bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2021–12–05
eight papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul
  1. Metabolic Reprogramming in the Tumor Microenvironment With Immunocytes and Immune Checkpoints.
  2. Targeting the metabolism of cancer stem cells by energy disruptor molecules.
  3. Fumarate is a terminal electron acceptor in the mammalian electron transport chain.
  4. Peroxisomal support of mitochondrial respiratory efficiency promotes ER stress survival.
  5. Targeting cancer metabolism in the era of precision oncology.
  6. SLC25A1 promotes tumor growth and survival by reprogramming energy metabolism in colorectal cancer.
  7. Factors Associated with Health Care Utilization at the End of Life for Patients with Acute Myeloid Leukemia.
  8. CD122-targeted interleukin-2 and αPD-L1 treat bladder cancer and melanoma via distinct mechanisms, including CD122-driven natural killer cell maturation.
  1. Front Oncol. 2021 ;11 759015
    Metabolic Reprogramming in the Tumor Microenvironment With Immunocytes and Immune Checkpoints.
    Yaolin Xu, Lijie He, Qiang Fu, Junzhe Hu.
      Immune checkpoint inhibitors (ICIs), Ipilimumab, Nivolumab, Pembrolizumab and Atezolizumab, have been applied in anti-tumor therapy and demonstrated exciting performance compared to conventional treatments. However, the unsatisfactory response rates, high recurrence and adaptive resistance limit their benefits. Metabolic reprogramming appears to be one of the crucial barriers to immunotherapy. The deprivation of required nutrients and altered metabolites not only promote tumor progression but also confer dysfunction on immune cells in the tumor microenvironment (TME). Glycolysis plays a central role in metabolic reprogramming and immunoregulation in the TME, and many therapies targeting glycolysis have been developed, and their combinations with ICIs are in preclinical and clinical trials. Additional attention has been paid to the role of amino acids, lipids, nucleotides and mitochondrial biogenesis in metabolic reprogramming and clinical anti-tumor therapy. This review attempts to describe reprogramming metabolisms within tumor cells and immune cells, from the aspects of glycolysis, amino acid metabolism, lipid metabolism, nucleotide metabolism and mitochondrial biogenesis and their impact on immunity in the TME, as well as the significance of targeting metabolism in anti-tumor therapy, especially in combination with ICIs. In particular, we highlight the expression mechanism of programmed cell death (ligand) 1 [PD-(L)1] in tumor cells and immune cells under reprogramming metabolism, and discuss in detail the potential of targeting key metabolic pathways to break resistance and improve the efficacy of ICIs based on results from current preclinical and clinical trials. Besides, we draw out biomarkers of potential predictive value in ICIs treatment from a metabolic perspective.
    Keywords:  PD-1; amino acid metabolism; glycolysis; immune checkpoints; lipid metabolism; mitochondrial biogenesis; nucleotide metabolism; the tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2021.759015
  2. Crit Rev Oncol Hematol. 2021 Nov 24. pii: S1040-8428(21)00332-2. [Epub ahead of print]169 103545
    Targeting the metabolism of cancer stem cells by energy disruptor molecules.
    Tahere Dadgar, Nasim Ebrahimi, Amir Reza Gholipour, Maryam Akbari, Leila Khani, Amirhossein Ahmadi, Michael R Hamblin.
      Cancer stem cells (CSCs) have been identified in various tumor types. CSCs are believed to contribute to tumor metastasis and resistance to conventional therapy. So targeting these cells could be an effective strategy to eliminate tumors and a promising new type of cancer treatment. Alterations in metabolism play an essential role in CSC biology and their resistance to treatment. The metabolic properties pathways in CSCs are different from normal cells, and to some extent, are different from regular tumor cells. Interestingly, CSCs can use other nutrients for their metabolism and growth. The different metabolism causes increased sensitivity of CSCs to agents that disrupt cellular homeostasis. Compounds that interfere with the central metabolic pathways are known as energy disruptors and can reduce CSC survival. This review highlights the differences between regular cancer cells and CSC metabolism and discusses the action mechanisms of energy disruptors at the cellular and molecular levels.
    Keywords:  Cancer; Cancer stem cells; Energy disruptors; Metabolism
    DOI:  https://doi.org/10.1016/j.critrevonc.2021.103545
  3. Science. 2021 Dec 03. 374(6572): 1227-1237
    Fumarate is a terminal electron acceptor in the mammalian electron transport chain.
    Jessica B Spinelli, Paul C Rosen, Hans-Georg Sprenger, Anna M Puszynska, Jessica L Mann, Julian M Roessler, Andrew L Cangelosi, Antonia Henne, Kendall J Condon, Tong Zhang, Tenzin Kunchok, Caroline A Lewis, Navdeep S Chandel, David M Sabatini.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/science.abi7495
  4. J Cell Sci. 2021 Dec 02. pii: jcs.259254. [Epub ahead of print]
    Peroxisomal support of mitochondrial respiratory efficiency promotes ER stress survival.
