bims-medica 2024-04-07 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024–04–07
twenty-two papers selected by
Brett Chrest, East Carolina University

Targeting Metabolic Dependencies Fueling the TCA Cycle to Circumvent Therapy Resistance in Acute Myeloid Leukemia.
Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.
A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity.
Genetics and diet shape the relationship between islet function and whole-body metabolism.
Anaerobic Lactate Production Is Associated With Decreased Microcirculatory Blood Flow and Decreased Mitochondrial Respiration Following Cardiovascular Surgery With Cardiopulmonary Bypass.
Optical imaging reveals chemotherapy-induced metabolic reprogramming of residual disease and recurrence.
Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria.
Impact of capillary and sarcolemmal proximity on mitochondrial structure and energetic function in skeletal muscle.
Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies.
Exercise increases TCA intermediate concentrations during low-calorie diet independent of insulin resistance among women with obesity.
Targeting NAD+ metabolism: Pre-clinical insights into potential cancer therapy strategies.
Association between class III obesity and overall survival in previously untreated younger patients with acute myeloid leukemia enrolled on SWOG S1203.
Anticancer sensitivity and biological aspect of 5-fluorouracil-resistant human colorectal cancer HCT116 cells in three-dimensional culture under high- and low-glucose conditions.
Malnutrition, sarcopenia and cachexia: exploring prevalence, overlap, and perceptions in older adults with cancer.
Proteomic insights into paediatric cancer: Unravelling molecular signatures and therapeutic opportunities.
Branched-chain amino acid supplementation drives dynamic changes in gut microbiota without impairing glucose and lipid homeostasis at the different stages of insulin resistance in mice on a high-fat diet.
Changes in the consumption of isoflavones, omega-6, and omega-3 fatty acids in women with metastatic breast cancer adopting a whole-food, plant-based diet: post-hoc analysis of nutrient intake data from an 8-week randomized controlled trial.
Unveiling the signaling network of FLT3-ITD AML improves drug sensitivity prediction.
SCAF1 drives the compositional diversity of mammalian respirasomes.
GSH-responsive degradable nanodrug for glucose metabolism intervention and induction of ferroptosis to enhance magnetothermal anti-tumor therapy.
Vitamin B12 status and folic acid supplementation influence mitochondrial heteroplasmy levels in mice.
Allosteric SHP2 inhibition enhances regorafenib's effectiveness in colorectal cancer treatment.

Cancer Res. 2024 Apr 01. 84(7): 950-952

Targeting Metabolic Dependencies Fueling the TCA Cycle to Circumvent Therapy Resistance in Acute Myeloid Leukemia.

Emeline Boët, Jean-Emmanuel Sarry.

Acute myeloid leukemia (AML) is one of the most prevalent blood cancers, characterized by a dismal survival rate. This poor outcome is largely attributed to AML cells that persist despite treatment and eventually result in relapse. Relapse-initiating cells exhibit diverse resistance mechanisms, encompassing genetic factors and, more recently discovered, nongenetic factors such as metabolic adaptations. Leukemic stem cells (LSC) rely on mitochondrial metabolism for their survival, whereas hematopoietic stem cells primarily depend on glycolysis. Furthermore, following treatments such as cytarabine, a standard in AML treatment for over four decades, drug-persisting leukemic cells exhibit an enhanced reliance on mitochondrial metabolism. In this issue of Cancer Research, two studies investigated dependencies of AML cells on two respiratory substrates, α-ketoglutarate and lactate-derived pyruvate, that support mitochondrial oxidative phosphorylation (OXPHOS) following treatment with the imipridone ONC-213 and the BET inhibitor INCB054329, respectively. Targeting lactate utilization by interfering with monocarboxylate transporter 1 (MCT1 or SLC16A1) or lactate dehydrogenase effectively sensitized cells to BET inhibition in vitro and in vivo. In addition, ONC-213 affected αKGDH, a pivotal NADH-producing enzyme of the TCA cycle, to induce a mitochondrial stress response through ATF4 activation that diminished the expression of the antiapoptotic protein MCL1, consequently promoting apoptosis of AML cells. In summary, targeting these mitochondrial dependencies might be a promising strategy to kill therapy-naïve and treatment-resistant OXPHOS-reliant LSCs and to delay or prevent relapse. See related articles by Monteith et al., p. 1101 and Su et al., p. 1084.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0019
bioRxiv. 2024 Mar 20. pii: 2024.03.20.586011. [Epub ahead of print]

Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission.

Anupama Tiwari, Jongyun Myeong, Arsalan Hashemiaghdam, Hao Zhang, Xianfeng Niu, Marissa A Laramie, Marion I Stunault, Jasmin Sponagel, Gary Patti, Leah Shriver, Vitaly Klyachko, Ghazaleh Ashrafi.

Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep, intense circuit activity, or dietary restrictions, posing significant metabolic stress. Here, we demonstrate that the mammalian brain utilizes pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability within a neuron and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation which in turn modulates mitochondrial pyruvate uptake. Importantly, our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in synaptic transmission, namely, the spatiotemporal pattern of synaptic vesicle release and the efficiency of vesicle retrieval, functions that have profound implications for synaptic plasticity. In summary, we identify pyruvate as a potent neuronal fuel and mitochondrial pyruvate uptake as a critical node for the metabolic control of synaptic transmission in hippocampal terminals.
HIGHLIGHTS: Serum pyruvate is taken up by the brain and efficiently oxidized in the TCA cycle.The mitochondrial pyruvate carrier (MPC) is essential for presynaptic energy metabolism.Acetylation of the MPC complex modulates mitochondrial pyruvate uptake.MPC activity regulates the release and retrieval of synaptic vesicles in nerve terminals.

