AML a new treatment option, with improved complete responses and a longer duration of response than other targeted mIDH1 treatment options. Olutasidenib provided clinical benefit with a manageable safety profile. Additional analyses to further characterize the safety and efficacy of olutasidenib in frontline and R/R settings as monotherapy and as combination therapy are ongoing.

Keywords:  2-hydroxyglutarate; IDH1 mutation; Olutasidenib; acute myeloid leukemia; differentiation syndrome

DOI:  https://doi.org/10.1080/17474086.2024.2354486
Cancers (Basel). 2024 Apr 25. pii: 1669. [Epub ahead of print]16(9):

Quantitative Optical Redox Imaging of Melanoma Xenografts with Different Metastatic Potentials.

April Peng, He N Xu, Lily Moon, Paul Zhang, Lin Z Li.

  To develop imaging biomarkers for tumors aggressiveness, our previous optical redox imaging (ORI) studies of the reduced nicotinamide adenine dinucleotide (NADH) and oxidized flavoproteins (Fp, containing flavin adenine dinucleotide, i.e., FAD) in tumor xenografts of human melanoma associated the high optical redox ratio (ORR = Fp/(Fp + NADH)) and its heterogeneity to the high invasive/metastatic potential, without having reported quantitative results for NADH and Fp. Here, we implemented a calibration procedure to facilitate imaging the nominal concentrations of tissue NADH and Fp in the mouse xenografts of two human melanoma lines, an indolent less metastatic A375P and a more metastatic C8161. Images of the redox indices (NADH, Fp, ORR) revealed the existence of more oxidized areas (OAs) and more reduced areas (RAs) within individual tumors. ORR was found to be higher and NADH lower in C8161 compared to that of A375P xenografts, both globally for the whole tumors and locally in OAs. The ORR in the OA can differentiate xenografts with a higher statistical significance than the global averaged ORR. H&E staining of the tumors indicated that the redox differences we identified were more likely due to intrinsically different cell metabolism, rather than variations in cell density.

Keywords:  NADH; cancer aggressiveness; flavoprotein FAD; fluorescence; invasion; redox state

DOI:  https://doi.org/10.3390/cancers16091669
Nat Rev Endocrinol. 2024 May 17.

AMPK as a mediator of tissue preservation: time for a shift in dogma?

Henning Tim Langer, Maria Rohm, Marcus DaSilva Goncalves, Lykke Sylow.

Ground-breaking discoveries have established 5'-AMP-activated protein kinase (AMPK) as a central sensor of metabolic stress in cells and tissues. AMPK is activated through cellular starvation, exercise and drugs by either directly or indirectly affecting the intracellular AMP (or ADP) to ATP ratio. In turn, AMPK regulates multiple processes of cell metabolism, such as the maintenance of cellular ATP levels, via the regulation of fatty acid oxidation, glucose uptake, glycolysis, autophagy, mitochondrial biogenesis and degradation, and insulin sensitivity. Moreover, AMPK inhibits anabolic processes, such as lipogenesis and protein synthesis. These findings support the notion that AMPK is a crucial regulator of cell catabolism. However, studies have revealed that AMPK's role in cell homeostasis might not be as unidirectional as originally thought. This Review explores emerging evidence for AMPK as a promoter of cell survival and an enhancer of anabolic capacity in skeletal muscle and adipose tissue during catabolic crises. We discuss AMPK-activating interventions for tissue preservation during tissue wasting in cancer-associated cachexia and explore the clinical potential of AMPK activation in wasting conditions. Overall, we provide arguments that call for a shift in the current dogma of AMPK as a mere regulator of cell catabolism, concluding that AMPK has an unexpected role in tissue preservation.

DOI: https://doi.org/10.1038/s41574-024-00992-y
Biochim Biophys Acta Mol Basis Dis. 2024 May 10. pii: S0925-4439(24)00218-7. [Epub ahead of print]1870(6): 167229

Integration of proteomic and metabolomic analysis reveal distinct metabolic alterations of prostate cancer-associated fibroblasts compared to normal fibroblasts from patient's stroma samples.

Guillermo Bordanaba-Florit, Félix Royo, Oihane E Albóniga, Aled Clayton, Juan Manuel Falcón-Pérez, Jason Webber.