    Imadeddin Hijazi, Emily Wang, Michelle Orozco, Sarah Pelton, Amy Chang.
      Endoplasmic reticulum stress (ERS) occurs when cellular demand for protein folding exceeds the capacity of the organelle. Adaptation and cell survival in response to ERS requires a critical contribution by mitochondria and peroxisomes. During ERS response, mitochondrial respiration increases to ameliorate reactive oxygen species (ROS) accumulation; we now show in yeast that peroxisome abundance also increases to promote an adaptive response. In pox1▵ cells, defective in peroxisomal ß oxidation of fatty acids, respiratory response to ERS is impaired, and ROS accrues. However, respiratory response to ERS is rescued, and ROS production is mitigated in pox1▵ cells by overexpression of Mpc1, the mitochondrial pyruvate carrier that provides another source of acetyl CoA to fuel the TCA cycle and oxidative phosphorylation. Using proteomics, select mitochondrial proteins were identified that undergo upregulation by ERS to remodel respiratory machinery. Several peroxisome-based proteins were also increased, corroborating the peroxisomal role in ERS adaptation. Finally, ERS stimulates assembly of respiratory complexes into higher order supercomplexes, underlying increased electron transfer efficiency. Our results highlight peroxisomal and mitochondrial support for ERS adaptation to favor cell survival.
    Keywords:  Endoplasmic reticulum; Mitochondria; Stress survival
    DOI:  https://doi.org/10.1242/jcs.259254
  5. Nat Rev Drug Discov. 2021 Dec 03.
    Targeting cancer metabolism in the era of precision oncology.
    Zachary E Stine, Zachary T Schug, Joseph M Salvino, Chi V Dang.
      One hundred years have passed since Warburg discovered alterations in cancer metabolism, more than 70 years since Sidney Farber introduced anti-folates that transformed the treatment of childhood leukaemia, and 20 years since metabolism was linked to oncogenes. However, progress in targeting cancer metabolism therapeutically in the past decade has been limited. Only a few metabolism-based drugs for cancer have been successfully developed, some of which are in - or en route to - clinical trials. Strategies for targeting the intrinsic metabolism of cancer cells often did not account for the metabolism of non-cancer stromal and immune cells, which have pivotal roles in tumour progression and maintenance. By considering immune cell metabolism and the clinical manifestations of inborn errors of metabolism, it may be possible to isolate undesirable off-tumour, on-target effects of metabolic drugs during their development. Hence, the conceptual framework for drug design must consider the metabolic vulnerabilities of non-cancer cells in the tumour immune microenvironment, as well as those of cancer cells. In this Review, we cover the recent developments, notable milestones and setbacks in targeting cancer metabolism, and discuss the way forward for the field.
    DOI:  https://doi.org/10.1038/s41573-021-00339-6
  6. Cell Death Dis. 2021 Nov 27. 12(12): 1108
    SLC25A1 promotes tumor growth and survival by reprogramming energy metabolism in colorectal cancer.
    Ying Yang, Jiaxing He, Bo Zhang, Zhansheng Zhang, Guozhan Jia, Shiqi Liu, Tao Wu, Xianli He, Nan Wang.
      Abnormal lipid metabolism has been commonly observed in various human cancers, including colorectal cancer (CRC). The mitochondrial citrate carrier SLC25A1 (also known as mitochondrial citrate/isocitrate carrier, CIC), has been shown to play an important role in lipid metabolism regulation. Our bioinformatics analysis indicated that SLC25A1 was markedly upregulated in CRC. However, the role of SLC25A1 in the pathogenesis and aberrant lipid metabolism in CRC remain unexplored. Here, we found that SLC25A1 expression was significantly increased in tumor samples of CRC as compared with paired normal samples, which is associated with poor survival in patients with CRC. Knockdown of SLC25A1 significantly inhibited the growth of CRC cells by suppressing the progression of the G1/S cell cycle and inducing cell apoptosis both in vitro and in vivo, whereas SLC25A1 overexpression suppressed the malignant phenotype. Additionally, we demonstrated that SLC25A1 reprogrammed energy metabolism to promote CRC progression through two mechanisms. Under normal conditions, SLC25A1 increased de novo lipid synthesis to promote CRC growth. During metabolic stress, SLC25A1 increased oxidative phosphorylation (OXPHOS) to protect protects CRC cells from energy stress-induced cell apoptosis. Collectively, SLC25A1 plays a pivotal role in the promotion of CRC growth and survival by reprogramming energy metabolism. It could be exploited as a novel diagnostic marker and therapeutic target in CRC.
    DOI:  https://doi.org/10.1038/s41419-021-04411-2
  7. J Palliat Med. 2021 Dec 03.
    Factors Associated with Health Care Utilization at the End of Life for Patients with Acute Myeloid Leukemia.