DOI: https://doi.org/10.1101/2024.03.20.586011
Res Sq. 2024 Mar 22. pii: rs.3.rs-4047706. [Epub ahead of print]

A Human Brain Map of Mitochondrial Respiratory Capacity and Diversity.

Martin Picard, Eugene Mosharov, Ayelet Rosenberg, Anna Monzel, Corey Osto, Linsey Stiles, Gorazd Rosoklija, Andrew Dwork, Snehal Bindra, Ya Zhang, Masashi Fujita, Madeline Mariani, Mihran Bakalian, David Sulzer, Philip De Jager, Vilas Menon, Orian Shirihai, John Mann, Mark Underwood, Maura Boldrini, Michel Thiebaut de Schotten.

Mitochondrial oxidative phosphorylation (OxPhos) powers brain activity 1,2 , and mitochondrial defects are linked to neurodegenerative and neuropsychiatric disorders 3,4 , underscoring the need to define the brain's molecular energetic landscape 5-10 . To bridge the cognitive neuroscience and cell biology scale gap, we developed a physical voxelization approach to partition a frozen human coronal hemisphere section into 703 voxels comparable to neuroimaging resolution (3x3x3 mm). In each cortical and subcortical brain voxel, we profiled mitochondrial phenotypes including OxPhos enzyme activities, mitochondrial DNA and volume density, and mitochondria-specific respiratory capacity. We show that the human brain contains a diversity of mitochondrial phenotypes driven by both topology and cell types. Compared to white matter, grey matter contains >50% more mitochondria. We show that the more abundant grey matter mitochondria also are biochemically optimized for energy transformation, particularly among recently evolved cortical brain regions. Scaling these data to the whole brain, we created a backward linear regression model integrating several neuroimaging modalities11, thereby generating a brain-wide map of mitochondrial distribution and specialization that predicts mitochondrial characteristics in an independent brain region of the same donor brain. This new approach and the resulting MitoBrainMap of mitochondrial phenotypes provide a foundation for exploring the molecular energetic landscape that enables normal brain functions, relating it to neuroimaging data, and defining the subcellular basis for regionalized brain processes relevant to neuropsychiatric and neurodegenerative disorders.

DOI: https://doi.org/10.21203/rs.3.rs-4047706/v1
Am J Physiol Endocrinol Metab. 2024 Apr 03.

Genetics and diet shape the relationship between islet function and whole-body metabolism.

Belinda Yau, Søren Madsen, Marin E Healy, Kristen C Cooke, Andreas M Fritzen, Ida H Thorius, Jacqueline Stöckli, David E James, Melkam A Kebede.

  Despite the fact that genes and the environment are known to play a central role in islet function, our knowledge of how these parameters interact to modulate insulin secretory function remains relatively poor. Presently, we performed ex vivo glucose-stimulated insulin secretion and insulin content assays in islets of 213 mice from 13 inbred mouse strains on chow, western diet, and ketogenic diet. Strikingly, among these 13 strains, islets from the commonly used C57BL/6J mouse strain were the least glucose responsive. Using matched metabolic phenotyping data, we performed correlation analyses of inter-islet parameters and found a positive correlation between basal and glucose-stimulated insulin secretion, but no relationship between insulin secretion and insulin content. Using in vivo metabolic measures, we found that metabolic health determines the relationship between ex vivo islet insulin secretion and fasting plasma insulin. Finally, we showed that islet glucose-stimulated insulin secretion decreased with ketogenic diet in almost all strains, concomitant with broader phenotypic changes, such as increased adiposity and glucose intolerance. This is an important finding as it should caution against the application of the ketogenic diet for beta-cell health. Together these data offer key insights into the intersection of diet and genetic background on islet function and whole-body metabolism.

Keywords:  Gene-diet interactions; High fat high sucrose diet; Islet function; Keto diet; genetic background

DOI:  https://doi.org/10.1152/ajpendo.00060.2024
Crit Care Med. 2024 Apr 05.

Anaerobic Lactate Production Is Associated With Decreased Microcirculatory Blood Flow and Decreased Mitochondrial Respiration Following Cardiovascular Surgery With Cardiopulmonary Bypass.

John C Greenwood, Fatima M Talebi, David H Jang, Audrey E Spelde, Emily K Gordon, Jiri Horak, Michael A Acker, Todd J Kilbaugh, Frances S Shofer, John G T Augoustides, Jacob S Brenner, Vladimir R Muzykantov, Jan Bakker, Benjamin S Abella.

