bims-almceb 2022-11-13 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2022–11–13
nine papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

Mitochondrial dynamics and oxidative phosphorylation as targets in cancer.
The Warburg effect and mitochondrial oxidative phosphorylation: Friends or foes?
The Potential Role of 3D In Vitro Acute Myeloid Leukemia Culture Models in Understanding Drug Resistance in Leukemia Stem Cells.
Metabolic Pathways, Enzymes, and Metabolites: Opportunities in Cancer Therapy.
Fatty acid metabolism predicts prognosis and NK cell immunosurveillance of acute myeloid leukemia patients.
The intersection of metabolism and inflammation is governed by the intracellular topology of hexokinases and the metabolic fate of glucose.
PD-L1 Activity Is Associated with Partial EMT and Metabolic Reprogramming in Carcinomas.
Metabolic Plasticity of Cancer Stem Cells in Response to Microenvironmental Cues.
[Current status and future perspective of CAR T-cell therapy for acute myeloid leukemia].

Endocr Relat Cancer. 2022 Nov 01. pii: ERC-22-0229. [Epub ahead of print]

Mitochondrial dynamics and oxidative phosphorylation as targets in cancer.

Kaylee B Punter, Charles Chu, Edmond Y W Chan.

It has long been recognised that cancer cells critically depend on reprogrammed patterns of metabolism that can enable robust and abnormally high levels of cell proliferation. As mitochondria form hubs of cellular metabolic activity, it is reasonable to propose that pathways within these organelles can form targets that can be manipulated to compromise the ability of cancer cells to cause disease. However, mitochondria are highly multi-functional and the full range of mechanistic inter-connections are still being unraveled to enable the full potential of targeting mitochondria in cancer therapeutics. Here, we aim to highlight the potential of modulating mitochondrial dynamics to target key metabolic or apoptotic pathways in cancer cells. Distinct roles have been demonstrated for mitochondrial fission and fusion in different cancer contexts. Targeting of factors mediating mitochondrial dynamics may be directly related to impairment of oxidative phosphorylation, which is essential to sustain cancer cell growth and can also alter sensitivity to chemotherapeutic compounds. This area is still lacking a unified model although further investigation will more comprehensively map the underlying molecular mechanisms to enable better rational therapeutic strategies based on these pathways.

DOI: https://doi.org/10.1530/ERC-22-0229
Biochim Biophys Acta Bioenerg. 2022 Oct 29. pii: S0005-2728(22)00401-7. [Epub ahead of print]1864(1): 148931

The Warburg effect and mitochondrial oxidative phosphorylation: Friends or foes?

M Martins Pinto, P Paumard, C Bouchez, S Ransac, S Duvezin-Caubet, J P Mazat, M Rigoulet, A Devin.

  Cancer cells display an altered energy metabolism, which was proposed to be the root of cancer. This early discovery was done by O. Warburg who conducted one of the first studies of tumor cell energy metabolism. Taking advantage of cancer cells that exhibited various growth rates, he showed that cancer cells display a decreased respiration and an increased glycolysis proportional to the increase in their growth rate, suggesting that they mainly depend on fermentative metabolism for ATP generation. Warburg's results and hypothesis generated controversies that are persistent to this day. It is thus of great importance to understand the mechanisms by which cancer cells can reversibly regulate the two pathways of their energy metabolism as well as the functioning of this metabolism in cell proliferation. In this review, we discuss of the origin of the decrease in cell respiratory rate, whether the Warburg effect is mandatory for an increased cell proliferation rate, the consequences of this effect on two major players of cell energy metabolism that are ATP and NADH, and the role of the microenvironment in the regulation of cellular respiration and metabolism both in cancer cell and in yeast.

Keywords:  Cancer; Mitochondria; Oxidative phosphorylation; Warburg effect

DOI:  https://doi.org/10.1016/j.bbabio.2022.148931
Cancers (Basel). 2022 Oct 26. pii: 5252. [Epub ahead of print]14(21):

The Potential Role of 3D In Vitro Acute Myeloid Leukemia Culture Models in Understanding Drug Resistance in Leukemia Stem Cells.

Basil Al-Kaabneh, Benjamin Frisch, Omar S Aljitawi.

  The complexity of the bone marrow (BM) microenvironment makes studying hematological malignancies in vitro a challenging task. Three-dimensional cell cultures are being actively studied, particularly due to their ability to serve as a bridge of the gap between 2D cultures and animal models. The role of 3D in vitro models in studying the mechanisms of chemotherapeutic resistance and leukemia stem cells (LSCs) in acute myeloid leukemia (AML) is not well-reviewed. We present an overview of 3D cell models used for studying AML, emphasizing the recent advancements in microenvironment modeling, chemotherapy testing, and resistance.

