bims-medica 2024-06-09 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024‒06‒09
seventeen papers selected by
Brett Chrest, East Carolina University

Imaging brain glucose metabolism in vivo reveals propionate as a major anaplerotic substrate in pyruvate dehydrogenase deficiency.
Ketogenic diet enhances the anti-cancer effects of PD-L1 blockade in renal cell carcinoma.
Metabolic dysregulation of tricarboxylic acid cycle and oxidative phosphorylation in glioblastoma.
Association between class III obesity and overall survival in previously untreated younger patients with acute myeloid leukemia enrolled on SWOG S1203.
CPT1A loss disrupts BCAA metabolism to confer therapeutic vulnerability in TP53-mutated liver cancer.
De novo and salvage purine synthesis pathways across tissues and tumors.
Obesogenic High-Fat Diet and MYC Cooperate to Promote Lactate Accumulation and Tumor Microenvironment Remodeling in Prostate Cancer.
Merging Metabolic Modeling and Imaging for Screening Therapeutic Targets in Colorectal Cancer.
Protocol for separating cancer cell subpopulations by metabolic activity using flow cytometry.
Liver mitochondrial coupling efficiency and its relationship to oxidative capacity and adenine nucleotide translocase content: A comparative study among crocodiles, birds and mammals.
Skeletal muscle PGC-1α remodels mitochondrial phospholipidome but does not alter energy efficiency for ATP synthesis.
IDH1 inhibition potentiates chemotherapy efficacy in pancreatic cancer.
Hungry for fat: Metabolic crosstalk with lipid-rich CAFs fuels pancreatic cancer.
Dietary intake, obesity, and physical activity in association with biliary tract cancer risk: Results from meta-analyses of individual-level data from prospective cohort studies of 723,326 adults.
Bidirectional relationship between pancreatic cancer and diabetes mellitus: a comprehensive literature review.
Sweet dreams could be made of this: carbohydrate-responsive element-binding protein (ChREBP) as a target for hepatocellular carcinoma therapy.
Dose-dependent effects of Dnmt3a in an inducible murine model of KrasG12D-driven leukemia.

Cell Metab. 2024 Jun 04. pii: S1550-4131(24)00178-5. [Epub ahead of print]36(6): 1394-1410.e12

Imaging brain glucose metabolism in vivo reveals propionate as a major anaplerotic substrate in pyruvate dehydrogenase deficiency.

Isaac Marin-Valencia, Arif Kocabas, Carlos Rodriguez-Navas, Vesselin Z Miloushev, Manuel González-Rodríguez, Hannah Lees, Kelly E Henry, Jake Vaynshteyn, Valerie Longo, Kofi Deh, Roozbeh Eskandari, Arsen Mamakhanyan, Marjan Berishaj, Kayvan R Keshari.

  A vexing problem in mitochondrial medicine is our limited capacity to evaluate the extent of brain disease in vivo. This limitation has hindered our understanding of the mechanisms that underlie the imaging phenotype in the brain of patients with mitochondrial diseases and our capacity to identify new biomarkers and therapeutic targets. Using comprehensive imaging, we analyzed the metabolic network that drives the brain structural and metabolic features of a mouse model of pyruvate dehydrogenase deficiency (PDHD). As the disease progressed in this animal, in vivo brain glucose uptake and glycolysis increased. Propionate served as a major anaplerotic substrate, predominantly metabolized by glial cells. A combination of propionate and a ketogenic diet extended lifespan, improved neuropathology, and ameliorated motor deficits in these animals. Together, intermediary metabolism is quite distinct in the PDHD brain-it plays a key role in the imaging phenotype, and it may uncover new treatments for this condition.

Keywords:  brain; glucose; imaging; ketogenic diet; metabolism; propionate; pyruvate; pyruvate dehydrogenase deficiency

DOI:  https://doi.org/10.1016/j.cmet.2024.05.002
Front Endocrinol (Lausanne). 2024 ;15 1344891

Ketogenic diet enhances the anti-cancer effects of PD-L1 blockade in renal cell carcinoma.

