bims-almceb 2022-12-18 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2022–12–18
twelve papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

Regulation of Metabolic Plasticity in Cancer Stem Cells and Implications in Cancer Therapy.
Nalbuphine suppresses leukemia stem cells and acts synergistically with chemotherapy drugs via inhibiting Ras/Raf/Mek/Erk pathway.
Integrated single-cell transcriptome analysis of CD34 + enriched leukemic stem cells revealed intra- and inter-patient transcriptional heterogeneity in pediatric acute myeloid leukemia.
Metabolism in Cancer Stem Cells: Targets for Clinical Treatment.
UCP2 as a Cancer Target through Energy Metabolism and Oxidative Stress Control.
Targeting lactate metabolism for cancer immunotherapy - a matter of precision.
Therapeutic Targeting of Glutaminolysis as a Novel Strategy to Combat Cancer Stem Cells.
AML-derived extracellular vesicles negatively regulate stem cell pool size: A step toward bone marrow failure.
Editorial: Targeting intra- and extracellular signals contributing to cancer stemness and metastasis in aggressive cancers, Volume II.
Evolving landscape of PD-L2: bring new light to checkpoint immunotherapy.
The transcriptomic landscape of elderly acute myeloid leukemia identifies B7H3 and BANP as a favorable signature in high-risk patients.
How can we design a better care model to address the acute distress of an acute leukemia diagnosis? Care models to address the acute distress of an acute leukemia diagnosis.

Cancers (Basel). 2022 Nov 30. pii: 5912. [Epub ahead of print]14(23):

Regulation of Metabolic Plasticity in Cancer Stem Cells and Implications in Cancer Therapy.

Styliani Papadaki, Angeliki Magklara.

  Cancer stem cells (CSCs), a subpopulation of tumor cells with self-renewal capacity, have been associated with tumor initiation, progression, and therapy resistance. While the bulk of tumor cells mainly use glycolysis for energy production, CSCs have gained attention for their ability to switch between glycolysis and oxidative phosphorylation, depending on their energy needs and stimuli from their microenvironment. This metabolic plasticity is mediated by signaling pathways that are also implicated in the regulation of CSC properties, such as the Wnt/β-catenin, Notch, and Hippo networks. Two other stemness-associated processes, autophagy and hypoxia, seem to play a role in the metabolic switching of CSCs as well. Importantly, accumulating evidence has linked the metabolic plasticity of CSCs to their increased resistance to treatment. In this review, we summarize the metabolic signatures of CSCs and the pathways that regulate them; we especially highlight research data that demonstrate the metabolic adaptability of these cells and their role in stemness and therapy resistance. As the development of drug resistance is a major challenge for successful cancer treatment, the potential of specific elimination of CSCs through targeting their metabolism is of great interest and it is particularly examined.

Keywords:  aerobic glycolysis; autophagy; cancer stem cells; drug resistance; glycolysis; hypoxia; metabolic plasticity; metabolic reprogramming; metabolism; oxidative phosphorylation

DOI:  https://doi.org/10.3390/cancers14235912
Anticancer Agents Med Chem. 2022 Dec 13.

Nalbuphine suppresses leukemia stem cells and acts synergistically with chemotherapy drugs via inhibiting Ras/Raf/Mek/Erk pathway.

Jinliang Xiao, Weilian Wang, Jiapeng Dan.

   AIMS: Retrospective clinical studies have shown that opioids could potentially affect the risk of cancer recurrence and metastasis. Better understanding of the effects of opioids on cancer will help to select the optimal anesthetic regimens to achieve better outcomes in cancer patients.
BACKGROUND: Increasing evidence has shown the direct effects of opioids on bulk cancer cells and cancer stem cells. Opioid such as nalbuphine is approved to control cancer-associated pain but little is known on their possible cancer effects.
OBJECTIVE: To assess the biological effects of nalbuphine on acute myeloid leukemia (AML) differentiated and stem/progenitor CD34+ cells.
METHOD: AML CD34+ cells were isolated with colony formation, growth and apoptosis assays performed. Biochemical and immunoblotting analyses were conducted in AML cells exposed to nalbuphine.
RESULT: Nalbuphine at clinically relevant concentrations was active against a panel of AML cell lines with varying IC50. Importantly, nalbuphine augmented the efficacy of cytarabine and daunorubicin in decreasing AML cell viability/growth. Besides bulk AML cells, we noted that nalbuphine was effective and selective in decreasing viability and colony formation of AML CD34+ cells while sparing normal hematopoietic CD34+ cells. The action of nalbuphine on AML cells is not associated with opioid receptors but via inhibiting Ras/Raf/MEK/ERK signaling pathway. Overexpression of constitutively active Ras partially but significantly reversed the inhibitory effects of nalbuphine on AML cells.
CONCLUSION: Our findings reveal the selective anti-AML activity of nalbuphine and its ability in inhibiting Ras signaling. Our work suggests that nalbuphine may be beneficial for leukemia patients.