Keywords:  acute myeloid leukemia (AML); allogeneic hematopoietic stem cell transplant (Allo-HSCT); bone marrow (BM); decellularized Wharton jelly matrix (DWJM); extra cellular matrix (ECM); hematopoietic stem/progenitor cells (HSPCs); leukemia stem cells (LSCs); mesenchymal stem cells (MSCs); minimum residual disease (MRD); myelodysplastic syndrome (MDS)

DOI:  https://doi.org/10.3390/cancers14215252
Cancers (Basel). 2022 Oct 27. pii: 5268. [Epub ahead of print]14(21):

Metabolic Pathways, Enzymes, and Metabolites: Opportunities in Cancer Therapy.

Rishabh Kumar, Anurag Mishra, Priyanka Gautam, Zainab Feroz, Sivakumar Vijayaraghavalu, Eviania M Likos, Girish C Shukla, Munish Kumar.

  Metabolic reprogramming enables cancer cells to proliferate and produce tumor biomass under a nutrient-deficient microenvironment and the stress of metabolic waste. A cancer cell adeptly undergoes a variety of adaptations in metabolic pathways and differential expression of metabolic enzyme genes. Metabolic adaptation is mainly determined by the physiological demands of the cancer cell of origin and the host tissue. Numerous metabolic regulators that assist cancer cell proliferation include uncontrolled anabolism/catabolism of glucose metabolism, fatty acids, amino acids metabolism, nucleotide metabolism, tumor suppressor genes, microRNAs, and many regulatory enzymes and genes. Using this paradigm, we review the current understanding of metabolic reprogramming in tumors and discuss the new strategies of cancer metabolomics that can be tapped into for cancer therapeutics.

Keywords:  Warburg effect; amino acid metabolism; cancer metabolism; cancer therapeutics; fatty acid metabolism; glycolysis; microRNA; oncogenes; tumor suppressor genes

DOI:  https://doi.org/10.3390/cancers14215268
Front Oncol. 2022 ;12 1018154

Fatty acid metabolism predicts prognosis and NK cell immunosurveillance of acute myeloid leukemia patients.

Zhitao Ye, Yishan Li, Xiaobin Tian, Yan Wei, Yanhui Yu, Kaibin Lai, Keyue Yang, Zixuan Qiu, Jianqing Lin, Meng Zhao, Dongjun Lin, Xiaojun Xu.

   Background: Cell metabolic reprogramming is a hallmark of tumor prognosis, and fatty acid metabolism (FAM) plays a crucial role in the tumor microenvironment (TME). However, the relationship between FAM, TME, and prognosis of acute myeloid leukemia (AML) patients remains elusive.
Methods: We extracted the single-cell RNA sequencing (scRNA-Seq) and bulk transcriptome data of AML patients from the TCGA and GEO databases and assessed the relationship between FAM, TME, and AML patient prognosis. We also performed functional enrichment (FE) assay to evaluate the significance of FAM in anti-AML immunosurveillance.
Results: Our scRNA-Seq analysis revealed that the leukemic stem cell (LSC)-enriched population exhibited elevated levels of FAM-related genes. Using these FAM-related genes, we developed a prognostic model that accurately estimated AML patient outcome. FE analysis showed that FAM was strongly related to alterations of TME-based immunosurveillance in AML patients. More importantly, we demonstrated that FAM inhibition via pharmaceutical targeting of PLA2G4A, a highly expressed FAM gene in AML patients with poor prognosis, enhanced the NK cell-mediated immunosurveillance in leukemia cells.
Conclusions: Leukemic stem cell (LSC)-enriched population exhibited elevated levels of FAM-related genes. We have successfully established the FAM formula that predicts AML patient prognosis and alterations in the TME-based immunosurveillance. We also found that PLA2G4A was a highly expressed FAM gene in AML patients with poor prognoses. Pharmaceutical targeting of PLA2G4A increased the expression of NKG2DL in leukemia cells in vitro and thus enhanced the NK cell-mediated immunosurveillance.

Keywords:  NK cells; acute myeloid leukemia; fatty acid metabolism; prognostic model; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2022.1018154
Immunometabolism (Cobham). 2022 Oct;4(4): e00011

The intersection of metabolism and inflammation is governed by the intracellular topology of hexokinases and the metabolic fate of glucose.

Juan F Codocedo, Gary E Landreth.