Jeremy Richard, Céline Beauvillain, Maxime Benoit, Magalie Barth, Cécile Aubert, Cyrielle Rolley, Sarah Bellal, Jennifer Bourreau, Matthieu Ferragu, Souhil Lebdai, Arnaud Chevrollier, Daniel Henrion, Vincent Procaccio, Pierre Bigot.

  Introduction: Clear cell renal cell carcinoma (ccRCC) is characterized by a predominant metabolic reprogramming triggering energy production by anaerobic glycolysis at the expense of oxydative phosphorylation. Ketogenic diet (KD), which consists of high fat and low carbohydrate intake, could bring required energy substrates to healthy cells while depriving tumor cells of glucose. Our objective was to evaluate the effect of KD on renal cancer cell tumor metabolism and growth proliferation.Methods: Growth cell proliferation and mitochondrial metabolism of ACHN and Renca renal carcinoma cells were evaluated under ketone bodies (KB) exposure. In vivo studies were performed with mice (nude or Balb/c) receiving a xenograft of ACHN cells or Renca cells, respectively, and were then split into 2 feeding groups, fed either with standard diet or a 2:1 KD ad libitum. To test the effect of KD associated to immunotherapy, Balb/c mice were treated with anti-PDL1 mAb. Tumor growth was monitored.
Results: In vitro, KB exposure was associated with a significant reduction of ACHN and Renca cell proliferation and viability, while increasing mitochondrial metabolism. In mice, KD was associated with tumor growth reduction and PDL-1 gene expression up-regulation. In Balb/c mice adjuvant KD was associated to a better response to anti-PDL-1 mAb treatment.
Conclusion: KB reduced the renal tumor cell growth proliferation and improved mitochondrial respiration and biogenesis. KD also slowed down tumor growth of ACHN and Renca in vivo. We observed that PDL-1 was significantly overexpressed in tumor in mice under KD. Response to anti-PDL-1 mAb was improved in mice under KD. Further studies are needed to confirm the therapeutic benefit of adjuvant KD combined with immunotherapy in patients with kidney cancer.

Keywords:  PDL1; adjuvant ketogenic diet; immunotherapy; metabolic reprogramming; mitochondrial biogenesis; renal cell carcinoma

DOI:  https://doi.org/10.3389/fendo.2024.1344891
Rev Neurosci. 2024 Jun 07.

Metabolic dysregulation of tricarboxylic acid cycle and oxidative phosphorylation in glioblastoma.

Cristina Trejo-Solís, Norma Serrano-García, Rosa Angelica Castillo-Rodríguez, Diana Xochiquetzal Robledo-Cadena, Dolores Jimenez-Farfan, Álvaro Marín-Hernández, Daniela Silva-Adaya, Citlali Ekaterina Rodríguez-Pérez, Juan Carlos Gallardo-Pérez.

  Glioblastoma multiforme (GBM) exhibits genetic alterations that induce the deregulation of oncogenic pathways, thus promoting metabolic adaptation. The modulation of metabolic enzyme activities is necessary to generate nucleotides, amino acids, and fatty acids, which provide energy and metabolic intermediates essential for fulfilling the biosynthetic needs of glioma cells. Moreover, the TCA cycle produces intermediates that play important roles in the metabolism of glucose, fatty acids, or non-essential amino acids, and act as signaling molecules associated with the activation of oncogenic pathways, transcriptional changes, and epigenetic modifications. In this review, we aim to explore how dysregulated metabolic enzymes from the TCA cycle and oxidative phosphorylation, along with their metabolites, modulate both catabolic and anabolic metabolic pathways, as well as pro-oncogenic signaling pathways, transcriptional changes, and epigenetic modifications in GBM cells, contributing to the formation, survival, growth, and invasion of glioma cells. Additionally, we discuss promising therapeutic strategies targeting key players in metabolic regulation. Therefore, understanding metabolic reprogramming is necessary to fully comprehend the biology of malignant gliomas and significantly improve patient survival.