Keywords:  AML; Hematopoietic stem cells; Nalbuphine; Opioids receptor; Ras

DOI:  https://doi.org/10.2174/1871520623666221213120258
Ann Hematol. 2022 Dec 17.

Integrated single-cell transcriptome analysis of CD34 + enriched leukemic stem cells revealed intra- and inter-patient transcriptional heterogeneity in pediatric acute myeloid leukemia.

Deepshi Thakral, Vivek Kumar Singh, Ritu Gupta, Nitu Jha, Aafreen Khan, Gurvinder Kaur, Sandeep Rai, Vijay Kumar, Manisha Supriya, Sameer Bakhshi, Rachna Seth.

  To gain insights into the idiosyncrasies of CD34 + enriched leukemic stem cells, we investigated the nature and extent of transcriptional heterogeneity by single-cell sequencing in pediatric AML. Whole transcriptome analysis of 28,029 AML single cells was performed using the nanowell cartridge-based barcoding technology. Integrated transcriptional analysis identified unique leukemic stem cell clusters of each patient and intra-patient heterogeneity was revealed by multiple LSC-enriched clusters differing in their cell cycle processes and BCL2 expression. All LSC-enriched clusters exhibited gene expression profile of dormancy and self-renewal. Upregulation of genes involved in non-coding RNA processing and ribonucleoprotein assembly were observed in LSC-enriched clusters relative to HSC. The genes involved in regulation of apoptotic processes, response to cytokine stimulus, and negative regulation of transcription were upregulated in LSC-enriched clusters as compared to the blasts. Validation of top altered genes in LSC-enriched clusters confirmed upregulation of TCF7L2, JUP, ARHGAP25, LPAR6, and PRDX1 genes, and serine/threonine kinases (STK24, STK26). Upregulation of LPAR6 showed trend towards MRD positive status (Odds ratio = 0.126; 95% CI = 0.0144-1.10; p = 0.067) and increased expression of STK26 significantly correlated with higher RFS (HR = 0.231; 95% CI = 0.0506-1.052; p = 0.04). Our findings addressed the inter- and intra-patient diversity within AML LSC and potential signaling and chemoresistance-associated targets that warrant investigation in larger cohort that may guide precision medicine in the near future.

Keywords:  Acute myeloid leukemia; DEGs; Gene expression profile; Leukemic stem cells; Pediatric AML; Single-cell sequencing; Transcriptional heterogeneity

DOI:  https://doi.org/10.1007/s00277-022-05021-4
Cells. 2022 Nov 26. pii: 3790. [Epub ahead of print]11(23):

Metabolism in Cancer Stem Cells: Targets for Clinical Treatment.

Gui-Min Wen, Xiao-Yan Xu, Pu Xia.

  Cancer stem cells (CSCs) have high tumorigenicity, high metastasis and high resistance to treatment. They are the key factors for the growth, metastasis and drug resistance of malignant tumors, and are also the important reason for the occurrence and recurrence of tumors. Metabolic reprogramming refers to the metabolic changes that occur when tumor cells provide sufficient energy and nutrients for themselves. Metabolic reprogramming plays an important role in regulating the growth and activity of cancer cells and cancer stem cells. In addition, the immune cells or stromal cells in the tumor microenvironment (TME) will change due to the metabolic reprogramming of cancer cells. Summarizing the characteristics and molecular mechanisms of metabolic reprogramming of cancer stem cells will provide new ideas for the comprehensive treatment of malignant tumors. In this review, we summarized the changes of the main metabolic pathways in cancer cells and cancer stem cells.

Keywords:  ALDH1; cancer stem cell; ferroptosis; metabolism; tumor microenvironment

DOI:  https://doi.org/10.3390/cells11233790
Int J Mol Sci. 2022 Dec 01. pii: 15077. [Epub ahead of print]23(23):

UCP2 as a Cancer Target through Energy Metabolism and Oxidative Stress Control.

Angèle Luby, Marie-Clotilde Alves-Guerra.

  Despite numerous therapies, cancer remains one of the leading causes of death worldwide due to the lack of markers for early detection and response to treatment in many patients. Technological advances in tumor screening and renewed interest in energy metabolism have allowed us to identify new cellular players in order to develop personalized treatments. Among the metabolic actors, the mitochondrial transporter uncoupling protein 2 (UCP2), whose expression is increased in many cancers, has been identified as an interesting target in tumor metabolic reprogramming. Over the past decade, a better understanding of its biochemical and physiological functions has established a role for UCP2 in (1) protecting cells from oxidative stress, (2) regulating tumor progression through changes in glycolytic, oxidative and calcium metabolism, and (3) increasing antitumor immunity in the tumor microenvironment to limit cancer development. With these pleiotropic roles, UCP2 can be considered as a potential tumor biomarker that may be interesting to target positively or negatively, depending on the type, metabolic status and stage of tumors, in combination with conventional chemotherapy or immunotherapy to control tumor development and increase response to treatment. This review provides an overview of the latest published science linking mitochondrial UCP2 activity to the tumor context.

