bims-almceb 2022-10-23 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2022–10–23
eight papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

HSF1 is a driver of leukemia stem cell self-renewal in acute myeloid leukemia.
Cancer Stem Cells And Anti-Tumor Immunity.
PI3K Targeting in Non-solid Cancer.
Microfluidic chip with reversible interface for noninvasive remission status monitoring and prognosis prediction of acute myeloid leukemia.
Therapeutic resistance in acute myeloid leukemia cells is mediated by a novel ATM/mTOR pathway regulating oxidative phosphorylation.
Natural products targeting human lactate dehydrogenases for cancer therapy: A mini review.
Identification of fatty acid signature to predict prognosis and guide clinical therapy in patients with ovarian cancer.
Metabolic regulation of immune responses to cancer.

Nat Commun. 2022 Oct 16. 13(1): 6107

HSF1 is a driver of leukemia stem cell self-renewal in acute myeloid leukemia.

Qianze Dong, Yan Xiu, Yang Wang, Christina Hodgson, Nick Borcherding, Craig Jordan, Jane Buchanan, Eric Taylor, Brett Wagner, Mariah Leidinger, Carol Holman, Dennis J Thiele, Sean O'Brien, Hai-Hui Xue, Jinming Zhao, Qingchang Li, Howard Meyerson, Brendan F Boyce, Chen Zhao.

Acute myeloid leukemia (AML) is maintained by self-renewing leukemic stem cells (LSCs). A fundamental problem in treating AML is that conventional therapy fails to eliminate LSCs, which can reinitiate leukemia. Heat shock transcription factor 1 (HSF1), a central regulator of the stress response, has emerged as an important target in cancer therapy. Using genetic Hsf1 deletion and a direct HSF1 small molecule inhibitor, we show that HSF1 is specifically required for the maintenance of AML, while sparing steady-state and stressed hematopoiesis. Mechanistically, deletion of Hsf1 dysregulates multifaceted genes involved in LSC stemness and suppresses mitochondrial oxidative phosphorylation through downregulation of succinate dehydrogenase C (SDHC), a direct HSF1 target. Forced expression of SDHC largely restores the Hsf1 ablation-induced AML developmental defect. Importantly, the growth and engraftment of human AML cells are suppressed by HSF1 inhibition. Our data provide a rationale for developing efficacious small molecules to specifically target HSF1 in AML.

DOI: https://doi.org/10.1038/s41467-022-33861-1
Curr Stem Cell Res Ther. 2022 Oct 17.

Cancer Stem Cells And Anti-Tumor Immunity.

Merve Yılmaz, Fuat Kaplan, Ilgen Mender, Sergei M Gryaznov, Z Gunnur Dikmen.

  Cancer stem cells (CSCs) are correlated with poor clinical outcome due to their contribution to chemotherapy resistance and formation of metastasis. Multiple cell surface and enzymatic markers have been characterized to identify CSCs, which is important for diagnosis, therapy, and prognosis. This review underlines the role of CSCs and circulating tumor cells (CTCs) in tumor relapse and metastasis, the characteristics of CSC and CTC biomarkers, and the techniques used for the detection of these cells. We also summarized novel therapeutic approaches toward targeting CSCs, especially focusing on the role of immune checkpoint blockades (ICB), such as anti-programmed death 1 (anti-PD1) and anti-programmed death ligand-1 (anti-PDL1) therapies. Additionally, we address an intriguing new mechanism of action for small molecular drugs, such as telomere targeted therapy 6-thio-2'deoxyguanosine (6-thio-dG), and how it reshapes tumor microenvironment to overcome ICB resistance. There are indications, that, personalized cancer therapy targeting CSC populations in conjunction with immune-mediated strategy hold promise for the removal of residual therapy-resistant CSCs in the near future.

Keywords:  Anti-tumor immunity; Cancer stem cells; Circulating tumor cells; Functional assays; Surface markers

DOI:  https://doi.org/10.2174/1574888X18666221017142032
Curr Top Microbiol Immunol. 2022 ;436 393-407

PI3K Targeting in Non-solid Cancer.

Hye Na Kim, Heather Ogana, Vanessa Sanchez, Cydney Nichols, Yong-Mi Kim.