  The prostate gland is a complex and heterogeneous organ composed of epithelium and stroma. Whilst many studies into prostate cancer focus on epithelium, the stroma is known to play a key role in disease with the emergence of a cancer-associated fibroblasts (CAF) phenotype associated upon disease progression. In this work, we studied the metabolic rewiring of stromal fibroblasts following differentiation to a cancer-associated, myofibroblast-like, phenotype. We determined that CAFs were metabolically more active compared to normal fibroblasts. This corresponded with a heightened lipogenic metabolism, as both reservoir species and building block compounds. Interestingly, lipid metabolism affects mitochondria functioning yet the mechanisms of lipid-mediated functions are unclear. Data showing oxidised fatty acids and glutathione system are elevated in CAFs, compared to normal fibroblasts, strengthens the hypothesis that increased metabolic activity is related to mitochondrial activity. This manuscript describes mechanisms responsible for the altered metabolic flux and shows that prostate cancer-derived extracellular vesicles can increase basal respiration in normal fibroblasts, mirroring that of the disease-like phenotype. This indicates that extracellular vesicles derived from prostate cancer cells may drive an altered oxygen-dependent metabolism associated to mitochondria in CAFs.

Keywords:  Extracellular vesicles; Human primary fibroblasts; Mass spectrometry; Metabolism; Prostate cancer

DOI:  https://doi.org/10.1016/j.bbadis.2024.167229
J Cachexia Sarcopenia Muscle. 2024 May 14.

Skeletal muscle hypertrophy rewires glucose metabolism: An experimental investigation and systematic review.

Philipp Baumert, Sakari Mäntyselkä, Martin Schönfelder, Marie Heiber, Mika Jos Jacobs, Anandini Swaminathan, Petras Minderis, Mantas Dirmontas, Karin Kleigrewe, Chen Meng, Michael Gigl, Ildus I Ahmetov, Tomas Venckunas, Hans Degens, Aivaras Ratkevicius, Juha J Hulmi, Henning Wackerhage.

  BACKGROUND: Proliferating cancer cells shift their metabolism towards glycolysis, even in the presence of oxygen, to especially generate glycolytic intermediates as substrates for anabolic reactions. We hypothesize that a similar metabolic remodelling occurs during skeletal muscle hypertrophy.METHODS: We used mass spectrometry in hypertrophying C2C12 myotubes in vitro and plantaris mouse muscle in vivo and assessed metabolomic changes and the incorporation of the [U-13C6]glucose tracer. We performed enzyme inhibition of the key serine synthesis pathway enzyme phosphoglycerate dehydrogenase (Phgdh) for further mechanistic analysis and conducted a systematic review to align any changes in metabolomics during muscle growth with published findings. Finally, the UK Biobank was used to link the findings to population level.
RESULTS: The metabolomics analysis in myotubes revealed insulin-like growth factor-1 (IGF-1)-induced altered metabolite concentrations in anabolic pathways such as pentose phosphate (ribose-5-phosphate/ribulose-5-phosphate: +40%; P = 0.01) and serine synthesis pathway (serine: -36.8%; P = 0.009). Like the hypertrophy stimulation with IGF-1 in myotubes in vitro, the concentration of the dipeptide l-carnosine was decreased by 26.6% (P = 0.001) during skeletal muscle growth in vivo. However, phosphorylated sugar (glucose-6-phosphate, fructose-6-phosphate or glucose-1-phosphate) decreased by 32.2% (P = 0.004) in the overloaded muscle in vivo while increasing in the IGF-1-stimulated myotubes in vitro. The systematic review revealed that 10 metabolites linked to muscle hypertrophy were directly associated with glycolysis and its interconnected anabolic pathways. We demonstrated that labelled carbon from [U-13C6]glucose is increasingly incorporated by ~13% (P = 0.001) into the non-essential amino acids in hypertrophying myotubes, which is accompanied by an increased depletion of media serine (P = 0.006). The inhibition of Phgdh suppressed muscle protein synthesis in growing myotubes by 58.1% (P < 0.001), highlighting the importance of the serine synthesis pathway for maintaining muscle size. Utilizing data from the UK Biobank (n = 450 243), we then discerned genetic variations linked to the serine synthesis pathway (PHGDH and PSPH) and to its downstream enzyme (SHMT1), revealing their association with appendicular lean mass in humans (P < 5.0e-8).
CONCLUSIONS: Understanding the mechanisms that regulate skeletal muscle mass will help in developing effective treatments for muscle weakness. Our results provide evidence for the metabolic rewiring of glycolytic intermediates into anabolic pathways during muscle growth, such as in serine synthesis.

