bims-almceb 2021-10-17 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2021–10–17
eight papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

Lipid droplets as metabolic determinants for stemness and chemoresistance in cancer.
Cancer Stem Cell for Tumor Therapy.
Metabolic Program of Regulatory B Lymphocytes and Influence in the Control of Malignant and Autoimmune Situations.
Metabolic Modifications, Inflammation, and Cancer Immunotherapy.
Targeting Tim-3 in Cancer With Resistance to PD-1/PD-L1 Blockade.
Immunity in acute myeloid leukemia: where the immune response and targeted therapy meet.
Steering Mast Cells or Their Mediators as a Prospective Novel Therapeutic Approach for the Treatment of Hematological Malignancies.
KAT2A complexes ATAC and SAGA play unique roles in cell maintenance and identity in hematopoiesis and leukemia.

World J Stem Cells. 2021 Sep 26. 13(9): 1307-1317

Lipid droplets as metabolic determinants for stemness and chemoresistance in cancer.

Alba Royo-García, Sarah Courtois, Beatriz Parejo-Alonso, Pilar Espiau-Romera, Patricia Sancho.

  Previously regarded as simple fat storage particles, new evidence suggests that lipid droplets (LDs) are dynamic and functional organelles involved in key cellular processes such as membrane biosynthesis, lipid metabolism, cell signalling and inflammation. Indeed, an increased LD content is one of the most apparent features resulting from lipid metabolism reprogramming necessary to support the basic functions of cancer cells. LDs have been associated to different cellular processes involved in cancer progression and aggressiveness, such as tumorigenicity, invasion and metastasis, as well as chemoresistance. Interestingly, all of these processes are controlled by a subpopulation of highly aggressive tumoral cells named cancer stem cells (CSCs), suggesting that LDs may be fundamental elements for stemness in cancer. Considering the key role of CSCs on chemoresistance and disease relapse, main factors of therapy failure, the design of novel therapeutic approaches targeting these cells may be the only chance for long-term survival in cancer patients. In this sense, their biology and functional properties render LDs excellent candidates for target discovery and design of combined therapeutic strategies. In this review, we summarise the current knowledge identifying LDs and CSCs as main contributors to cancer aggressiveness, metastasis and chemoresistance.

Keywords:  Cancer stem cells; Chemoresistance; Lipid droplets; Lipid metabolism; Lipids; Stemness

DOI:  https://doi.org/10.4252/wjsc.v13.i9.1307
Cancers (Basel). 2021 Sep 26. pii: 4814. [Epub ahead of print]13(19):

Cancer Stem Cell for Tumor Therapy.

Binjie Huang, Xin Yan, Yumin Li.

  Tumors pose a significant threat to human health. Although many methods, such as operations, chemotherapy and radiotherapy, have been proposed to eliminate tumor cells, the results are unsatisfactory. Targeting therapy has shown potential due to its specificity and efficiency. Meanwhile, it has been revealed that cancer stem cells (CSCs) play a crucial role in the genesis, development, metastasis and recurrence of tumors. Thus, it is feasible to inhibit tumors and improve prognosis via targeting CSCs. In this review, we provide a comprehensive understanding of the biological characteristics of CSCs, including mitotic pattern, metabolic phenotype, therapeutic resistance and related mechanisms. Finally, we summarize CSCs targeted strategies, including targeting CSCs surface markers, targeting CSCs related signal pathways, targeting CSC niches, targeting CSC metabolic pathways, inducing differentiation therapy and immunotherapy (tumor vaccine, CAR-T, oncolytic virus, targeting CSCs-immune cell crosstalk and immunity checkpoint inhibitor). We highlight the potential of immunity therapy and its combinational anti-CSC therapies, which are composed of different drugs working in different mechanisms.

Keywords:  CSCs; metabolic phenotype; mitotic division pattern; targeted strategy; therapeutic resistance; tumor therapy

DOI:  https://doi.org/10.3390/cancers13194814
Front Immunol. 2021 ;12 735463

Metabolic Program of Regulatory B Lymphocytes and Influence in the Control of Malignant and Autoimmune Situations.

Cristian Iperi, Anne Bordron, Maryvonne Dueymes, Jacques-Olivier Pers, Christophe Jamin.