Keywords:  glioma; metabolism; oncogenic signaling pathways

DOI:  https://doi.org/10.1515/revneuro-2024-0054
Leukemia. 2024 Jun 03.

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

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

There has been ongoing debate on the association between obesity and outcomes in acute myeloid leukemia (AML). Currently few studies 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/10.1038/s41375-024-02288-6
Cancer Lett. 2024 May 31. pii: S0304-3835(24)00400-2. [Epub ahead of print]595 217006

CPT1A loss disrupts BCAA metabolism to confer therapeutic vulnerability in TP53-mutated liver cancer.

Yanfeng Liu, Fan Wang, Guoquan Yan, Yu Tong, Wenyun Guo, Songling Li, Yifei Qian, Qianyu Li, Yu Shu, Lei Zhang, Yonglong Zhang, Qiang Xia.

  Driver genomic mutations in tumors define specific molecular subtypes that display distinct malignancy competence, therapeutic resistance and clinical outcome. Although TP53 mutation has been identified as the most common mutation in hepatocellular carcinoma (HCC), current understanding on the biological traits and therapeutic strategies of this subtype has been largely unknown. Here, we reveal that fatty acid β oxidation (FAO) is remarkable repressed in TP53 mutant HCC and which links to poor prognosis in HCC patients. We further demonstrate that carnitine palmitoyltransferase 1 (CPT1A), the rate-limiting enzyme of FAO, is universally downregulated in liver tumor tissues, and which correlates with poor prognosis in HCC and promotes HCC progression in the de novo liver tumor and xenograft tumor models. Mechanically, hepatic Cpt1a loss disrupts lipid metabolism and acetyl-CoA production. Such reduction in acetyl-CoA reduced histone acetylation and epigenetically reprograms branched-chain amino acids (BCAA) catabolism, and leads to the accumulation of cellular BCAAs and hyperactivation of mTOR signaling. Importantly, we reveal that genetic ablation of CPT1A renders TP53 mutant liver cancer mTOR-addicted and sensitivity to mTOR inhibitor AZD-8055 treatment. Consistently, Cpt1a loss in HCC directs tumor cell therapeutic response to AZD-8055. CONCLUSION: Our results show genetic evidence for CPT1A as a metabolic tumor suppressor in HCC and provide a therapeutic approach for TP53 mutant HCC patients.

Keywords:  BCAA metabolism; CPT1A; Fatty acid β oxidation; Hepatocellular carcinoma; TP53 mutant

DOI:  https://doi.org/10.1016/j.canlet.2024.217006
Cell. 2024 May 30. pii: S0092-8674(24)00520-8. [Epub ahead of print]

De novo and salvage purine synthesis pathways across tissues and tumors.

Diem H Tran, Dohun Kim, Rushendhiran Kesavan, Harrison Brown, Trishna Dey, Mona Hoseini Soflaee, Hieu S Vu, Alpaslan Tasdogan, Jason Guo, Divya Bezwada, Houssam Al Saad, Feng Cai, Ashley Solmonson, Halie Rion, Rawand Chabatya, Salma Merchant, Nathan J Manales, Vanina T Tcheuyap, Megan Mulkey, Thomas P Mathews, James Brugarolas, Sean J Morrison, Hao Zhu, Ralph J DeBerardinis, Gerta Hoxhaj.

  Purine nucleotides are vital for RNA and DNA synthesis, signaling, metabolism, and energy homeostasis. To synthesize purines, cells use two principal routes: the de novo and salvage pathways. Traditionally, it is believed that proliferating cells predominantly rely on de novo synthesis, whereas differentiated tissues favor the salvage pathway. Unexpectedly, we find that adenine and inosine are the most effective circulating precursors for supplying purine nucleotides to tissues and tumors, while hypoxanthine is rapidly catabolized and poorly salvaged in vivo. Quantitative metabolic analysis demonstrates comparative contribution from de novo synthesis and salvage pathways in maintaining purine nucleotide pools in tumors. Notably, feeding mice nucleotides accelerates tumor growth, while inhibiting purine salvage slows down tumor progression, revealing a crucial role of the salvage pathway in tumor metabolism. These findings provide fundamental insights into how normal tissues and tumors maintain purine nucleotides and highlight the significance of purine salvage in cancer.

