bims-almceb 2021-06-13 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2021–06–13
nine papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

Cholesterol Metabolic Reprogramming in Cancer and Its Pharmacological Modulation as Therapeutic Strategy.
High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity.
DDIT3 Directs a Dual Mechanism to Balance Glycolysis and Oxidative Phosphorylation during Glutamine Deprivation.
Apoptotic signals at the endoplasmic reticulum-mitochondria interface.
Increased glycolysis is an early consequence of palmitate lipotoxicity mediated by redox signaling.
The Role of Metabolism in the Development of Personalized Therapies in Acute Myeloid Leukemia.
AXL inhibition in macrophages stimulates host-versus-leukemia immunity and eradicates naive and treatment resistant leukemia.
Current Status of CAR T Cell Therapy for Leukemias.
The Bidirectional Relationship Between Cancer Epigenetics and Metabolism.

Front Oncol. 2021 ;11 682911

Cholesterol Metabolic Reprogramming in Cancer and Its Pharmacological Modulation as Therapeutic Strategy.

Isabella Giacomini, Federico Gianfanti, Maria Andrea Desbats, Genny Orso, Massimiliano Berretta, Tommaso Prayer-Galetti, Eugenio Ragazzi, Veronica Cocetta.

  Cholesterol is a ubiquitous sterol with many biological functions, which are crucial for proper cellular signaling and physiology. Indeed, cholesterol is essential in maintaining membrane physical properties, while its metabolism is involved in bile acid production and steroid hormone biosynthesis. Additionally, isoprenoids metabolites of the mevalonate pathway support protein-prenylation and dolichol, ubiquinone and the heme a biosynthesis. Cancer cells rely on cholesterol to satisfy their increased nutrient demands and to support their uncontrolled growth, thus promoting tumor development and progression. Indeed, transformed cells reprogram cholesterol metabolism either by increasing its uptake and de novo biosynthesis, or deregulating the efflux. Alternatively, tumor can efficiently accumulate cholesterol into lipid droplets and deeply modify the activity of key cholesterol homeostasis regulators. In light of these considerations, altered pathways of cholesterol metabolism might represent intriguing pharmacological targets for the development of exploitable strategies in the context of cancer therapy. Thus, this work aims to discuss the emerging evidence of in vitro and in vivo studies, as well as clinical trials, on the role of cholesterol pathways in the treatment of cancer, starting from already available cholesterol-lowering drugs (statins or fibrates), and moving towards novel potential pharmacological inhibitors or selective target modulators.

Keywords:  cancer; cancer therapy; cholesterol; metabolic reprogramming; metabolic targeting agents; pharmacological modulation; pharmacological targeting

DOI:  https://doi.org/10.3389/fonc.2021.682911
Cell Rep. 2021 Jun 08. pii: S2211-1247(21)00562-3. [Epub ahead of print]35(10): 109212

High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity.

Miyeko D Mana, Amanda M Hussey, Constantine N Tzouanas, Shinya Imada, Yesenia Barrera Millan, Dorukhan Bahceci, Dominic R Saiz, Anna T Webb, Caroline A Lewis, Peter Carmeliet, Maria M Mihaylova, Alex K Shalek, Ömer H Yilmaz.

  Obesity is an established risk factor for cancer in many tissues. In the mammalian intestine, a pro-obesity high-fat diet (HFD) promotes regeneration and tumorigenesis by enhancing intestinal stem cell (ISC) numbers, proliferation, and function. Although PPAR (peroxisome proliferator-activated receptor) nuclear receptor activity has been proposed to facilitate these effects, their exact role is unclear. Here we find that, in loss-of-function in vivo models, PPARα and PPARδ contribute to the HFD response in ISCs. Mechanistically, both PPARs do so by robustly inducing a downstream fatty acid oxidation (FAO) metabolic program. Pharmacologic and genetic disruption of CPT1A (the rate-controlling enzyme of mitochondrial FAO) blunts the HFD phenotype in ISCs. Furthermore, inhibition of CPT1A dampens the pro-tumorigenic consequences of a HFD on early tumor incidence and progression. These findings demonstrate that inhibition of a HFD-activated FAO program creates a therapeutic opportunity to counter the effects of a HFD on ISCs and intestinal tumorigenesis.