OBJECTIVES: Quantify the relationship between perioperative anaerobic lactate production, microcirculatory blood flow, and mitochondrial respiration in patients after cardiovascular surgery with cardiopulmonary bypass.
DESIGN: Serial measurements of lactate-pyruvate ratio (LPR), microcirculatory blood flow, plasma tricarboxylic acid cycle cycle intermediates, and mitochondrial respiration were compared between patients with a normal peak lactate (≤ 2 mmol/L) and a high peak lactate (≥ 4 mmol/L) in the first 6 hours after surgery. Regression analysis was performed to quantify the relationship between clinically relevant hemodynamic variables, lactate, LPR, and microcirculatory blood flow.
SETTING: This was a single-center, prospective observational study conducted in an academic cardiovascular ICU.
PATIENTS: One hundred thirty-two patients undergoing elective cardiovascular surgery with cardiopulmonary bypass.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: Patients with a high postoperative lactate were found to have a higher LPR compared with patients with a normal postoperative lactate (14.4 ± 2.5 vs. 11.7 ± 3.4; p = 0.005). Linear regression analysis found a significant, negative relationship between LPR and microcirculatory flow index (r = -0.225; β = -0.037; p = 0.001 and proportion of perfused vessels: r = -0.17; β = -0.468; p = 0.009). There was not a significant relationship between absolute plasma lactate and microcirculation variables. Last, mitochondrial complex I and complex II oxidative phosphorylation were reduced in patients with high postoperative lactate levels compared with patients with normal lactate (22.6 ± 6.2 vs. 14.5 ± 7.4 pmol O2/s/106 cells; p = 0.002).
CONCLUSIONS: Increased anaerobic lactate production, estimated by LPR, has a negative relationship with microcirculatory blood flow after cardiovascular surgery. This relationship does not persist when measuring lactate alone. In addition, decreased mitochondrial respiration is associated with increased lactate after cardiovascular surgery. These findings suggest that high lactate levels after cardiovascular surgery, even in the setting of normal hemodynamics, are not simply a type B phenomenon as previously suggested.

DOI: https://doi.org/10.1097/CCM.0000000000006289
Sci Adv. 2024 Apr 05. 10(14): eadj7540

Optical imaging reveals chemotherapy-induced metabolic reprogramming of residual disease and recurrence.

Enakshi D Sunassee, Riley J Deutsch, Victoria W D'Agostino, Pol Castellano-Escuder, Elizabeth A Siebeneck, Olga Ilkayeva, Brian T Crouch, Megan C Madonna, Jeffrey Everitt, James V Alvarez, Gregory M Palmer, Matthew D Hirschey, Nirmala Ramanujam.

Fewer than 20% of triple-negative breast cancer patients experience long-term responses to mainstay chemotherapy. Resistant tumor subpopulations use alternative metabolic pathways to escape therapy, survive, and eventually recur. Here, we show in vivo, longitudinal metabolic reprogramming in residual disease and recurrence of triple-negative breast cancer xenografts with varying sensitivities to the chemotherapeutic drug paclitaxel. Optical imaging coupled with metabolomics reported an increase in non-glucose-driven mitochondrial metabolism and an increase in intratumoral metabolic heterogeneity during regression and residual disease in resistant MDA-MB-231 tumors. Conversely, sensitive HCC-1806 tumors were primarily reliant on glucose uptake and minimal changes in metabolism or heterogeneity were observed over the tumors' therapeutic life cycles. Further, day-matched resistant HCC-1806 tumors revealed a higher reliance on mitochondrial metabolism and elevated metabolic heterogeneity compared to sensitive HCC-1806 tumors. Together, metabolic flexibility, increased reliance on mitochondrial metabolism, and increased metabolic heterogeneity are defining characteristics of persistent residual disease, features that will inform the appropriate type and timing of therapies.

DOI: https://doi.org/10.1126/sciadv.adj7540
Sci Adv. 2024 Apr 05. 10(14): eadl0389

Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria.

Zhenqi Zhou, Alice Ma, Timothy M Moore, Dane M Wolf, Nicole Yang, Peter Tran, Mayuko Segawa, Alexander R Strumwasser, Wenjuan Ren, Kai Fu, Jonathan Wanagat, Alexander M van der Bliek, Rachelle Crosbie-Watson, Marc Liesa, Linsey Stiles, Rebecca Acin-Perez, Sushil Mahata, Orian Shirihai, Mark O Goodarzi, Michal Handzlik, Christian M Metallo, David W Walker, Andrea L Hevener.

The dynamin-related guanosine triphosphatase, Drp1 (encoded by Dnm1l), plays a central role in mitochondrial fission and is requisite for numerous cellular processes; however, its role in muscle metabolism remains unclear. Here, we show that, among human tissues, the highest number of gene correlations with DNM1L is in skeletal muscle. Knockdown of Drp1 (Drp1-KD) promoted mitochondrial hyperfusion in the muscle of male mice. Reduced fatty acid oxidation and impaired insulin action along with increased muscle succinate was observed in Drp1-KD muscle. Muscle Drp1-KD reduced complex II assembly and activity as a consequence of diminished mitochondrial translocation of succinate dehydrogenase assembly factor 2 (Sdhaf2). Restoration of Sdhaf2 normalized complex II activity, lipid oxidation, and insulin action in Drp1-KD myocytes. Drp1 is critical in maintaining mitochondrial complex II assembly, lipid oxidation, and insulin sensitivity, suggesting a mechanistic link between mitochondrial morphology and skeletal muscle metabolism, which is clinically relevant in combatting metabolic-related diseases.

DOI: https://doi.org/10.1126/sciadv.adl0389
J Physiol. 2024 Apr 02.

Impact of capillary and sarcolemmal proximity on mitochondrial structure and energetic function in skeletal muscle.

Hailey A Parry, T Bradley Willingham, Kevin A Giordano, Yuho Kim, Shureed Qazi, Jay R Knutson, Christian A Combs, Brian Glancy.