  Despite the therapeutic progress, relapse remains a major problem in the treatment of acute lymphoblastic leukemia (ALL). Most leukemia cells that survive chemotherapy are found in the bone marrow (BM), thus resistance to chemotherapy and other treatments may be partially attributed to pro-survival signaling to leukemic cells mediated by leukemia cell-microenvironment interactions. Adhesion of leukemia cells to BM stromal cells may lead to cell adhesion-mediated drug resistance (CAM-DR) mediating intracellular signaling changes that support survival of leukemia cells. In ALL and chronic lymphocytic leukemia (CLL), adhesion-mediated activation of the PI3K/AKT signaling pathway has been shown to be critical in CAM-DR. PI3K targeting inhibitors have been approved for CLL and have been evaluated preclinically in ALL. However, PI3K inhibition has yet to be approved for clinical use in ALL. Here, we review the role of PI3K signaling for normal hematopoietic and leukemia cells and summarize preclinical inhibitors of PI3K in ALL.

Keywords:  Acute lymphoblastic leukemia (ALL); Cell adhesion mediated drug resistance (CAM-DR); PI3K/AKT; PI3Kγ; PI3Kδ

DOI:  https://doi.org/10.1007/978-3-031-06566-8_17
Biosens Bioelectron. 2022 Oct 12. pii: S0956-5663(22)00843-0. [Epub ahead of print]219 114803

Microfluidic chip with reversible interface for noninvasive remission status monitoring and prognosis prediction of acute myeloid leukemia.

Qian Lai, Juan Song, Jie Zha, Huijian Zheng, Manman Deng, Yilong Liu, Wei Lin, Zhi Zhu, Huimin Zhang, Bing Xu, Chaoyong Yang.

  Acute myeloid leukemia (AML) requires close monitoring of remission status for timely disease management. Liquid biopsy serves as a noninvasive approach for evaluating treatment response and guiding therapeutic modifications. Herein, we designed a non-invasive Leukemic stem cell Specific Capture Chip (LSC-Chip) with reversible recognition interface for AML remission status monitoring and prognosis prediction. A stem cell marker CD34 antibody coated herringbone chip with disulfide linkers was designed to capture and release leukemic stem cells (LSCs) in peripheral blood for efficient LSC enumeration and downstream single-cell analysis. Samples from 32 AML patients and 10 healthy donors were recruited for LSC enumeration and prognosis-associated subtyping with panels of official LSC markers (CD34+/CD123+/CD38-) and (Tie2+/CD34+/CD123+/CD38-), respectively. A cutoff value of 2.5 LSCs per milliliters of peripheral blood can be used to precisely distinguish non-remission AML patients from complete remission group. Moreover, single-cell RNA-seq of LSCs was performed to check different transcriptional profiles of LSC subtypes. Overall, the LSC-Chip with reversible recognition interface enabled reliable detection of LSCs from AML patient samples for noninvasive remission status monitoring and prognosis prediction in clinical AML management.

Keywords:  Acute myeloid leukemia (AML); Leukemic stem cells (LSCs); Microfluidic chip; Single-cell analysis; Therapeutic evaluation

DOI:  https://doi.org/10.1016/j.bios.2022.114803
Elife. 2022 Oct 19. pii: e79940. [Epub ahead of print]11

Therapeutic resistance in acute myeloid leukemia cells is mediated by a novel ATM/mTOR pathway regulating oxidative phosphorylation.

Hae J Park, Mark A Gregory, Vadym Zaberezhnyy, Andrew Goodspeed, Craig T Jordan, Jeffrey S Kieft, James DeGregori.

  While leukemic cells are susceptible to various therapeutic insults, residence in the bone marrow microenvironment typically confers protection from a wide range of drugs. Thus, understanding the unique molecular changes elicited by the marrow is of critical importance towards improving therapeutic outcomes. In the present study, we demonstrate that aberrant activation of oxidative phosphorylation serves to induce therapeutic resistance in FLT3 mutant human AML cells challenged with FLT3 inhibitor drugs. Importantly, our findings show that AML cells are protected from apoptosis following FLT3 inhibition due to marrow-mediated activation of ATM, which in turn up-regulates oxidative phosphorylation via mTOR signaling. mTOR is required for the bone marrow stroma-dependent maintenance of protein translation, with selective polysome enrichment of oxidative phosphorylation transcripts, despite FLT3 inhibition. To investigate the therapeutic significance of this finding, we tested the mTOR inhibitor everolimus in combination with the FLT3 inhibitor quizartinib in primary human AML xenograft models. While marrow resident AML cells were highly resistant to quizartinib alone, the addition of everolimus induced profound reduction in tumor burden and prevented relapse. Taken together, these data provide a novel mechanistic understanding of marrow-based therapeutic resistance, and a promising strategy for improved treatment of FLT3 mutant AML patients.

Keywords:  cancer biology; human

DOI:  https://doi.org/10.7554/eLife.79940
Front Chem. 2022 ;10 1013670

Natural products targeting human lactate dehydrogenases for cancer therapy: A mini review.