Keywords:  Apc; Cpt1a; Ppar; fatty acid oxidation; high-fat diet; intestinal stem cells

DOI:  https://doi.org/10.1016/j.celrep.2021.109212
Adv Sci (Weinh). 2021 06;8(11): e2003732

DDIT3 Directs a Dual Mechanism to Balance Glycolysis and Oxidative Phosphorylation during Glutamine Deprivation.

Mingyue Li, Rick Francis Thorne, Ronghua Shi, Xu Dong Zhang, Jingmin Li, Jingtong Li, Qingyuan Zhang, Mian Wu, Lianxin Liu.

  Extracellular glutamine represents an important energy source for many cancer cells and its metabolism is intimately involved in maintaining redox homeostasis. The heightened metabolic activity within tumor tissues can result in glutamine deficiency, necessitating metabolic reprogramming responses. Here, dual mechanisms involving the stress-responsive transcription factor DDIT3 (DNA damage induced transcript 3) that establishes an interrelationship between glycolysis and mitochondrial respiration are revealed. DDIT3 is induced during glutamine deprivation to promote glycolysis and adenosine triphosphate production via suppression of the negative glycolytic regulator TIGAR. In concert, a proportion of the DDIT3 pool translocates to the mitochondria and suppresses oxidative phosphorylation through LONP1-mediated down-regulation of COQ9 and COX4. This in turn dampens the sustained levels of reactive oxygen species that follow glutamine withdrawal. Together these mechanisms constitute an adaptive survival mechanism permitting tumor cells to survive metabolic stress induced by glutamine starvation.

Keywords:  COQ9; COX4; DDIT3/CHOP; electron transfer chain; glutamine deprivation; glycolysis

DOI:  https://doi.org/10.1002/advs.202003732
Adv Protein Chem Struct Biol. 2021 ;pii: S1876-1623(21)00025-0. [Epub ahead of print]126 307-343

Apoptotic signals at the endoplasmic reticulum-mitochondria interface.

Flavia Giamogante, Elena Poggio, Lucia Barazzuol, Alberto Covallero, Tito Calì.

  The maintenance of cellular homeostasis involves the participation of multiple organelles, such as the endoplasmic reticulum (ER) and mitochondria. Specifically, ER plays a key role in calcium (Ca2+) storage, lipid synthesis, protein folding, and assembly, while mitochondria are the "energy factories" and provide energy to drive intracellular processes. Hence, alteration in ER or mitochondrial homeostasis has detrimental effects on cell survival, being linked to the triggering of apoptosis, a programmed form of cell death. Besides, ER stress conditions affect mitochondria functionality and vice-versa, as ER and mitochondria communicate via mitochondria-associated ER membranes (MAMs) to carry out a number of fundamental cellular functions. It is not surprising, thus, that also MAMs perturbations are involved in the regulation of apoptosis. This chapter intends to accurately discuss the involvement of MAMs in apoptosis, highlighting their crucial role in controlling this delicate cellular process.

Keywords:  Apoptosis; Bioenergetics; Calcium signaling; ER-mitochondria contact sites; MAMs; Organelle tethering

DOI:  https://doi.org/10.1016/bs.apcsb.2021.02.007
Redox Biol. 2021 Jun 01. pii: S2213-2317(21)00184-1. [Epub ahead of print]45 102026

Increased glycolysis is an early consequence of palmitate lipotoxicity mediated by redox signaling.

Pamela A Kakimoto, Julian David C Serna, Vitor de Miranda Ramos, Antonio Zorzano, Alicia J Kowaltowski.