Keywords:  Warburg effect; lactate; metabolomics; resistance exercise; serine synthesis pathway

DOI:  https://doi.org/10.1002/jcsm.13468
EXCLI J. 2024 ;23 523-533

Mitochondrial fatty acid beta-oxidation: a possible therapeutic target for skeletal muscle lipotoxicity in peripheral artery disease myopathy.

Cassandra E Bradley, Emma Fletcher, Trevor Wilkinson, Andrew Ring, Lucas Ferrer, Dimitrios Miserlis, Pal Pacher, Panagiotis Koutakis.

  Peripheral artery disease (PAD) is an atherosclerotic disease impacting over 200 million individuals and the prevalence increases with age. PAD occurs when plaque builds up within the peripheral arteries, leading to reduced blood flow and oxygen supply to the outer extremities. Individuals who experience PAD suffer from ischemia, which is typically accompanied by significant damage to skeletal muscles. Additionally, this tissue damage affects mitochondria, causing them to become dysregulated and dysfunctional, resulting in decreased metabolic rates. As there is no known cure for PAD, researchers are exploring potential therapeutic targets by examining coexisting cardiovascular conditions and metabolic risk factors, such as the aging process. Among these comorbidities, type-two diabetes mellitus and obesity are particularly common in PAD cases. These conditions, along with aging itself, are associated with an elevated accumulation of ectopic lipids within skeletal muscles, similar to what is observed in PAD. Researchers have attempted to reduce excess lipid accumulation by increasing the rate of fatty acid beta oxidation. Manipulating acetyl coenzyme A carboxylase 2, a key regulatory protein of fatty acid beta oxidation, has been the primary focus of such research. When acetyl coenzyme A carboxylase 2 is inhibited, it interrupts the conversion of acetyl-CoA into malonyl-CoA, resulting in an increase in the rate of fatty acid beta oxidation. By utilizing samples from PAD patients and applying the pharmacological strategies developed for acetyl coenzyme A carboxylase 2 in diabetes and obesity to PAD, a potential new therapeutic avenue may emerge, offering hope for improved quality of life for individuals suffering from PAD.

Keywords:  acetyl coenzyme A carboxylase 2 (ACC2); age; ectopic lipids; fatty acid beta oxidation (FAO); mitochondria; peripheral artery disease (PAD)

DOI:  https://doi.org/10.17179/excli2024-7004
Free Radic Biol Med. 2024 May 11. pii: S0891-5849(24)00457-X. [Epub ahead of print]220 312-323

Lactate regulates respiratory efficiency and mitochondrial dynamics in primary rat podocytes.

Irena Audzeyenka, Maria Szrejder, Patrycja Rachubik, Klaudia Grochowalska, Tomasz Kulesza, Dorota Rogacka, Magdalena Narajczyk, Agnieszka Piwkowska.

  Podocytes are crucial for regulating glomerular permeability. They have foot processes that are integral to the renal filtration barrier. Understanding their energy metabolism could shed light on the pathogenesis of filtration barrier injury. Lactate has been increasingly recognized as more than a waste product and has emerged as a significant metabolic fuel and reserve. The recent identification of lactate transporters in podocytes, the expression of which is modulated by glucose levels and lactate, highlights lactate's relevance. The present study investigated the impact of lactate on podocyte respiratory efficiency and mitochondrial dynamics. We confirmed lactate oxidation in podocytes, suggesting its role in cellular energy production. Under conditions of glucose deprivation or lactate supplementation, a significant shift was seen toward oxidative phosphorylation, reflected by an increase in the oxygen consumption rate/extracellular acidification rate ratio. Notably, lactate dehydrogenase A (LDHA) and lactate dehydrogenase B (LDHB) isoforms, which are involved in lactate conversion to pyruvate, were detected in podocytes for the first time. The presence of lactate led to higher intracellular pyruvate levels, greater LDH activity, and higher LDHB expression. Furthermore, lactate exposure increased mitochondrial DNA-to-nuclear DNA ratios and resulted in upregulation of the mitochondrial biogenesis markers peroxisome proliferator-activated receptor coactivator-1α and transcription factor A mitochondrial, regardless of glucose availability. Changes in mitochondrial size and shape were observed in lactate-exposed podocytes. These findings suggest that lactate is a pivotal energy source for podocytes, especially during energy fluctuations. Understanding lactate's role in podocyte metabolism could offer insights into renal function and pathologies that involve podocyte injury.