    Dagny M Vaughn, P Connor Johnson, Annemarie D Jagielo, Carlisle E W Topping, Matthew J Reynolds, Alison R Kavanaugh, Jason A Webb, Amir T Fathi, Gabriela Hobbs, Andrew Brunner, Nina O'Connor, Selina Luger, Bhavana Bhatnagar, Thomas W LeBlanc, Areej El-Jawahri.
      Background: Patients (≥60 years) with acute myeloid leukemia (AML) often receive intense health care utilization at the end of life (EOL). However, factors associated with their health care use at the EOL are unknown. Methods: We conducted a secondary analysis of 168 deceased patients with AML within the United States. We assessed quality of life (QOL) (Functional-Assessment-Cancer-Therapy-Leukemia), and psychological distress (Hospital-Anxiety-and-Depression Scale [HADS]; Patient-Health-Questionnaire-9 [PHQ-9]) at diagnosis. We used multivariable logistic regression models to examine the association between patient-reported factors and the following outcomes: (1) hospitalizations in the last 7 days of life, (2) receipt of chemotherapy in the last 30 days of life, and (3) hospice utilization. Results: About 66.7% (110/165) were hospitalized in the last 7 days of life, 51.8% (71/137) received chemotherapy in the last 30 days of life, and 40.7% (70/168) utilized hospice. In multivariable models, higher education (odds ratio [OR] = 1.54, p = 0.006) and elevated baseline depression symptoms (PHQ-9: OR = 1.09, p = 0.028) were associated with higher odds of hospitalization in the last seven days of life, while higher baseline QOL (OR = 0.98, p = 0.009) was associated with lower odds of hospitalization at the EOL. Higher baseline depression symptoms were associated with receipt of chemotherapy at the EOL (HADS-Depression: OR = 1.10, p = 0.042). Higher education was associated with lower hospice utilization (OR = 0.356, p = 0.024). Conclusions: Patients with AML who are more educated, with higher baseline depression symptoms and lower QOL, were more likely to experience high health care utilization at the EOL. These populations may benefit from interventions to optimize the quality of their EOL care.
    Keywords:  acute myeloid leukemia; end-of-life; health care utilization; palliative care
    DOI:  https://doi.org/10.1089/jpm.2021.0249
  8. Oncoimmunology. 2021 ;10(1): 2006529
    CD122-targeted interleukin-2 and αPD-L1 treat bladder cancer and melanoma via distinct mechanisms, including CD122-driven natural killer cell maturation.
    Ryan M Reyes, Chenghao Zhang, Yilun Deng, Niannian Ji, Neelam Mukherjee, Alvaro S Padron, Curtis A Clark, Robert S Svatek, Tyler J Curiel.
      Bladder cancer (BC) and melanoma are amenable to immune checkpoint blockade (ICB) therapy, yet most patients with advanced/metastatic disease do not respond. CD122-targeted interleukin (IL)-2 can improve ICB efficacy, but mechanisms are unclear. We tested αPD-L1 and CD122-directed immunotherapy with IL-2/αIL-2 complexes (IL-2c) in primary and metastatic bladder and melanoma tumors. IL-2c treatment of orthotopic MB49 and MBT-2 BC generated NK cell antitumor immunity through enhanced activation, reduced exhaustion, and promotion of a mature, effector NK cell phenotype. By comparison, subcutaneous B16-F10 melanoma, which is IL-2c sensitive, requires CD8+ T and not NK cells, yet we found αPD-L1 efficacy requires both CD8+ T and NK cells. We then explored αPD-L1 and IL-2c mechanisms at distinct metastatic sites and found intraperitoneal B16-F10 metastases were sensitive to αPD-L1 and IL-2c, with IL-2c but not αPD-L1, increasing CD122+ mature NK cell function, confirming conserved IL-2c effects in distinct cancer types and anatomic compartments. αPD-L1 failed to control tumor growth and prolong survival in B16-F10 lung metastases, yet IL-2c treated B16-F10 lung metastases effectively even in T cell and adaptive immunity deficient mice, which was abrogated by NK cell depletion in wild-type mice. Flow cytometric analyses of NK cells in B16-F10 lung metastases suggest that IL-2c directly boosts NK cell activation and effector function. Thus, αPD-L1 and IL-2c mediate nonredundant, immune microenvironment-specific treatment mechanisms involving CD8+ T and NK cells in primary and metastatic BC and melanoma. Mechanistic differences suggest effective treatment combinations including in other tumors or sites, warranting further studies.
    Keywords:  CD122; Il-2; NK cells; Preclinical; bladder cancer; immune checkpoint blockade; immunotherapy; lymphocyte activation; melanoma; metastasis; tumor microenvironment; urinary tissue-specific microenvironment
    DOI:  https://doi.org/10.1080/2162402X.2021.2006529
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