  Exposure to toxic levels of fatty acids (lipotoxicity) leads to cell damage and death and is involved in the pathogenesis of the metabolic syndrome. Since the metabolic consequences of lipotoxicity are still poorly understood, we studied the bioenergetic effects of the saturated fatty acid palmitate, quantifying changes in mitochondrial morphology, real-time oxygen consumption, ATP production sources, and extracellular acidification in hepatoma cells. Surprisingly, glycolysis was enhanced by the presence of palmitate as soon as 1 h after stimulus, while oxygen consumption and oxidative phosphorylation were unchanged, despite overt mitochondrial fragmentation. Palmitate only induced mitochondrial fragmentation if glucose and glutamine were available, while glycolytic enhancement did not require glutamine, showing it is independent of mitochondrial morphological changes. Redox state was altered by palmitate, as indicated by NAD(P)H quantification. Furthermore, the mitochondrial antioxidant mitoquinone, or a selective inhibitor of complex I electron leakage (S1QEL) further enhanced palmitate-induced glycolysis. Our results demonstrate that palmitate overload and lipotoxicity involves an unexpected and early increase in glycolytic flux, while, surprisingly, no changes in oxidative phosphorylation are observed. Interestingly, enhanced glycolysis involves signaling by mitochondrially-generated oxidants, uncovering a novel regulatory mechanism for this pathway.

Keywords:  Glycolysis; Mitochondria; Oxidative stress; Palmitic acid; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.redox.2021.102026
Front Oncol. 2021 ;11 665291

The Role of Metabolism in the Development of Personalized Therapies in Acute Myeloid Leukemia.

Vilma Dembitz, Paolo Gallipoli.

  Despite significant recent advances in our understanding of the biology and genetics of acute myeloid leukemia (AML), current AML therapies are mostly based on a backbone of standard chemotherapy which has remained mostly unchanged for over 20 years. Several novel therapies, mostly targeting neomorphic/activating recurrent mutations found in AML patients, have only recently been approved following encouraging results, thus providing the first evidence of a more precise and personalized approach to AML therapy. Rewired metabolism has been described as a hallmark of cancer and substantial evidence of its role in AML establishment and maintenance has been recently accrued in preclinical models. Interestingly, unique metabolic changes are generated by specific AML recurrent mutations or in response to diverse AML therapies, thus creating actionable metabolic vulnerabilities in specific patient groups. In this review we will discuss the current evidence supporting a role for rewired metabolism in AML pathogenesis and how these metabolic changes can be leveraged to develop novel personalized therapies.

Keywords:  acute myeloid leukemia; drug resistance; leukemic stem cell; metabolism; personalized therapy

DOI:  https://doi.org/10.3389/fonc.2021.665291
Cancer Discov. 2021 Jun 08. pii: candisc.1378.2020. [Epub ahead of print]

AXL inhibition in macrophages stimulates host-versus-leukemia immunity and eradicates naive and treatment resistant leukemia.

Irene Tirado-Gonzalez, Arnaud Descot, Devona Soetopo, Aleksandra Nevmerzhitskaya, Alexander Schaffer, Ivan-Maximiliano Kur, Ewelina Czlonka, Carolin Wachtel, Ioanna Tsoukala, Luise Muller, Anna-Lena Schafer, Maresa Weitmann, Petra Dinse, Emily Alberto, Michele C Buck, Jonathan J M Landry, Bianka Baying, Julia Slotta-Huspenina, Jenny Roesler, Patrick N Harter, Anne-Sophie Kubasch, Jörn Meinel, Eiman Elwakeel, Elisabeth Strack, Christine Tran Quang, Omar Abdel-Wahab, Marc Schmitz, Andreas Weigert, Tobias Schmid, Uwe Platzbecker, Vladimir Benes, Jacques Ghysdael, Halvard Bonig, Katharina S Gotze, Carla V Rothlin, Sourav Ghosh, Hind Medyouf.