Huankai Yao, Feng Yang, Yan Li.

  Reprogramming cancer metabolism has become the hallmark of cancer progression. As the key enzyme catalyzing the conversion of pyruvate to lactate in aerobic glycolysis of cancer cells, human lactate dehydrogenase (LDH) has been a promising target in the discovery of anticancer agents. Natural products are important sources of new drugs. Up to now, some natural compounds have been reported with the activity to target LDH. To give more information on the development of LDH inhibitors and application of natural products, herein, we reviewed the natural compounds with inhibition of LDH from diverse structures and discussed the future direction of the discovery of natural LDH inhibitors for cancer therapy.

Keywords:  Warburg effect; cancer metabolism; inhibitors; lactate dehydrogenase; natural products

DOI:  https://doi.org/10.3389/fchem.2022.1013670
Front Oncol. 2022 ;12 979565

Identification of fatty acid signature to predict prognosis and guide clinical therapy in patients with ovarian cancer.

Tiefeng Cao, Jiaqi Dong, Jiaming Huang, Zihao Tang, Huimin Shen.

  High-grade serous ovarian cancer (HGSOC) is a heterogeneous cancer characterized by high relapse rate. Approximately 80% of women are diagnosed with late-stage disease, and 15-25% of patients experience primary treatment resistance. Ovarian cancer brings tremendous suffering and is the most malignant type in all gynecologic malignancies. Metabolic reprogramming in tumor microenvironment (TME), especially fatty acid metabolism, has been identified to play a crucial role in cancer prognosis. Yet, the underlying mechanism of fatty acid metabolism on ovarian cancer progression is severely understudied. Recently, studies have demonstrated the role of fatty acid metabolism reprogramming in immune cells, but their roles on cancer cell metastasis and cancer immunotherapy response are poorly characterized. Here, we reported that the fatty acid-related genes are aberrantly varied between ovarian cancer and normal samples. Using samples in publicly databases and bio-informatic analyses with fatty acid-related genes, we disentangled that cancer cases can be classified into high- and low-risk groups related with prognosis. Furthermore, the nomogram model was constructed to predict the overall survival. Additionally, we reported that different immune cells infiltration was presented between groups, and immunotherapy response differed in two groups. Results showed that our signature may have good prediction value on immunotherapy efficacy, especially for anti-PD-1 and anti-CTLA-4. Our study systematically marked the critical association between cancer immunity in TME and fatty acid metabolism, and bridged immune phenotype and metabolism programming in tumors, thereby constructed the metabolic-related prognostic model and help to understand the underlying mechanism of immunotherapy response.

Keywords:  cancer immunity; fatty-acid metabolism; ovarian cancer; prognosis; therapy response

DOI:  https://doi.org/10.3389/fonc.2022.979565
Cancer Biol Med. 2022 Oct 24. pii: j.issn.2095-3941.2022.0381. [Epub ahead of print]

Metabolic regulation of immune responses to cancer.

Jannis Wißfeld, Anke Werner, Xin Yan, Nora Ten Bosch, Guoliang Cui.

  The tumor microenvironment is an ecosystem composed of multiple types of cells, such as tumor cells, immune cells, and cancer-associated fibroblasts. Cancer cells grow faster than non-cancerous cells and consume larger amounts of nutrients. The rapid growth characteristic of cancer cells fundamentally alters nutrient availability in the tumor microenvironment and results in reprogramming of immune cell metabolic pathways. Accumulating evidence suggests that cellular metabolism of nutrients, such as lipids and amino acids, beyond being essential to meet the bioenergetic and biosynthetic demands of immune cells, also regulates a broad spectrum of cellular signal transduction, and influences immune cell survival, differentiation, and anti-tumor effector function. The cancer immunometabolism research field is rapidly evolving, and exciting new discoveries are reported in high-profile journals nearly weekly. Therefore, all new findings in this field cannot be summarized within this short review. Instead, this review is intended to provide a brief introduction to this rapidly developing research field, with a focus on the metabolism of two classes of important nutrients-lipids and amino acids-in immune cells. We highlight recent research on the roles of lipids and amino acids in regulating the metabolic fitness and immunological functions of T cells, macrophages, and natural killer cells in the tumor microenvironment. Furthermore, we discuss the possibility of "editing" metabolic pathways in immune cells to act synergistically with currently available immunotherapies in enhancing anti-tumor immune responses.

Keywords:  Lipids; NK cells; T cells; amino acids; anti-tumor immunity; cancer; immunometabolism; metabolism

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2022.0381