  Mitochondria within skeletal muscle cells are located either between the muscle contractile apparatus (interfibrillar mitochondria, IFM) or beneath the cell membrane (subsarcolemmal mitochondria, SSM), with several structural and functional differences reported between IFM and SSM. However, recent 3D imaging studies demonstrate that mitochondria are particularly concentrated in the proximity of capillaries embedded in sarcolemmal grooves rather than in proximity to the sarcolemma itself (paravascular mitochondria, PVM). To evaluate the impact of capillary vs. sarcolemmal proximity, we compared the structure and function of skeletal muscle mitochondria located either lateral to embedded capillaries (PVM), adjacent to the sarcolemma but not in PVM pools (SSM) or interspersed between sarcomeres (IFM). Mitochondrial morphology and interactions were assessed by 3D electron microscopy coupled with machine learning segmentation, whereas mitochondrial energy conversion was assessed by two-photon microscopy of mitochondrial membrane potential, content, calcium, NADH redox and flux in live, intact cells. Structurally, although PVM and SSM were similarly larger than IFM, PVM were larger, rounder and had more physical connections to neighbouring mitochondria compared to both IFM and SSM. Functionally, PVM had similar or greater basal NADH flux compared to SSM and IFM, respectively, despite a more oxidized NADH pool and a greater membrane potential, signifying a greater activation of the electron transport chain in PVM. Together, these data indicate that proximity to capillaries has a greater impact on resting mitochondrial energy conversion and distribution in skeletal muscle than the sarcolemma alone. KEY POINTS: Capillaries have a greater impact on mitochondrial energy conversion in skeletal muscle than the sarcolemma. Paravascular mitochondria are larger, and the outer mitochondrial membrane is more connected with neighbouring mitochondria. Interfibrillar mitochondria are longer and have greater contact sites with other organelles (i.e. sarcoplasmic reticulum and lipid droplets). Paravascular mitochondria have greater activation of oxidative phosphorylation than interfibrillar mitochondria at rest, although this is not regulated by calcium.

Keywords:  energy function; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1113/JP286246
Nat Commun. 2024 Mar 30. 15(1): 2803

Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies.

Saeed Daneshmandi, Jee Eun Choi, Qi Yan, Cameron R MacDonald, Manu Pandey, Mounika Goruganthu, Nathan Roberts, Prashant K Singh, Richard M Higashi, Andrew N Lane, Teresa W-M Fan, Jianmin Wang, Philip L McCarthy, Elizabeth A Repasky, Hemn Mohammadpour.

Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC mitochondrial fitness controls the efficacy of doxorubicin chemotherapy in a preclinical lymphoma model. Mechanistically, we show that triggering STAT3 signaling via β2-adrenergic receptor (β2-AR) activation leads to improved MDSC function through metabolic reprograming, marked by sustained mitochondrial respiration and higher ATP generation which reduces AMPK signaling, altering energy metabolism. Furthermore, induced STAT3 signaling in MDSCs enhances glutamine consumption via the TCA cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species via regulation of Nrf2 and the oxidative stress response, enhancing MDSC survival. Using β2-AR blockade, we target the STAT3 pathway and ATP and itaconate metabolism, disrupting ATP generation by the electron transport chain and decreasing itaconate generation causing diminished MDSC mitochondrial fitness. This disruption increases the response to doxorubicin and could be tested clinically.

DOI: https://doi.org/10.1038/s41467-024-47096-9
Physiol Rep. 2024 Apr;12(7): e15987

Exercise increases TCA intermediate concentrations during low-calorie diet independent of insulin resistance among women with obesity.

Tristan J Ragland, Steven K Malin.

  Tricarboxylic acid cycle intermediates (TCAi) have been proposed to act as myokines that influence energy metabolism. We determined if 2-weeks of low-calorie diet with interval exercise (LCD + INT) would increase TCAi more than a low-calorie diet (LCD). Twenty-three women were randomized to 2-weeks of LCD (n = 12, 48.4 ± 2.5 years, 37.8 ± 1.5 kg/m2, ~1200 kcal/d) or LCD + INT (n = 11, 47.6 ± 4.3 years, 37.9 ± 2.3 kg/m2; 60 min/d supervised INT of 3 min 90% & 50% HRpeak). TCAi and amino acids (AA) were measured at 0 min of a 75 g OGTT, while glucose, insulin, and FFA were obtained at 0, 30, 60, 90, 120, and 180 min to assess total area under the curve (tAUC180min) and insulin resistance (IR; tAUC180min of Glucose × Insulin). Fuel use (indirect calorimetry) was also collected at 0, 60, 120, and 180 min as was fitness (VO2peak) and body composition (BodPod). Treatments reduced weight (p < 0.001), fasting RER (p = 0.01), and IR (p = 0.03), although LCD + INT increased VO2peak (p = 0.02) and maintained RER tAUC180min (p = 0.05) versus LCD. Treatments increased FFA tAUC180min (p = 0.005), cis-aconitate, isocitrate, and succinate (p ≤ 0.02), as well as reduced phenylalanine and tryptophan, cysteine (p ≤ 0.005). However, LCD + INT increased malate, citrate, α-ketoglutarate, and alanine more than LCD (p ≤ 0.04). Thus, INT enhanced LCD effects on some TCAi in women with obesity independent of IR.

Keywords:  amino acids; diabetes; interval training; obesity; tricarboxylic acid cycle

DOI:  https://doi.org/10.14814/phy2.15987
Endocrinology. 2024 Apr 03. pii: bqae043. [Epub ahead of print]

Targeting NAD+ metabolism: Pre-clinical insights into potential cancer therapy strategies.