Keywords:  cancer metabolism; de novo purine synthesis; in vivo isotope tracing; nucleotide diet; nucleotide metabolism; purine bases; purine degradation; purine salvage; tissue; tumor growth

DOI:  https://doi.org/10.1016/j.cell.2024.05.011
Cancer Res. 2024 Jun 04. 84(11): 1834-1855

Obesogenic High-Fat Diet and MYC Cooperate to Promote Lactate Accumulation and Tumor Microenvironment Remodeling in Prostate Cancer.

Nadia Boufaied, Paolo Chetta, Tarek Hallal, Stefano Cacciatore, Daniela Lalli, Carole Luthold, Kevin Homsy, Eddie L Imada, Sudeepa Syamala, Cornelia Photopoulos, Anna Di Matteo, Anna de Polo, Alessandra Maria Storaci, Ying Huang, Francesca Giunchi, Patricia A Sheridan, Gregory Michelotti, Quang-De Nguyen, Xin Zhao, Yang Liu, Elai Davicioni, Daniel E Spratt, Simone Sabbioneda, Giovanni Maga, Lorelei A Mucci, Claudia Ghigna, Luigi Marchionni, Lisa M Butler, Leigh Ellis, François Bordeleau, Massimo Loda, Valentina Vaira, David P Labbé, Giorgia Zadra.

Cancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation of metabolites that reprogram the tumor microenvironment (TME) and drive cancer could facilitate development of precision nutrition approaches. Using the Hi-MYC prostate cancer mouse model, we demonstrated that an obesogenic high-fat diet (HFD) rich in saturated fats accelerates the development of c-MYC-driven invasive prostate cancer through metabolic rewiring. Although c-MYC modulated key metabolic pathways, interaction with an obesogenic HFD was necessary to induce glycolysis and lactate accumulation in tumors. These metabolic changes were associated with augmented infiltration of CD206+ and PD-L1+ tumor-associated macrophages (TAM) and FOXP3+ regulatory T cells, as well as with the activation of transcriptional programs linked to disease progression and therapy resistance. Lactate itself also stimulated neoangiogenesis and prostate cancer cell migration, which were significantly reduced following treatment with the lactate dehydrogenase inhibitor FX11. In patients with prostate cancer, high saturated fat intake and increased body mass index were associated with tumor glycolytic features that promote the infiltration of M2-like TAMs. Finally, upregulation of lactate dehydrogenase, indicative of a lactagenic phenotype, was associated with a shorter time to biochemical recurrence in independent clinical cohorts. This work identifies cooperation between genetic drivers and systemic metabolism to hijack the TME and promote prostate cancer progression through oncometabolite accumulation. This sets the stage for the assessment of lactate as a prognostic biomarker and supports strategies of dietary intervention and direct lactagenesis blockade in treating advanced prostate cancer.SIGNIFICANCE: Lactate accumulation driven by high-fat diet and MYC reprograms the tumor microenvironment and promotes prostate cancer progression, supporting the potential of lactate as a biomarker and therapeutic target in prostate cancer. See related commentary by Frigo, p. 1742.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-0519
bioRxiv. 2024 May 25. pii: 2024.05.24.595756. [Epub ahead of print]

Merging Metabolic Modeling and Imaging for Screening Therapeutic Targets in Colorectal Cancer.

Niki Tavakoli, Emma J Fong, Abigail Coleman, Yu-Kai Huang, Mathias Bigger, Michael E Doche, Seungil Kim, Heinz-Josef Lenz, Nicholas A Graham, Paul Macklin, Stacey D Finley, Shannon M Mumenthaler.