  Metabolic pathways have been studied for a while in eukaryotic cells. During glycolysis, glucose enters into the cells through the Glut1 transporter to be phosphorylated and metabolized generating ATP molecules. Immune cells can use additional pathways to adapt their energetic needs. The pentose phosphate pathway, the glutaminolysis, the fatty acid oxidation and the oxidative phosphorylation generate additional metabolites to respond to the physiological requirements. Specifically, in B lymphocytes, these pathways are activated to meet energetic demands in relation to their maturation status and their functional orientation (tolerance, effector or regulatory activities). These metabolic programs are differentially involved depending on the receptors and the co-activation molecules stimulated. Their induction may also vary according to the influence of the microenvironment, i.e. the presence of T cells, cytokines … promoting the expression of particular transcription factors that direct the energetic program and modulate the number of ATP molecule produced. The current review provides recent advances showing the underestimated influence of the metabolic pathways in the control of the B cell physiology, with a particular focus on the regulatory B cells, but also in the oncogenic and autoimmune evolution of the B cells.

Keywords:  B lymphocytes; Breg cells; autoimmunity; cancer; metabolism; regulatory activity

DOI:  https://doi.org/10.3389/fimmu.2021.735463
Front Oncol. 2021 ;11 703681

Metabolic Modifications, Inflammation, and Cancer Immunotherapy.

Sihao Zheng, Qibin Song, Pingfeng Zhang.

  Cancer immunotherapy has accomplished significant progresses on treatment of various cancers in the past decade; however, recent studies revealed more and more heterogeneity in tumor microenvironment which cause unneglectable therapy resistance. A central phenomenon in tumor malignancy is metabolic dysfunctionality; it reprograms metabolic homeostasis in tumor and stromal cells thus affecting metabolic modifications on specific proteins. These posttranslational modifications include glycosylation and palmitoylation, which usually alter the protein localization, stability, and function. Many of these proteins participate in acute or chronic inflammation and play critical roles in tumorigenesis and progression. Therefore, targeting these metabolic modifications in immune checkpoints and inflammation provides an attractive therapeutic strategy for certain cancers. In this review, we summarize the recent progresses on metabolic modifications in this field, focus on the mechanisms on how glycosylation and palmitoylation regulate innate immune and inflammation, and we further discuss designing new immunotherapy targeting metabolic modifications. We aim to improve immunotherapy or targeted-therapy response and achieve more accurate individual therapy.

Keywords:  PD-1/PD-L1; cancer immunotherapy; glycosylation; inflammation; metabolic modifications; palmitoylation

DOI:  https://doi.org/10.3389/fonc.2021.703681
Front Oncol. 2021 ;11 731175

Targeting Tim-3 in Cancer With Resistance to PD-1/PD-L1 Blockade.

Tian Tian, Zhaoming Li.

  Programmed death receptor 1 (PD-1) or programmed death ligand 1 (PD-L1) blocking therapy has completely changed the treatment pattern of malignant tumors. It has been tested in a wide range of malignant tumors and achieved clinical success. It might be a promising cancer treatment strategy. However, one of the important disadvantages of PD-1/PD-L1 blocking therapy is that only a few patients have a positive response to it. In addition, primary or acquired drug resistance can also lead to cancer recurrence in patients with clinical response. Therefore, it is very important to overcome the resistance of PD-1/PD-L1 blocking therapy and improve the overall response rate of patients to the immunotherapy. T cell immunoglobulin and mucin domain molecule 3 (Tim-3) belongs to the co-inhibitory receptor family involved in immune checkpoint function. Due to adaptive resistance, the expression of Tim-3 is up-regulated in PD-1/PD-L1 blocking therapy resistant tumors. Therefore, blocking the immune checkpoint Tim-3 might antagonize the resistance of PD-1/PD-L1 blocking therapy. This review systematically introduces the preclinical and clinical data of combined blockade of Tim-3 and PD-1/PD-L1 in cancer immunotherapy, and discusses the prospect of overcoming the drug resistance of PD-1/PD-L1 blockade therapy through blockade of Tim-3.

Keywords:  PD-1; PD-L1; Tim-3; drug resistance; immune checkpoint

DOI:  https://doi.org/10.3389/fonc.2021.731175
Eur J Immunol. 2021 Oct 14.

Immunity in acute myeloid leukemia: where the immune response and targeted therapy meet.

Avner Fink, Eric Hung, Indranil Singh, Yinon Ben-Neriah.