Acute leukemias are systemic malignancies associated with a dire outcome. Due to low immunogenicity, leukemias display a remarkable ability to evade immune control and are often resistant to checkpoint blockade. Here, we discover that leukemia cells actively establish a suppressive environment to prevent immune attacks by co-opting a signaling axis that skews macrophages towards a tumor promoting tissue repair phenotype, namely the GAS6/AXL axis. Using aggressive leukemia models, we demonstrate that ablation of the AXL receptor specifically in macrophages, or its ligand GAS6 in the environment, stimulates anti-leukemic immunity and elicits effective and lasting NK- and T-cell dependent immune response against naive and treatment resistant leukemia. Remarkably, AXL deficiency in macrophages also enables PD1 checkpoint blockade in PD1-refractory leukemias. Lastly, we provide proof-of-concept that a clinical grade AXL inhibitor can be used in combination with standard of care therapy to cure established leukemia, regardless on AXL expression in malignant cells.

DOI: https://doi.org/10.1158/2159-8290.CD-20-1378
Curr Treat Options Oncol. 2021 Jun 07. 22(7): 62

Current Status of CAR T Cell Therapy for Leukemias.

Katherine Harris, James L LaBelle, Michael R Bishop.

   OPINION STATEMENT: Chimeric antigen receptor (CAR) T-cell therapy has become the standard of care for children and young adults with relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL), and it is a highly promising therapy under investigation for adults with relapsed disease. Despite having potentially life-threatening toxicities, such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, the benefits of CAR T-cell therapy far outweigh these risks, particularly as increased experience and improved supportive care measures are mitigating these toxicities. CAR T cells can result in complete remission for significant proportion of patients with relapsed and refractory B-ALL and permit them to proceed to potentially curative allogeneic hematopoietic stem cell transplantation (allo-HSCT). CAR T cells may also be curative by themselves. Herein lie the greatest challenges and questions for clinical investigators, specifically, how are CAR T cells best employed and how do we overcome mechanisms of resistance to them? The primary clinical question is the timing and even the necessity of allo-HSCT. Relative to resistance, we know that target antigen loss, specifically CD19, is a major contributor to resistance. However, current investigations of alternative targets, such CD22, and CAR T cells expressing dual targeting antigen receptors have demonstrated encouraging initial results and provide a high degree of optimism that the efficacy and the broader application of CAR T-cell therapy will gradually increase in B-ALL. That optimism is not as high and the challenges are increased for the application of CAR T cells in T-cell leukemias and acute myeloid leukemia due to the relative lack of suitable leukemia surface targets that are not also expressed on normal hematopoietic progenitors. Despite these significant challenges, considerable research is being conducted into the development of CAR T cells for these diseases utilizing unique technologies, which may be applicable to other diseases.

Keywords:  Acute lymphoblastic leukemia; CAR T cells; Immunotherapy; Leukemia; Mechanisms of resistance; Toxicities

DOI:  https://doi.org/10.1007/s11864-021-00859-8
Annu Rev Cancer Biol. 2021 Mar;5(1): 235-257

The Bidirectional Relationship Between Cancer Epigenetics and Metabolism.

Luke T Izzo, Hayley C Affronti, Kathryn E Wellen.

  Metabolic and epigenetic reprogramming are characteristics of cancer cells that, in many cases, are linked. Oncogenic signaling, diet, and tumor microenvironment each influence the availability of metabolites that are substrates or inhibitors of epigenetic enzymes. Reciprocally, altered expression or activity of chromatin-modifying enzymes can exert direct and indirect effects on cellular metabolism. In this article, we discuss the bidirectional relationship between epigenetics and metabolism in cancer. First, we focus on epigenetic control of metabolism, highlighting evidence that alterations in histone modifications, chromatin remodeling, or the enhancer landscape can drive metabolic features that support growth and proliferation. We then discuss metabolic regulation of chromatin-modifying enzymes and roles in tumor growth and progression. Throughout, we highlight proposed therapeutic and dietary interventions that leverage metabolic-epigenetic cross talk and have the potential to improve cancer therapy.

Keywords:  cancer; cell metabolism; chromatin modification; epigenetics

DOI:  https://doi.org/10.1146/annurev-cancerbio-070820-035832