Cancer-associated fibroblasts (CAFs) play a key role in metabolic reprogramming and are well-established contributors to drug resistance in colorectal cancer (CRC). To exploit this metabolic crosstalk, we integrated a systems biology approach that identified key metabolic targets in a data-driven method and validated them experimentally. This process involved high-throughput computational screening to investigate the effects of enzyme perturbations predicted by a computational model of CRC metabolism to understand system-wide effects efficiently. Our results highlighted hexokinase (HK) as one of the crucial targets, which subsequently became our focus for experimental validation using patient-derived tumor organoids (PDTOs). Through metabolic imaging and viability assays, we found that PDTOs cultured in CAF conditioned media exhibited increased sensitivity to HK inhibition. Our approach emphasizes the critical role of integrating computational and experimental techniques in exploring and exploiting CRC-CAF crosstalk.

DOI: https://doi.org/10.1101/2024.05.24.595756
STAR Protoc. 2024 Jun 01. pii: S2666-1667(24)00270-3. [Epub ahead of print]5(2): 103105

Protocol for separating cancer cell subpopulations by metabolic activity using flow cytometry.

Wiktoria Blaszczak, Bobby White, Pawel Swietach.

  Cells, even from the same line, can maintain heterogeneity in metabolic activity. Here, we present a protocol, adapted for fluorescence-activated cell sorting (FACS), that separates resuspended cells according to their metabolic rate. We describe steps for driving lactate efflux, which produces an alkaline transient proportional to fermentative rate. This pH signature, measured using pH-sensitive dyes, identifies cells with the highest metabolic rate. We then describe a fluorimetric assay of oxygen consumption and acid production to confirm the metabolic contrast between subpopulations. For complete details on the use and execution of this protocol, please refer to Blaszczak et al.1.

Keywords:  Cancer; Flow Cytometry; Metabolism

DOI:  https://doi.org/10.1016/j.xpro.2024.103105
Mitochondrion. 2024 Jun 04. pii: S1567-7249(24)00067-9. [Epub ahead of print] 101909

Liver mitochondrial coupling efficiency and its relationship to oxidative capacity and adenine nucleotide translocase content: A comparative study among crocodiles, birds and mammals.

Damien Roussel, Nathan Roussel, Yann Voituron, Benjamin Rey.

  The primary objective of this study was to assess whether adenine nucleotide translocase (ANT) content could be associated with phylogenetic disparities in mitochondrial coupling efficiency, within liver mitochondria obtained from rats, crocodiles, and ducklings. Our measurements included mitochondrial membrane conductance, ANT content, and oxidative phosphorylation fluxes at various steady-state rates. We observed significant variations in liver mitochondrial coupling efficiency across the three species. These variations correlated with interspecific differences in mitochondrial oxidative capacity and, to a lesser extent, the ANT content of liver mitochondria. These findings expand upon previous research by highlighting the pivotal role of oxidative capacity and ANT in modulating mitochondrial efficiency on an interspecific scale.

Keywords:  Adenine nucleotide translocase (ANT); Archosaurs; Liver; Oxidative phosphorylation; Proton leak

DOI:  https://doi.org/10.1016/j.mito.2024.101909
bioRxiv. 2024 May 26. pii: 2024.05.22.595374. [Epub ahead of print]

Skeletal muscle PGC-1α remodels mitochondrial phospholipidome but does not alter energy efficiency for ATP synthesis.

Takuya Karasawa, Ran Hee Choi, Cesar A Meza, J Alan Maschek, James E Cox, Katsuhiko Funai.