  Acute myeloid leukemia (AML) is a highly aggressive disease with high relapse and mortality rates. Recent years have shown a surge in novel therapeutic development for AML, both in clinical and preclinical stages. These developments include targeted therapies based on AML specific molecular signatures as well as more general immune modulation and vaccination studies. In this review, we will explore the evolving arena of AML therapy and suggest some intriguing connections between immune system modulation and targeted therapy. Improved understanding of the immune system involvement in various stages of the disease and the crosstalk between immune effectors, targeted therapy and AML cells can provide a better framework for designing the next generation of AML therapies. This article is protected by copyright. All rights reserved.

Keywords:  Microbiome; Myc; Targeted Cancer Therapy; Transcription Inhibitors; p53

DOI:  https://doi.org/10.1002/eji.202048945
Front Oncol. 2021 ;11 731323

Steering Mast Cells or Their Mediators as a Prospective Novel Therapeutic Approach for the Treatment of Hematological Malignancies.

Deeksha Mehtani, Niti Puri.

  Tumor cells require signaling and close interaction with their microenvironment for their survival and proliferation. In the recent years, Mast cells have earned a greater importance for their presence and role in cancers. It is known that mast cells are attracted towards tumor microenvironment by secreted soluble chemotactic factors. Mast cells seem to exert a pro-tumorigenic role in hematological malignancies with a few exceptions where they showed anti-cancerous role. This dual role of mast cells in tumor growth and survival may be dependent on the intrinsic characteristics of the particular tumor, differences in tumor microenvironment according to tumor type, and the interactions and heterogeneity of mediators released by mast cells in the tumor microenvironment. In many studies, Mast cells and their mediators have been shown to affect tumor survival and growth, prognosis, inflammation, tumor vascularization and angiogenesis. Modulating mast cell accumulation, viability, activity and mediator release patterns may thus be important in controlling these malignancies. In this review, we emphasize on the role of mast cells in lymphoid malignancies and discuss strategies for targeting and steering mast cells or their mediators as a potential therapeutic approach for the treatment of these malignancies.

Keywords:  blood cancer; cancer therapeutics; hematological malignancy; leukemia; lymphoid neoplasms; lymphoma; mast cells; myeloma

DOI:  https://doi.org/10.3389/fonc.2021.731323
Blood Adv. 2021 Oct 15. pii: bloodadvances.2020002842. [Epub ahead of print]

KAT2A complexes ATAC and SAGA play unique roles in cell maintenance and identity in hematopoiesis and leukemia.

Liliana Arede, Elena Foerner, Selinde Sterre Wind, Rashmi Kulkarni, Ana Filipa Domingues, George Giotopoulos, Svenja Kleinwächter, Maximilian Mollenhauer-Starkl, Holly Davison, Aditya Chandru, Ryan Asby, Ralph Samarista, Shikha Gupta, Dorian Forte, Antonio Curti, Elisabeth Scheer, Brian James Patrick Huntly, Laszlo Tora, Cristina Pina.

Epigenetic histone modifiers are key regulators of cell fate decisions in normal and malignant hematopoiesis. Their enzymatic activities are of particular significance as putative therapeutic targets in leukemia. In contrast, less is known about the contextual role in which those enzymatic activities are exercised, and specifically, how different macromolecular complexes configure the same enzymatic activity with distinct molecular and cellular consequences. We focus on KAT2A, a lysine acetyltransferase responsible for Histone 3 Lysine 9 acetylation, which we recently identified as a dependence in Acute Myeloid Leukemia stem cells, and that participates in 2 distinct macromolecular complexes: Ada Two-A-Containing (ATAC) and Spt-Ada-Gcn5-Acetyltransferase (SAGA). Through analysis of human cord blood hematopoietic stem cells and progenitors, and of myeloid leukemia cells, we identify unique respective contributions of the ATAC complex to regulation of biosynthetic activity in undifferentiated self-renewing cells, and of the SAGA complex to stabilisation or correct progression of cell type-specific programs with putative preservation of cell identity. Cell type and stage-specific dependencies on ATAC and SAGA-regulated programs explain multi-level KAT2A requirements in leukemia and in erythroid lineage specification and development. Importantly, they set a paradigm against which lineage specification and identity can be explored across developmental stem cell systems.

DOI: https://doi.org/10.1182/bloodadvances.2020002842