Ayça N Mogol, Alanna Z Kaminsky, David J Dutton, Zeynep Madak Erdogan.

  NAD+ is one of the most important metabolites for cellular activities, and its biosynthesis mainly occurs through the salvage pathway using the NAMPT enzyme. The main NAD consumers, PARP and SIRT enzymes, are heavily involved in DNA repair and chromatin remodeling. Since cancer cells shift their energy production pathway, NAD levels are significantly affected. NAD's roles in cell survival led to the use of NAD depletion in cancer therapies. NAMPT inhibition (alone or in combination with other cancer therapies, including endocrine therapy and chemotherapy) results in decreased cell viability and tumor burden for many cancer types. Many NAMPT inhibitors (NAMPTi) tested before were discontinued due to toxicity; however, a novel NAMPTi, KPT-9274, is a promising, low-toxicity option currently in clinical trials.

Keywords:  NAD; NAMPT; cancer; metabolism

DOI:  https://doi.org/10.1210/endocr/bqae043
Res Sq. 2024 Mar 11. pii: rs.3.rs-4020184. [Epub ahead of print]

Association between class III obesity and overall survival in previously untreated younger patients with acute myeloid leukemia enrolled on SWOG S1203.

Mary-Elizabeth Percival, Michelle Zhang, Megan Othus, Kerry McMillen, Harry Erba, Guillermo Garcia-Manero, John Pagel, Mohamed Sorror.

There has been ongoing debate on the association between obesity and outcomes in acute myeloid leukemia (AML). Currently there are few studies that have stratified outcomes by class I obesity, class II obesity, and class III obesity; and a more nuanced understanding is becoming increasingly important with the rising prevalence of obesity. We examined the association between body mass index (BMI) and outcomes in previously untreated AML in younger patients (age ≤60) enrolled in SWOG S1203 (n=729). Class III obesity was associated with an increased rate of early death (p=0.004) and worse overall survival (OS) in multivariate analysis (hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.62-3.80 versus normal weight). Class III obesity was also associated with worse OS after allogeneic hematopoietic cell transplant (HR 2.37, 95% CI 1.24-4.54 versus normal weight). These findings highlight the unique risk of class III obesity in AML, and the importance of further investigation to better characterize this patient population.

DOI: https://doi.org/10.21203/rs.3.rs-4020184/v1
Nucleosides Nucleotides Nucleic Acids. 2024 Mar 31. 1-11

Anticancer sensitivity and biological aspect of 5-fluorouracil-resistant human colorectal cancer HCT116 cells in three-dimensional culture under high- and low-glucose conditions.

Chinatsu Kurasaka, Nana Nishizawa, Yoko Ogino, Akira Sato.

  5-Fluorouracil (5-FU) is a commonly used anticancer drug for colorectal cancer (CRC). Therefore, it is crucial to elucidate the mechanisms that contribute to 5-FU resistance. We established an acquired 5-FU resistant cell line, HCT116RF10, derived from CRC cells and investigated its energy metabolism as well as the underlying mechanism of 5-FU resistance. We examined the sensitivity to 5-FU and the formation of tumor spheres in parental HCT116 cells and 5-FU-resistant HCT116RF10 cells under 3D culture conditions at high-glucose (HG 25 mM) and low-glucose (LG 5.5 mM) concentrations. These results suggested that the tumor spheres of parental HCT116 cells displayed higher sensitivity to 5-FU under LG conditions than under HG conditions. HCT116RF10 tumor spheres exhibited comparable sensitivity to 5-FU under HG and LG conditions. Furthermore, under HG conditions, there was a marked decrease in extracellular lactate in the HCT116RF10 tumor sphere compared to that in the LG tumor sphere. Similarly, HCT116 tumor spheres showed decreased extracellular lactate levels under LG conditions compared to those grown under HG conditions. Moreover, the evidence reveals that the tumor spheres of HCT116RF10 and HCT116 cells exhibit disparate dependencies on energy metabolism, glycolysis, and mitochondrial respiration under both HG and LG conditions. These results have important clinical implications for overcoming 5-FU resistance and enhancing antitumor treatment strategies.

Keywords:  3D culture; 5-fluorouracil; colorectal cancer cells; drug resistance; tumor sphere

DOI:  https://doi.org/10.1080/15257770.2024.2332414
Eur J Clin Nutr. 2024 Apr 05.

Malnutrition, sarcopenia and cachexia: exploring prevalence, overlap, and perceptions in older adults with cancer.

Alex F Bullock, Michael J Patterson, Lewis W Paton, David C Currow, Miriam J Johnson.