  Background: Exercise training is thought to improve the mitochondrial energy efficiency of skeletal muscle. Some studies suggest exercise training increases the efficiency for ATP synthesis by oxidative phosphorylation (OXPHOS), but the molecular mechanisms are unclear. We have previously shown that exercise remodels the lipid composition of mitochondrial membranes, and some of these changes could contribute to improved OXPHOS efficiency (ATP produced by O2 consumed or P/O). Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is a transcriptional co-activator that coordinately regulates exercise-induced adaptations including mitochondria. We hypothesized that increased PGC-1α activity is sufficient to remodel mitochondrial membrane lipids and promote energy efficiency.Methods: Mice with skeletal muscle-specific overexpression of PGC-1α (MCK-PGC-1α) and their wildtype littermates were used for this study. Lipid mass spectrometry and quantitative PCR were used to assess muscle mitochondrial lipid composition and their biosynthesis pathway. The abundance of OXPHOS enzymes was determined by western blot assay. High-resolution respirometry and fluorometry analysis were used to characterize mitochondrial bioenergetics (ATP production, O2 consumption, and P/O) for permeabilized fibers and isolated mitochondria.
Results: Lipidomic analyses of skeletal muscle mitochondria from wildtype and MCK-PGC-1α mice revealed that PGC-1α increases the concentrations of cone-shaped lipids such as phosphatidylethanolamine (PE), cardiolipin (CL), and lysophospholipids, while decreases the concentrations of phosphatidylcholine (PC), phosphatidylinositol (PI) and phosphatidic acid (PA). However, while PGC-1α overexpression increased the abundance of OXPHOS enzymes in skeletal muscle and the rate of O2 consumption (JO2), P/O values were unaffected with PGC-1α in permeabilized fibers or isolated mitochondria.
Conclusions: Collectively, overexpression of PGC-1α promotes the biosynthesis of mitochondrial PE and CL but neither PGC-1α nor the mitochondrial membrane lipid remodeling induced in MCK-PGC-1α mice is sufficient to increase the efficiency for mitochondrial ATP synthesis. These findings suggest that exercise training may increase OXPHOS efficiency by a PGC-1α-independent mechanism, and question the hypothesis that mitochondrial lipids directly affect OXPHOS enzymes to improve efficiency for ATP synthesis.

Keywords:  exercise; mitochondria; phospholipids; skeletal muscle

DOI:  https://doi.org/10.1101/2024.05.22.595374
Cancer Res. 2024 Jun 06.

IDH1 inhibition potentiates chemotherapy efficacy in pancreatic cancer.

Mehrdad Zarei, Omid Hajihassani, Jonathan J Hue, Alexander W Loftus, Hallie J Graor, Faith Nakazzi, Parnian Naji, Christina S Boutros, Vinayak Uppin, Ali Vaziri-Gohar, Akram Shalaby, John M Asara, Luke D Rothermel, Jonathan R Brody, Jordan M Winter.

Pancreatic ductal adenocarcinoma (PDAC) is associated with a five-year overall survival rate of just 13%, and development of chemotherapy resistance is nearly universal. PDAC cells overexpress wild-type IDH1 that can enable them to overcome metabolic stress, suggesting it could represent a therapeutic target in PDAC. Here, we found that anti-IDH1 therapy enhanced the efficacy of conventional chemotherapeutics. Chemotherapy treatment induced ROS and increased TCA cycle activity in PDAC cells, along with the induction of wild-type IDH1 expression as a key resistance factor. IDH1 facilitated PDAC survival following chemotherapy treatment by supporting mitochondrial function and antioxidant defense to neutralize reactive oxygen species through the generation of alpha-ketoglutarate and NADPH, respectively. Pharmacologic inhibition of wild-type IDH1 with ivosidenib synergized with conventional chemotherapeutics in vitro and potentiated the efficacy of sub-therapeutic doses of these drugs in vivo in murine PDAC models. This promising treatment approach is translatable through available and safe oral inhibitors and provides the basis of an open and accruing clinical trial testing this combination (NCT05209074).

DOI: https://doi.org/10.1158/0008-5472.CAN-23-1895
Cell Metab. 2024 Jun 04. pii: S1550-4131(24)00183-9. [Epub ahead of print]36(6): 1172-1174

Hungry for fat: Metabolic crosstalk with lipid-rich CAFs fuels pancreatic cancer.

Kostas A Papavassiliou, Athanasios G Papavassiliou.