Keywords:  LDHA; LDHB; Lactate dehydrogenase; Mitochondrial biogenesis; Oxidative phosphorylation

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.05.022
Nutrients. 2024 Apr 29. pii: 1348. [Epub ahead of print]16(9):

Ketogenic Diet Protects from Experimental Colitis in a Mouse Model Regardless of Dietary Fat Source.

Lotta Luiskari, Jere Lindén, Markku Lehto, Hanne Salmenkari, Riitta Korpela.

  While ketogenic diets (KDs) may have potential as adjunct treatments for gastrointestinal diseases, there is little knowledge on how the fat source of these diets impacts intestinal health. The objective of this study was to investigate how the source of dietary fat of KD influences experimental colitis. We fed nine-week-old male C57BL/6J mice (n = 36) with a low-fat control diet or KD high either in saturated fatty acids (SFA-KD) or polyunsaturated linoleic acid (LA-KD) for four weeks and then induced colitis with dextran sodium sulfate (DSS). To compare the diets, we analyzed macroscopic and histological changes in the colon, intestinal permeability to fluorescein isothiocyanate-dextran (FITC-dextran), and the colonic expression of tight junction proteins and inflammatory markers. While the effects were more pronounced with LA-KD, both KDs markedly alleviated DSS-induced histological lesions. LA-KD prevented inflammation-related weight loss and the shortening of the colon, as well as preserved Il1b and Tnf expression at a healthy level. Despite no significant between-group differences in permeability to FITC-dextran, LA-KD mitigated changes in tight junction protein expression. Thus, KDs may have preventive potential against intestinal inflammation, with the level of the effect being dependent on the dietary fat source.

Keywords:  colitis; dietary fat; intestinal inflammation; ketogenic diet

DOI:  https://doi.org/10.3390/nu16091348
Proc Natl Acad Sci U S A. 2024 May 21. 121(21): e2314604121

iATPSnFR2: A high-dynamic-range fluorescent sensor for monitoring intracellular ATP.

Jonathan S Marvin, Alexandros C Kokotos, Mukesh Kumar, Camila Pulido, Ariana N Tkachuk, Jocelyn Shuxin Yao, Timothy A Brown, Timothy A Ryan.

  We developed a significantly improved genetically encoded quantitative adenosine triphosphate (ATP) sensor to provide real-time dynamics of ATP levels in subcellular compartments. iATPSnFR2 is a variant of iATPSnFR1, a previously developed sensor that has circularly permuted superfolder green fluorescent protein (GFP) inserted between the ATP-binding helices of the ε-subunit of a bacterial F0-F1 ATPase. Optimizing the linkers joining the two domains resulted in a ~fivefold to sixfold improvement in the dynamic range compared to the previous-generation sensor, with excellent discrimination against other analytes, and affinity variants varying from 4 µM to 500 µM. A chimeric version of this sensor fused to either the HaloTag protein or a suitable spectrally separated fluorescent protein provides an optional ratiometric readout allowing comparisons of ATP across cellular regions. Subcellular targeting the sensor to nerve terminals reveals previously uncharacterized single-synapse metabolic signatures, while targeting to the mitochondrial matrix allowed direct quantitative probing of oxidative phosphorylation dynamics.

Keywords:  ATP; fluorescent sensor; neuronal metabolism

DOI:  https://doi.org/10.1073/pnas.2314604121
bioRxiv. 2024 Apr 29. pii: 2024.04.29.591168. [Epub ahead of print]

Spatial hepatocyte plasticity of gluconeogenesis during the metabolic transitions between fed, fasted and starvation states.