BACKGROUND: Older adults with cancer are a growing population requiring tailored care to achieve optimum treatment outcomes. Their care is complicated by under-recognised and under-treated wasting disorders: malnutrition, sarcopenia, and cachexia. We aimed to investigate the prevalence, overlap, and patients' views and experiences of malnutrition, sarcopenia, and cachexia, in older adults with cancer.
METHODS: Mixed-methods study with cross-sectional study and qualitative interviews. Interviews were thematically analysed through a phenomenological lens, with feedback loop analysis investigating relationships between themes and findings synthesised using modified critical interpretative synthesis.
FINDINGS: n = 30 were screened for malnutrition, sarcopenia, and cachexia, n = 8 completed semi-structured interviews. Eighteen (60.0%) were malnourished, 16 (53.3%) sarcopenic, and 17 (56.7%) cachexic. One or more condition was seen in 80%, and all three in 30%. In univariate analysis, Rockwood clinical frailty score (OR 2.94 [95% CI: 1.26-6.89, p = 0.013]) was associated with sarcopenia, reported percentage meal consumption (OR 2.28 [95% CI: 1.24-4.19, p = 0.008]), and visible wasting (OR 8.43 [95% CI: 1.9-37.3] p = 0.005) with malnutrition, and percentage monthly weight loss (OR 8.71 [95% CI: 1.87-40.60] p = 0.006) with cachexia. Screening tools identified established conditions rather than 'risk'. Nutritional and functional problems were often overlooked, overshadowed, and misunderstood by both patients and (in patients' perceptions) by clinicians; misattributed to ageing, cancer, or comorbidities. Patients viewed these conditions as both personal impossibilities, yet accepted inevitabilities.
CONCLUSION: Perceptions, identification, and management of these conditions needs to improve, and their importance recognised by clinicians and patients so those truly 'at risk' are identified whilst conditions are more remediable to interventions.

DOI: https://doi.org/10.1038/s41430-024-01433-9
Pediatr Blood Cancer. 2024 Mar 31. e30980

Proteomic insights into paediatric cancer: Unravelling molecular signatures and therapeutic opportunities.

Bhavna D Padhye, Urwah Nawaz, Peter G Hains, Roger R Reddel, Phillip J Robinson, Qing Zhong, Rebecca C Poulos.

  Survival rates in some paediatric cancers have improved greatly over recent decades, in part due to the identification of diagnostic, prognostic and predictive molecular signatures, and the development of risk-directed therapies. However, other paediatric cancers have proved difficult to treat, and there is an urgent need to identify novel biomarkers that reveal therapeutic opportunities. The proteome is the total set of expressed proteins present in a cell or tissue at a point in time, and is vastly more dynamic than the genome. Proteomics holds significant promise for cancer research, as proteins are ultimately responsible for cellular phenotype and are the target of most anticancer drugs. Here, we review the discoveries, opportunities and challenges of proteomic analyses in paediatric cancer, with a focus on mass spectrometry (MS)-based approaches. Accelerating incorporation of proteomics into paediatric precision medicine has the potential to improve survival and quality of life for children with cancer.

Keywords:  biomarkers; machine learning; mass spectrometry; paediatric cancer; precision medicine; proteomics

DOI:  https://doi.org/10.1002/pbc.30980
Nutrition. 2024 Feb 26. pii: S0899-9007(24)00060-1. [Epub ahead of print]123 112410

Branched-chain amino acid supplementation drives dynamic changes in gut microbiota without impairing glucose and lipid homeostasis at the different stages of insulin resistance in mice on a high-fat diet.

Rui Liu, Yang Yang, Guanjin Shi, Lei Zhang.

   OBJECTIVE: The potential role of dietary branched-chain amino acids on circulating branched-chain amino acid levels and their relationship with metabolic health are complex, and the literature is inconsistent. We aimed to explore the dynamic effects of branched-chain amino acid supplementation on glucose and lipid homeostasis at different stages of insulin resistance in high-fat diet-fed mice.
METHODS: Male C57BL/6J mice were fed with a normal chow diet, high-fat diet, or high-fat diet supplemented with 100% branched-chain amino acids for 12 or 24 wk. Metabolic parameters and gut microbiota profiling were performed at these two time points.
RESULTS: High-fat diet feeding caused varying degrees of branched-chain amino acid metabolic disorders in two different stages of insulin resistance. Supplementing with branched-chain amino acids further exacerbated branched-chain amino acid accumulation in the early stage of insulin resistance (12 wk), while adding branched-chain amino acids did not further elevate branched-chain amino acid levels in the hyperglycemia and hyperinsulinemia stage (24 wk). Compared with the high-fat diet group, branched-chain amino acid supplementation did not affect body weight; liver total cholesterol and triacylglycerol levels; and serum glucose, insulin, total cholesterol, triacylglycerol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels as well as glucose tolerance at these two time points but triggered dynamic changes in the gut bacterial diversity and gut microbiota composition and abundance, especially in the genus associated with obesity and related metabolic disorders.
CONCLUSION: Dietary branched-chain amino acid supplementation drives dynamic changes in circulating branched-chain amino acid levels and gut microbiome without subsequent effects on glucose and lipid homeostasis in high-fat diet-induced obese mice within the parameters of our study.

Keywords:  Branched-chain amino acids; Glucose and lipids homeostasis; Gut microbiota; High-fat diet; Insulin resistance

DOI:  https://doi.org/10.1016/j.nut.2024.112410
Front Nutr. 2024 ;11 1338392

Changes in the consumption of isoflavones, omega-6, and omega-3 fatty acids in women with metastatic breast cancer adopting a whole-food, plant-based diet: post-hoc analysis of nutrient intake data from an 8-week randomized controlled trial.

Jean Lee, Erin K Campbell, Eva Culakova, Lisa M Blanchard, Nellie Wixom, Luke J Peppone, Thomas M Campbell.