  Hexokinases (HKs) catalyze the first and irreversible step of glucose metabolism. Its product, glucose-6-phosphate (G-6P) serves as a precursor for catabolic processes like glycolysis for adenosine 5'-triphosphate (ATP) production and anabolic pathways including the pentose phosphate pathway (PPP) for the generation of intermediaries like nicotinamide adenine dinucleotide phosphate (NADPH) and ribulose-5-P. Thus, the cellular fate of glucose is important not only for growth and maintenance, but also to determine different cellular activities. Studies in immune cells have demonstrated an intimate linkage between metabolic pathways and inflammation, however the precise molecular mechanisms that determine the cellular fate of glucose during inflammation or aging are not completely understood. Here we discuss a study by De Jesus et al that describes the role of HK1 cytosolic localization as a critical regulator of glucose flux by shunting glucose into the PPP at the expense of glycolysis, exacerbating the inflammatory response of macrophages. The authors convincingly demonstrate a novel mechanism that is independent of its mitochondrial functions, but involve the association to a protein complex that inhibits glycolysis at the level of glyceraldehyde 3-phosphate dehydrogenase. We expand the discussion by comparing previous studies related to the HK2 isoform and how cells have evolved to regulate the mitochondrial association of these two isoforms by non-redundant mechanism.

Keywords:  glucose; hexokinase

DOI:  https://doi.org/10.1097/IN9.0000000000000011
Curr Oncol. 2022 Oct 31. 29(11): 8285-8301

PD-L1 Activity Is Associated with Partial EMT and Metabolic Reprogramming in Carcinomas.

Srinath Muralidharan, Manas Sehgal, R Soundharya, Susmita Mandal, Sauma Suvra Majumdar, M Yeshwanth, Aryamaan Saha, Mohit Kumar Jolly.

  Immune evasion and metabolic reprogramming are hallmarks of cancer progression often associated with a poor prognosis and frequently present significant challenges for cancer therapies. Recent studies have highlighted the dynamic interaction between immunosuppression and the dysregulation of energy metabolism in modulating the tumor microenvironment to promote cancer aggressiveness. However, a pan-cancer association among these two hallmarks, and a potent common driver for them-epithelial-mesenchymal transition (EMT)-remains to be done. This meta-analysis across 184 publicly available transcriptomic datasets as well as The Cancer Genome Atlas (TCGA) data reveals that an enhanced PD-L1 activity signature along with other immune checkpoint markers correlate positively with a partial EMT and an elevated glycolysis signature but a reduced OXPHOS signature in many carcinomas. These trends were also recapitulated in single-cell, RNA-seq, time-course EMT induction data across cell lines. Furthermore, across multiple cancer types, concurrent enrichment of glycolysis and PD-L1 results in worse outcomes in terms of overall survival as compared to enrichment for only PD-L1 activity or expression. These results highlight potential functional synergy among these interconnected axes of cellular plasticity in enabling metastasis and multi-drug resistance in cancer.

Keywords:  glycolysis; immune checkpoint molecules; meta-analysis; metabolic plasticity; oxidative phosphorylation; partial EMT

DOI:  https://doi.org/10.3390/curroncol29110654
Cancers (Basel). 2022 Oct 29. pii: 5345. [Epub ahead of print]14(21):

Metabolic Plasticity of Cancer Stem Cells in Response to Microenvironmental Cues.

Yunong Xie, Stephanie Ma, Man Tong.

  An increasing body of evidence suggests that cancer stem cells (CSCs) utilize reprogrammed metabolic strategies to adapt to a hostile tumor microenvironment (TME) for survival and stemness maintenance. Such a metabolic alteration in CSCs is facilitated by microenvironmental cues including metabolites such as glucose, amino acids and lipids, and environmental properties such as hypoxic and acidic TME. Similarly, metabolites uptake from the diet exerts critical imprints to the metabolism profile of CSCs and directly influence the maintenance of the CSC population. Moreover, CSCs interact with tumor-infiltrating cells inside the CSC niche to promote cancer stemness, ultimately contributing to tumor development and progression. Understanding the underlying mechanisms of how CSCs employ metabolic plasticity in response to different microenvironmental cues represents a therapeutic opportunity for better cancer treatment.

Keywords:  cancer metabolism; cancer stem cells; plasticity; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers14215345
Rinsho Ketsueki. 2022 ;63(10): 1446-1453

[Current status and future perspective of CAR T-cell therapy for acute myeloid leukemia].

Yozo Nakazawa.

  For over a decade, various chimeric antigen receptor (CAR)-modified T-cells targeting myeloid antigens have been researched and developed overseas for relapsed/refractory acute myeloid leukemia (AML). However, none of them is domestically and internationally nearing approval. Clinical trial results on CAR T-cells targeting LeY, CD33, NKG2D ligands, CD38, or CD123 have been reported; however, they have not shown significant clinical benefit. More recently, several promising studies in CLL1 CAR T-cells have been reported in China, which attracted attention. We started a first-in-human clinical trial of GMR CAR T-cells in patients with CD116-positive myeloid neoplasms, particularly AML and juvenile myelomonocytic leukemia, in 2021. CAR T-cells can be a promising and practical treatment option for patients with relapsed/refractory AML.

Keywords:  AML; CAR T; CLL1; GMR

DOI:  https://doi.org/10.11406/rinketsu.63.1446