Junichi Okada, Austin Landgraf, Alus M Xiaoli, Li Liu, Maxwell Horton, Victor L Schuster, Fajun Yang, Simone Sidoli, Yunping Qiu, Irwin J Kurland, Carolina Eliscovich, Kosaku Shinoda, Jeffrey E Pessin.

The liver acts as a master regulator of metabolic homeostasis in part by performing gluconeogenesis. This process is dysregulated in type 2 diabetes, leading to elevated hepatic glucose output. The parenchymal cells of the liver (hepatocytes) are heterogeneous, existing on an axis between the portal triad and the central vein, and perform distinct functions depending on location in the lobule. Here, using single cell analysis of hepatocytes across the liver lobule, we demonstrate that gluconeogenic gene expression ( Pck1 and G6pc ) is relatively low in the fed state and gradually increases first in the periportal hepatocytes during the initial fasting period. As the time of fasting progresses, pericentral hepatocyte gluconeogenic gene expression increases, and following entry into the starvation state, the pericentral hepatocytes show similar gluconeogenic gene expression to the periportal hepatocytes. Similarly, pyruvate-dependent gluconeogenic activity is approximately 10-fold higher in the periportal hepatocytes during the initial fasting state but only 1.5-fold higher in the starvation state. In parallel, starvation suppresses canonical beta-catenin signaling and modulates expression of pericentral and periportal glutamine synthetase and glutaminase, resulting in an enhanced pericentral glutamine-dependent gluconeogenesis. These findings demonstrate that hepatocyte gluconeogenic gene expression and gluconeogenic activity are highly spatially and temporally plastic across the liver lobule, underscoring the critical importance of using well-defined feeding and fasting conditions to define the basis of hepatic insulin resistance and glucose production.

DOI: https://doi.org/10.1101/2024.04.29.591168
Mol Cell. 2024 May 16. pii: S1097-2765(24)00324-1. [Epub ahead of print]84(10): 1964-1979.e6

Unraveling ETC complex I function in ferroptosis reveals a potential ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.

Chao Mao, Guang Lei, Amber Horbath, Min Wang, Zhengze Lu, Yuelong Yan, Xiaoguang Liu, Lavanya Kondiparthi, Xiong Chen, Jun Cheng, Qidong Li, Zhihao Xu, Li Zhuang, Bingliang Fang, Joseph R Marszalek, Masha V Poyurovsky, Kellen Olszewski, Boyi Gan.

  The role of the mitochondrial electron transport chain (ETC) in regulating ferroptosis is not fully elucidated. Here, we reveal that pharmacological inhibition of the ETC complex I reduces ubiquinol levels while decreasing ATP levels and activating AMP-activated protein kinase (AMPK), the two effects known for their roles in promoting and suppressing ferroptosis, respectively. Consequently, the impact of complex I inhibitors on ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition is limited. The pharmacological inhibition of complex I in LKB1-AMPK-inactivated cells, or genetic ablation of complex I (which does not trigger apparent AMPK activation), abrogates the AMPK-mediated ferroptosis-suppressive effect and sensitizes cancer cells to GPX4-inactivation-induced ferroptosis. Furthermore, complex I inhibition synergizes with radiotherapy (RT) to selectively suppress the growth of LKB1-deficient tumors by inducing ferroptosis in mouse models. Our data demonstrate a multifaceted role of complex I in regulating ferroptosis and propose a ferroptosis-inducing therapeutic strategy for LKB1-deficient cancers.

Keywords:  AMPK; ETC complex I; LKB1; cancer therapy; ferroptosis; lipid peroxidation; mitochondria

DOI:  https://doi.org/10.1016/j.molcel.2024.04.009
Nat Rev Neurol. 2024 May 17.

IDH inhibition in gliomas: from preclinical models to clinical trials.

Roberta Rudà, Craig Horbinski, Martin van den Bent, Matthias Preusser, Riccardo Soffietti.