   Background: Diets rich in minimally processed plant-based foods are recommended to breast cancer patients, and some may have an interest in whole-food, plant-based (WFPB) diets that avoid animal-based foods, added fats, and refined sugars. Within WFPB diets, the intakes of isoflavones, omega-6 polyunsaturated fatty acids (n-6 PUFAs), and omega-3 polyunsaturated FAs (n-3 PUFAs), which have been discussed in reference to breast cancer outcomes, have not been well characterized.
Methods: Women with stage IV breast cancer on stable therapy were randomized 2:1 into (1) a WFPB intervention (N = 21) or (2) usual care (N = 11) for 8 weeks. Three meals per day were provided. Outcomes presented here include dietary intake of isoflavones, n-3 and n-6- PUFAs, which were assessed using three-day food records at baseline and 8 weeks. Baseline and 8-week mean intake within groups were compared using the Wilcoxon signed-rank test and between control and intervention groups by a two-sample t-test.
Results: The WFPB intervention participants increased their daily consumption of total isoflavones from a mean of 0.8 mg/day to 14.5 mg/day (p < 0.0001) and decreased the n-6:n-3 ratio of their diet from a mean of 9.3 to 3.7 (p < 0.0001). Within the WFPB group, linoleic acid (n-6 PUFA) consumption decreased by a mean of 3.8 g (p = 0.0095), from 12.8 g/day to 9.0 g/day; total n-3 PUFA consumption increased by a mean of 1.1 g (p = 0.0005), from 1.6 g/day to 2.7 g/day.
Conclusion: Transitioning to a WFPB diet resulted in significantly increased isoflavone intake and decreased n-6:n-3 ratio in women with breast cancer.

Keywords:  breast cancer; isoflavones; omega-3 polyunsaturated fatty acids; omega-6 polyunsaturated fatty acids; omega-6/-3 ratio; plant-based diet; soy; vegan diet

DOI:  https://doi.org/10.3389/fnut.2024.1338392
Elife. 2024 Apr 02. pii: RP90532. [Epub ahead of print]12

Unveiling the signaling network of FLT3-ITD AML improves drug sensitivity prediction.

Sara Latini, Veronica Venafra, Giorgia Massacci, Valeria Bica, Simone Graziosi, Giusj Monia Pugliese, Marta Iannuccelli, Filippo Frioni, Gessica Minnella, John Donald Marra, Patrizia Chiusolo, Gerardo Pepe, Manuela Helmer Citterich, Dimitros Mougiakakos, Martin Böttcher, Thomas Fischer, Livia Perfetto, Francesca Sacco.

  Currently, the identification of patient-specific therapies in cancer is mainly informed by personalized genomic analysis. In the setting of acute myeloid leukemia (AML), patient-drug treatment matching fails in a subset of patients harboring atypical internal tandem duplications (ITDs) in the tyrosine kinase domain of the FLT3 gene. To address this unmet medical need, here we develop a systems-based strategy that integrates multiparametric analysis of crucial signaling pathways, and patient-specific genomic and transcriptomic data with a prior knowledge signaling network using a Boolean-based formalism. By this approach, we derive personalized predictive models describing the signaling landscape of AML FLT3-ITD positive cell lines and patients. These models enable us to derive mechanistic insight into drug resistance mechanisms and suggest novel opportunities for combinatorial treatments. Interestingly, our analysis reveals that the JNK kinase pathway plays a crucial role in the tyrosine kinase inhibitor response of FLT3-ITD cells through cell cycle regulation. Finally, our work shows that patient-specific logic models have the potential to inform precision medicine approaches.

Keywords:  Boolean model; acute myeloid leukemia; cancer biology; cancer therapy; computational biology; drug resistance; human; mouse; systems biology; tyrosine kinase

DOI:  https://doi.org/10.7554/eLife.90532
Nat Struct Mol Biol. 2024 Apr 04.

SCAF1 drives the compositional diversity of mammalian respirasomes.

Irene Vercellino, Leonid A Sazanov.

Supercomplexes of the respiratory chain are established constituents of the oxidative phosphorylation system, but their role in mammalian metabolism has been hotly debated. Although recent studies have shown that different tissues/organs are equipped with specific sets of supercomplexes, depending on their metabolic needs, the notion that supercomplexes have a role in the regulation of metabolism has been challenged. However, irrespective of the mechanistic conclusions, the composition of various high molecular weight supercomplexes remains uncertain. Here, using cryogenic electron microscopy, we demonstrate that mammalian (mouse) tissues contain three defined types of 'respirasome', supercomplexes made of CI, CIII2 and CIV. The stoichiometry and position of CIV differs in the three respirasomes, of which only one contains the supercomplex-associated factor SCAF1, whose involvement in respirasome formation has long been contended. Our structures confirm that the 'canonical' respirasome (the C-respirasome, CICIII2CIV) does not contain SCAF1, which is instead associated to a different respirasome (the CS-respirasome), containing a second copy of CIV. We also identify an alternative respirasome (A-respirasome), with CIV bound to the 'back' of CI, instead of the 'toe'. This structural characterization of mouse mitochondrial supercomplexes allows us to hypothesize a mechanistic basis for their specific role in different metabolic conditions.

DOI: https://doi.org/10.1038/s41594-024-01255-0
J Nanobiotechnology. 2024 Apr 03. 22(1): 147

GSH-responsive degradable nanodrug for glucose metabolism intervention and induction of ferroptosis to enhance magnetothermal anti-tumor therapy.

Zhen Liao, E Wen, Yi Feng.