Some cancers prefer to metabolize lipids for their growth and metastasis. In a recent Cancer Cell study, Niu et al. revealed that SET domain containing 2, histone lysine methyltransferase (SETD2)-deficient pancreatic cancer cells induce the differentiation of lipid-laden cancer-associated fibroblasts (CAFs), which, in turn, transport lipids to promote tumor growth.

DOI: https://doi.org/10.1016/j.cmet.2024.05.007
Int J Cancer. 2024 Jun 07.

Dietary intake, obesity, and physical activity in association with biliary tract cancer risk: Results from meta-analyses of individual-level data from prospective cohort studies of 723,326 adults.

Valerie Gunchick, Wanqing Wen, Guochong Jia, Lewis R Roberts, Jill Koshiol, Xiao-Ou Shu, Wei Zheng.

  Biliary tract cancer (BTC) is a rare and aggressive malignancy with increasing incidence. Most BTC cases are diagnosed with metastatic disease which carries a 5-year survival rate of <5%. Physical activity, diet, and obesity might be associated with BTC risk, but studies have been limited particularly in African descendants. We addressed this knowledge gap by evaluating associations of BTC risk with obesity, physical activity, and dietary intakes in 723,326 adult participants in four cohort studies conducted in China, the United Kingdom, and the United States. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) in each cohort; results were combined using meta-analysis. All cohorts had ≥11 median follow-up years with 839 incident BTC cases combined. BTC risk was positively associated with body mass index (BMI) and waist-to-hip ratio (WHR) whereas physical activity, fruit intake, and fish intake were inversely associated. HR and (95% CI) comparing BMI >35.0 to 18.5-24.9: 1.71 (1.26, 2.31), p-trend <.0001; comparing BMI-adjusted WHR top to bottom quartile: 1.20 (0.94, 1.53), p-trend = .05; comparing ≥15-0 metabolic equivalent task-hours/week 0.76 (0.61, 0.94), p-trend = .009; comparing highest to lowest intake tertile for fruit and fish 0.79 (0.66, 0.95), p-trend = .01; 0.82 (0.68, 0.98), p-trend = .04, respectively. Associations were, in general, similar across ancestry groups. Our study provides strong evidence for important roles of obesity, diet, and physical activity in BTC etiology and stresses the need for lifestyle modification to combat the rising incidence of this fatal malignancy.

Keywords:  biliary tract cancer; diet; epidemiology; obesity

DOI:  https://doi.org/10.1002/ijc.35048
Ann Med Surg (Lond). 2024 Jun;86(6): 3522-3529

Bidirectional relationship between pancreatic cancer and diabetes mellitus: a comprehensive literature review.

Shady Sapoor, Mahmoud Nageh, Noran Magdy Shalma, Rana Sharaf, Nooran Haroun, Esraa Salama, Tungki Pratama Umar, Sadish Sharma, Reem Sayad.

  Pancreatic cancer (PC) is a fatal malignant disease. It is well known that the relationship between PC and type 2 diabetes mellitus (T2DM) is a complicated bidirectional relationship. The most important factors causing increased risks of pancreatic cancer are hyperglycaemia, hyperinsulinemia, pancreatitis, and dyslipidemia. Genetics and the immune system also play an important role in the relationship between diabetes mellitus and pancreatic cancer. The primary contributors to this association involve insulin resistance and inflammatory processes within the tumour microenvironment. The combination of diabetes and obesity can contribute to PC by inducing hyperinsulinemia and influencing leptin and adiponectin levels. Given the heightened incidence of pancreatic cancer in diabetes patients compared to the general population, early screening for pancreatic cancer is recommended. Diabetes negatively impacts the survival of pancreatic cancer patients. Among patients receiving chemotherapy, it reduced their survival. The implementation of a healthy lifestyle, including weight management, serves as an initial preventive measure to mitigate the risk of disease development. The role of anti-diabetic drugs on survival is controversial; however, metformin may have a positive impact, especially in the early stages of cancer, while insulin therapy increases the risk of PC.

Keywords:  cancer survival; diabetes mellitus; insulin resistance; obesity; pancreatic cancer

DOI:  https://doi.org/10.1097/MS9.0000000000002036
Mol Oncol. 2024 Jun 04.