Gliomas are the most common malignant primary brain tumours in adults and cannot usually be cured with standard cancer treatments. Gliomas show intratumoural and intertumoural heterogeneity at the histological and molecular levels, and they frequently contain mutations in the isocitrate dehydrogenase 1 (IDH1) or IDH2 gene. IDH-mutant adult-type diffuse gliomas are subdivided into grade 2, 3 or 4 IDH-mutant astrocytomas and grade 2 or 3 IDH-mutant, 1p19q-codeleted oligodendrogliomas. The product of the mutated IDH genes, D-2-hydroxyglutarate (D-2-HG), induces global DNA hypermethylation and interferes with immunity, leading to stimulation of tumour growth. Selective inhibitors of mutant IDH, such as ivosidenib and vorasidenib, have been shown to reduce D-2-HG levels and induce cellular differentiation in preclinical models and to induce MRI-detectable responses in early clinical trials. The phase III INDIGO trial has demonstrated superiority of vorasidenib, a brain-penetrant pan-mutant IDH inhibitor, over placebo in people with non-enhancing grade 2 IDH-mutant gliomas following surgery. In this Review, we describe the pathway of development of IDH inhibitors in IDH-mutant low-grade gliomas from preclinical models to clinical trials. We discuss the practice-changing implications of the INDIGO trial and consider new avenues of investigation in the field of IDH-mutant gliomas.

DOI: https://doi.org/10.1038/s41582-024-00967-7
Int J Cancer. 2024 May 15.

Misspellings or "miscellings"-Non-verifiable and unknown cell lines in cancer research publications.

Danielle J Oste, Pranujan Pathmendra, Reese A K Richardson, Gracen Johnson, Yida Ao, Maya D Arya, Naomi R Enochs, Muhammed Hussein, Jinghan Kang, Aaron Lee, Jonathan J Danon, Guillaume Cabanac, Cyril Labbé, Amanda Capes Davis, Thomas Stoeger, Jennifer A Byrne.

  Reproducible laboratory research relies on correctly identified reagents. We have previously described gene research papers with wrongly identified nucleotide sequence(s), including papers studying miR-145. Manually verifying reagent identities in 36 recent miR-145 papers found that 56% and 17% of papers described misidentified nucleotide sequences and cell lines, respectively. We also found 5 cell line identifiers in miR-145 papers with misidentified nucleotide sequences and cell lines, and 18 cell line identifiers published elsewhere, that did not represent indexed human cell lines. These 23 identifiers were described as non-verifiable (NV), as their identities were unclear. Studying 420 papers that mentioned 8 NV identifier(s) found 235 papers (56%) that referred to 7 identifiers (BGC-803, BSG-803, BSG-823, GSE-1, HGC-7901, HGC-803, and MGC-823) as independent cell lines. We could not find any publications describing how these cell lines were established. Six cell lines were sourced from cell line repositories with externally accessible online catalogs, but these cell lines were not indexed as claimed. Some papers also stated that short tandem repeat (STR) profiles had been generated for three cell lines, yet no STR profiles could be identified. In summary, as NV cell lines represent new challenges to research integrity and reproducibility, further investigations are required to clarify their status and identities.

Keywords:  cancer; cell lines; non‐verifiable; reagents; wrongly identified

DOI:  https://doi.org/10.1002/ijc.34995
Sci Adv. 2024 May 17. 10(20): eado1463

Ketogenic diet induces p53-dependent cellular senescence in multiple organs.

Sung-Jen Wei, Joseph R Schell, E Sandra Chocron, Mahboubeh Varmazyad, Guogang Xu, Wan Hsi Chen, Gloria M Martinez, Felix F Dong, Prethish Sreenivas, Rolando Trevino, Haiyan Jiang, Yan Du, Afaf Saliba, Wei Qian, Brandon Lorenzana, Alia Nazarullah, Jenny Chang, Kumar Sharma, Erin Munkácsy, Nobuo Horikoshi, David Gius.

A ketogenic diet (KD) is a high-fat, low-carbohydrate diet that leads to the generation of ketones. While KDs improve certain health conditions and are popular for weight loss, detrimental effects have also been reported. Here, we show mice on two different KDs and, at different ages, induce cellular senescence in multiple organs, including the heart and kidney. This effect is mediated through adenosine monophosphate-activated protein kinase (AMPK) and inactivation of mouse double minute 2 (MDM2) by caspase-2, leading to p53 accumulation and p21 induction. This was established using p53 and caspase-2 knockout mice and inhibitors to AMPK, p21, and caspase-2. In addition, senescence-associated secretory phenotype biomarkers were elevated in serum from mice on a KD and in plasma samples from patients on a KD clinical trial. Cellular senescence was eliminated by a senolytic and prevented by an intermittent KD. These results have important clinical implications, suggesting that the effects of a KD are contextual and likely require individual optimization.