  The challenges associated with activating ferroptosis for cancer therapy primarily arise from obstacles related to redox and iron homeostasis, which hinder the susceptibility of tumor cells to ferroptosis. However, the specific mechanisms of ferroptosis resistance, especially those intertwined with abnormal metabolic processes within tumor cells, have been consistently underestimated. In response, we present an innovative glutathione-responsive magnetocaloric therapy nanodrug termed LFMP. LFMP consists of lonidamine (LND) loaded into PEG-modified magnetic nanoparticles with a Fe3O4 core and coated with disulfide bonds-bridged mesoporous silica shells. This nanodrug is designed to induce an accelerated ferroptosis-activating state in tumor cells by disrupting homeostasis. Under the dual effects of alternating magnetic fields and high concentrations of glutathione in the tumor microenvironment, LFMP undergoes disintegration, releasing drugs. LND intervenes in cell metabolism by inhibiting glycolysis, ultimately enhancing iron death and leading to synthetic glutathione consumption. The disulfide bonds play a pivotal role in disrupting intracellular redox homeostasis by depleting glutathione and inactivating glutathione peroxidase 4 (GPX4), synergizing with LND to enhance the sensitivity of tumor cells to ferroptosis. This process intensifies oxidative stress, further impairing redox homeostasis. Furthermore, LFMP exacerbates mitochondrial dysfunction, triggering ROS formation and lactate buildup in cancer cells, resulting in increased acidity and subsequent tumor cell death. Importantly, LFMP significantly suppresses tumor cell proliferation with minimal side effects both in vitro and in vivo, exhibiting satisfactory T2-weighted MR imaging properties. In conclusion, this magnetic hyperthermia-based nanomedicine strategy presents a promising and innovative approach for antitumor therapy.

Keywords:  Ferroptosis; Magnetothermal therapy; Mesoporous silica nanoparticle; Metabolic interference; Redox homeostasis

DOI:  https://doi.org/10.1186/s12951-024-02425-4
PNAS Nexus. 2024 Apr;3(4): pgae116

Vitamin B12 status and folic acid supplementation influence mitochondrial heteroplasmy levels in mice.

Darren J Walsh, David J Bernard, Joanna L Fiddler, Faith Pangilinan, Madison Esposito, Denise Harold, Martha S Field, Anne Parle-McDermott, Lawrence C Brody.

  One-carbon metabolism is a complex network of metabolic reactions that are essential for cellular function including DNA synthesis. Vitamin B12 and folate are micronutrients that are utilized in this pathway and their deficiency can result in the perturbation of one-carbon metabolism and subsequent perturbations in DNA replication and repair. This effect has been well characterized in nuclear DNA but to date, mitochondrial DNA (mtDNA) has not been investigated extensively. Mitochondrial variants have been associated with several inherited and age-related disease states; therefore, the study of factors that impact heteroplasmy are important for advancing our understanding of the mitochondrial genome's impact on human health. Heteroplasmy studies require robust and efficient mitochondrial DNA enrichment to carry out in-depth mtDNA sequencing. Many of the current methods for mtDNA enrichment can introduce biases and false-positive results. Here, we use a method that overcomes these limitations and have applied it to assess mitochondrial heteroplasmy in mouse models of altered one-carbon metabolism. Vitamin B12 deficiency was found to cause increased levels of mitochondrial DNA heteroplasmy across all tissues that were investigated. Folic acid supplementation also contributed to elevated mitochondrial DNA heteroplasmy across all mouse tissues investigated. Heteroplasmy analysis of human data from the Framingham Heart Study suggested a potential sex-specific effect of folate and vitamin B12 status on mitochondrial heteroplasmy. This is a novel relationship that may have broader consequences for our understanding of one-carbon metabolism, mitochondrial-related disease and the influence of nutrients on DNA mutation rates.

Keywords:  cobalamin; folic acid; heteroplasmy; mitochondria; vitamin B12

DOI:  https://doi.org/10.1093/pnasnexus/pgae116
Biochem Biophys Res Commun. 2024 Mar 26. pii: S0006-291X(24)00348-6. [Epub ahead of print]709 149812

Allosteric SHP2 inhibition enhances regorafenib's effectiveness in colorectal cancer treatment.

Xiao Han, Weicheng Wang, Rui Wang, Wei Zhang, Lijun Zhu, Qiang Xu, Wenjie Guo, Yanhong Gu.

  Colorectal cancer (CRC) is the third most common cancer globally. Regorafenib, a multi-target kinase inhibitor, has been approved for treating metastatic colorectal cancer patients who have undergone at least two prior standard anti-cancer therapies. However, regorafenib efficacy as a single agent remains suboptimal. A promising target at the crossroads of multiple signaling pathways is the Src homology 2 domain-containing protein tyrosine phosphatase (SHP2). However, a combination approach using SHP2 inhibitors (SHP099) and anti-angiogenic drugs (Regorafenib) has not been reported in current research. In this study, we conducted in vitro experiments combining SHP099 and regorafenib and established an MC-38 colon cancer allograft mouse model. Our results revealed that co-treatment with SHP099 and regorafenib significantly inhibited cell viability and altered the biological characteristics of tumor cells compared with treatment alone in vitro. Furthermore, the combination strategy demonstrated superior therapeutic efficacy compared to monotherapy with either drug. This was evidenced by reduced tumor size, decreased proliferation, increased apoptosis, normalized tumor microvasculature, and improved antitumor immune response in vivo. These findings suggest that the combination of an SHP2 inhibitor and regorafenib is a promising therapeutic approach for patients with colorectal cancer.

Keywords:  Colorectal cancer; Regorafenib; SHP099; SHP2 inhibitor; VEGFR

DOI:  https://doi.org/10.1016/j.bbrc.2024.149812