Sweet dreams could be made of this: carbohydrate-responsive element-binding protein (ChREBP) as a target for hepatocellular carcinoma therapy.

Maite G Fernández-Barrena, Matías A Avila.

  Rewiring of cellular metabolism is now fully recognized as a hallmark of cancer. Tumor cells reprogram metabolic pathways to meet the energetic and macromolecular demands to support unrestricted growth and survival under unfavorable conditions. It is becoming apparent that these adaptations underpin most of the traits that define a cancer cell's identity, including the ability to avoid immune surveillance, endure nutrient and oxygen restrictions, detach and migrate from their natural histological niche, and avert human-made aggressions (i.e., therapy). In a recent study, Benichou and collaborators identify carbohydrate-responsive element-binding protein (ChREBP), a master regulator of physiological glucose metabolism, as an oncogene in hepatocellular carcinoma (HCC) development. Upregulation of ChREBP expression results in a self-stimulatory loop interconnecting PI3K/AKT signaling and glucose metabolism to feed fatty acid and nucleotide synthesis supporting tumorigenesis. Importantly, pharmacological inhibition of ChREBP activity quells in vivo HCC tumor growth without causing systemic toxicity. This study identifies novel oncometabolic pathways and open up new avenues to improve the treatment of a deadly tumor.

Keywords:  ChREBP; PI3K‐AKT signaling; hepatocellular carcinoma; metabolic reprogramming; therapy

DOI:  https://doi.org/10.1002/1878-0261.13669
Exp Hematol. 2024 Jun 02. pii: S0301-472X(24)00107-3. [Epub ahead of print] 104248

Dose-dependent effects of Dnmt3a in an inducible murine model of KrasG12D-driven leukemia.

Jason H Rogers, Allison Rosen, Jaime M Reyes, Shamika Ketkar, Shannon E Conneely, Rohit Gupta, Luibin Yang, Matthew B Miller, Geraldo Medrano, Rogelio Aguilar, Nneka Uchenda, Margaret A Goodell, Rachel E Rau.

  DNMT3A mutations are frequently found in clonal hematopoiesis and a variety of hematologic malignancies including acute myeloid leukemia (AML). An assortment of mouse models have been engineered to explore the tumorigenic potential and malignant lineage bias due to loss of function of DNMT3A in consort with commonly co-mutated genes in myeloid malignancies such as Flt3, Nras, Kras, and c-Kit. We employed several tamoxifen-inducible Cre-ERT2 murine model systems to study the effects of constitutively active KrasG12D-driven myeloid leukemia (Kras) development together with heterozygous (3aHet) or homozygous Dnmt3a deletion (3aKO). Due to the rapid generation of diverse nonhematologic tumors appearing after tamoxifen induction, we employed a transplantation model. With pretransplant tamoxifen induction, most Kras mice died quickly of T-cell malignancies regardless of Dnmt3a status. Using post-transplant induction, we observed a dose-dependent effect of DNMT3A depletion that skewed the leukemic phenotype toward a myeloid lineage- 64% of 3aKO/Kras mice had exclusively myeloid disease compared with 36% of 3aHet/Kras, and only 13% of Kras mice. 3aKO combined with Kras led to increased disease burden, multi-organ infiltration, and faster disease progression. DOT1L inhibition exerted profound anti-leukemic effects in malignant 3aKO/Kras cells, but not malignant cells with Kras mutation alone, consistent with the known sensitivity of DNMT3A-mutant leukemia to DOT1L inhibition. RNAseq from malignant myeloid cells revealed that biallelic Dnmt3a deletion was associated with loss of cell cycle regulation, MYC activation, and TNF⍺ signaling. Overall, we have developed a robust model system for mechanistic and preclinical investigations of AML with DNMT3A and Ras pathway lesions.

Keywords:  Dnmt3a; Kras; hematologic malignancies; leukemia; murine transplant models

DOI:  https://doi.org/10.1016/j.exphem.2024.104248