DOI: https://doi.org/10.1126/sciadv.ado1463
PLoS One. 2024 ;19(5): e0302107

Exploring dietitians' practice and perspectives on the role of dietary patterns during cancer treatment: A qualitative study.

Annie R Curtis, Nicole Kiss, Katherine M Livingstone, Robin M Daly, Anna Ugalde.

BACKGROUND: Dietitians are nutrition professionals equipped with specialised skills required to prevent and treat malnutrition in cancer. Optimisation of dietary intake is recommended as the primary nutrition strategy for the treatment of cancer-related malnutrition. However, it is unclear whether dietary patterns, described as the combination, quantity, and frequency of food consumption, are considered. This study examined dietitians' current food-based management of malnutrition; explored dietitians' awareness of dietary patterns and assessed barriers and enablers to the use of dietary patterns in clinical practice.METHODS: This qualitative study consisted of semi-structured interviews with oncology dietitians. Dietitians were recruited through national nutrition societies, social media, and professional networks. Audio-recorded interviews were transcribed verbatim and analysed using inductive thematic analysis.
RESULTS: Fourteen oncology dietitians from across four Australian states and territories participated. Three themes were identified: (i) principles to guide nutritional care, (ii) dietary patterns as a gap in knowledge and practice, and (iii) opportunities for better care with systems as both a barrier and enabler. Dietetic practice was food-focussed, encouraging energy and protein-rich foods consistent with nutrient-focussed evidence-based guidelines. Dietitians encouraged one of two nutrition-related approaches, either encouraging intake of 'any tolerated food' or 'foods supportive on longer-term health'. Dietitians were generally unaware of dietary patterns and questioned their relevance in certain clinical situations. A multidisciplinary team approach, adequate food service and dissemination of dietary patterns research and education were identified as opportunities for better patient care.
CONCLUSIONS: Recommendations for the treatment of malnutrition vary between oncology dietitians and uncertainty exists regarding dietary patterns and their relevance in clinical practice. Further exploration into the role of dietary patterns to treat cancer-related malnutrition and education for dietitians are required prior to implementation of a dietary patterns approach into clinical practice.

DOI: https://doi.org/10.1371/journal.pone.0302107
Adv Sci (Weinh). 2024 May 17. e2308255

A PET-Surrogate Signature for the Interrogation of the Metabolic Status of Breast Cancers.

Stefano Confalonieri, Bronislava Matoskova, Rosa Pennisi, Flavia Martino, Agnese De Mario, Giorgia Miloro, Francesca Montani, Luca Rotta, Mahila Esmeralda Ferrari, Laura Gilardi, Francesco Ceci, Chiara Maria Grana, Rosario Rizzuto, Cristina Mammucari, Pier Paolo Di Fiore, Letizia Lanzetti.

  Metabolic alterations in cancers can be exploited for diagnostic, prognostic, and therapeutic purposes. This is exemplified by 18F-fluorodeoxyglucose (FDG)-positron emission tomography (FDG-PET), an imaging tool that relies on enhanced glucose uptake by tumors for diagnosis and staging. By performing transcriptomic analysis of breast cancer (BC) samples from patients stratified by FDG-PET, a 54-gene signature (PETsign) is identified that recapitulates FDG uptake. PETsign is independently prognostic of clinical outcome in luminal BCs, the most common and heterogeneous BC molecular subtype, which requires improved stratification criteria to guide therapeutic decision-making. The prognostic power of PETsign is stable across independent BC cohorts and disease stages including the earliest BC stage, arguing that PETsign is an ab initio metabolic signature. Transcriptomic and metabolomic analysis of BC cells reveals that PETsign predicts enhanced glycolytic dependence and reduced reliance on fatty acid oxidation. Moreover, coamplification of PETsign genes occurs frequently in BC arguing for their causal role in pathogenesis. CXCL8 and EGFR signaling pathways feature strongly in PETsign, and their activation in BC cells causes a shift toward a glycolytic phenotype. Thus, PETsign serves as a molecular surrogate for FDG-PET that could inform clinical management strategies for BC patients.

Keywords:  FDG‐PET; breast cancer; gene signature; glycolysis; metabolism

DOI:  https://doi.org/10.1002/advs.202308255
Front Oncol. 2024 ;14 1362786

Residual OXPHOS is required to drive primary and metastatic lung tumours in an orthotopic breast cancer model.

Patries Herst, Georgia Carson, Danielle Lewthwaite, David Eccles, Alfonso Schmidt, Andrew Wilson, Carole Grasso, David O'Sullivan, Jiri Neuzil, Melanie McConnell, Michael Berridge.

  Background: Fast adaptation of glycolytic and mitochondrial energy pathways to changes in the tumour microenvironment is a hallmark of cancer. Purely glycolytic ρ0 tumour cells do not form primary tumours unless they acquire healthy mitochondria from their micro-environment. Here we explored the effects of severely compromised respiration on the metastatic capability of 4T1 mouse breast cancer cells.Methods: 4T1 cell lines with different levels of respiratory capacity were generated; the Seahorse extracellular flux analyser was used to evaluate oxygen consumption rates, fluorescent confocal microscopy to assess the number of SYBR gold-stained mitochondrial DNA nucleoids, and the presence of the ATP5B protein in the cytoplasm and fluorescent in situ nuclear hybridization was used to establish ploidy. MinION nanopore RNA sequence analysis was used to compare mitochondrial DNA transcription between cell lines. Orthotopic injection was used to determine the ability of cells to metastasize to the lungs of female Balb/c mice.
Results: OXPHOS-deficient ATP5B-KO3.1 cells did not generate primary tumours. Severely OXPHOS compromised ρ0D5 cells generated both primary tumours and lung metastases. Cells generated from lung metastasis of both OXPHOS-competent and OXPHOS-compromised cells formed primary tumours but no metastases when re-injected into mice. OXPHOS-compromised cells significantly increased their mtDNA content, but this did not result in increased OXPHOS capacity, which was not due to decreased mtDNA transcription. Gene set enrichment analysis suggests that certain cells derived from lung metastases downregulate their epithelial-to-mesenchymal related pathways.
Conclusion: In summary, OXPHOS is required for tumorigenesis in this orthotopic mouse breast cancer model but even very low levels of OXPHOS are sufficient to generate both primary tumours and lung metastases.

Keywords:  breast cancer; glycolysis; intercellular mitochondrial transport; metastasis; orthotopic mouse model; oxidative phosphorylation

DOI:  https://doi.org/10.3389/fonc.2024.1362786
Foods. 2024 Apr 28. pii: 1363. [Epub ahead of print]13(9):

Steady-State Delivery and Chemical Modification of Food Nutrients to Improve Cancer Intervention Ability.

Sijia Hao, Peng Ge, Wentao Su, Yuxiao Wang, A M Abd El-Aty, Mingqian Tan.

  Cancer is a crucial global health problem, and prevention is an important strategy to reduce the burden of the disease. Daily diet is the key modifiable risk factor for cancer, and an increasing body of evidence suggests that specific nutrients in foods may have a preventive effect against cancer. This review summarizes the current evidence on the role of nutrients from foods in cancer intervention. It discusses the potential mechanisms of action of various dietary components, including phytochemicals, vitamins, minerals, and fiber. The findings of epidemiological and clinical studies on their association with cancer risk are highlighted. The foods are rich in bioactive compounds such as carotenoids, flavonoids, and ω-3 fatty acids, which have been proven to have anticancer properties. The effects of steady-state delivery and chemical modification of these food's bioactive components on anticancer and intervention are summarized. Future research should focus on identifying the specific bioactive compounds in foods responsible for their intervention effects and exploring the potential synergistic effects of combining different nutrients in foods. Dietary interventions that incorporate multiple nutrients and whole foods may hold promise for reducing the risk of cancer and improving overall health.

Keywords:  cancer; chemical modification; diet; nutritional intervention; steady state delivery

DOI:  https://doi.org/10.3390/foods13091363