Keywords:  cancer; metabolism; mitochondria; oxidative stress; therapies; uncoupling protein 2 (UCP2)

DOI:  https://doi.org/10.3390/ijms232315077
Semin Cancer Biol. 2022 Dec 07. pii: S1044-579X(22)00255-3. [Epub ahead of print]88 32-45

Targeting lactate metabolism for cancer immunotherapy - a matter of precision.

Christoph Heuser, Kathrin Renner, Marina Kreutz, Luca Gattinoni.

  Immune checkpoint inhibitors and adoptive T cell therapies have been valuable additions to the toolbox in the fight against cancer. These treatments have profoundly increased the number of patients with a realistic perspective toward a return to a cancer-free life. Yet, in a number of patients and tumor entities, cancer immunotherapies have been ineffective so far. In solid tumors, immune exclusion and the immunosuppressive tumor microenvironment represent substantial roadblocks to successful therapeutic outcomes. A major contributing factor to the depressed anti-tumor activity of immune cells in tumors is the harsh metabolic environment. Hypoxia, nutrient competition with tumor and stromal cells, and accumulating noxious waste products, including lactic acid, pose massive constraints to anti-tumor immune cells. Numerous strategies are being developed to exploit the metabolic vulnerabilities of tumor cells in the hope that these would also alleviate metabolism-inflicted immune suppression. While promising in principle, especially in combination with immunotherapies, these strategies need to be scrutinized for their effect on tumor-fighting immune cells, which share some of their key metabolic properties with tumor cells. Here, we provide an overview of strategies that seek to tackle lactate metabolism in tumor or immune cells to unleash anti-tumor immune responses, thereby opening therapeutic options for patients whose tumors are currently not treatable.

Keywords:  Acidification; Adoptive cell transfer; Checkpoint inhibition; Glycolysis; Immunotherapy; Lactate; Metabolism

DOI:  https://doi.org/10.1016/j.semcancer.2022.12.001
Int J Mol Sci. 2022 Dec 04. pii: 15296. [Epub ahead of print]23(23):

Therapeutic Targeting of Glutaminolysis as a Novel Strategy to Combat Cancer Stem Cells.

Ting-Wan Kao, Yao-Chen Chuang, Hsin-Lun Lee, Chia-Chun Kuo, Yao-An Shen.

  Rare subpopulations of cancer stem cells (CSCs) have the ability to self-renew and are the primary driving force behind cancer metastatic dissemination and the preeminent hurdle to cancer treatment. As opposed to differentiated, non-malignant tumor offspring, CSCs have sophisticated metabolic patterns that, depending on the kind of cancer, rely mostly on the oxidation of major fuel substrates such as glucose, glutamine, and fatty acids for survival. Glutaminolysis is a series of metabolic reactions that convert glutamine to glutamate and, eventually, α-ketoglutarate, an intermediate in the tricarboxylic acid (TCA) cycle that provides biosynthetic building blocks. These building blocks are mostly utilized in the synthesis of macromolecules and antioxidants for redox homeostasis. A recent study revealed the cellular and molecular interconnections between glutamine and cancer stemness in the cell. Researchers have increasingly focused on glutamine catabolism in their attempt to discover an effective therapy for cancer stem cells. Targeting catalytic enzymes in glutaminolysis, such as glutaminase (GLS), is achievable with small molecule inhibitors, some of which are in early-phase clinical trials and have promising safety profiles. This review summarizes the current findings in glutaminolysis of CSCs and focuses on novel cancer therapies that target glutaminolysis in CSCs.

Keywords:  cancer stem cells; glutaminase; glutaminolysis; metabolic compensation; therapeutic resistance

DOI:  https://doi.org/10.3390/ijms232315296
Curr Res Transl Med. 2022 Nov 30. pii: S2452-3186(22)00043-5. [Epub ahead of print]71(1): 103375

AML-derived extracellular vesicles negatively regulate stem cell pool size: A step toward bone marrow failure.

Bahrampour Shahrokh, Farsani Mehdi Allahbakhshian, Gharehbaghian Ahmad, Feizi Fatemeh, Mohammadi Mohammad Hossein.

   PURPOSE OF THE STUDY: Long-term repopulating hematopoietic stem cells (LTR-HSCs) have been previously shown to reside in close proximity to osteoblasts, where they take shelter in the bone marrow (BM) microenvironment against cytotoxic and apoptotic stimuli. Nevertheless, the function of the HSC niche is believed to undergo an adaptive evolutionary modification during leukemogenesis. Recent studies have demonstrated that leukemic clones can impact BM homing through extracellular vesicle (EV) secretion. However, the exact mechanism driving BM conversion is still unclear. In the present study, the human osteoblast cell line (MG-63) were subjected to various concentration of sera-derived EVs of patients with acute myeloid leukemia (AML) and healthy volunteers to assess if they are associated strongly enough to alter the expression pattern of cross-talk molecules involved in niche interactions.
METHOD: To gain a brief insight into the EVs secretion criteria, we first conducted a comparative analysis of sera-derived EVs by dynamic light scattering (DLS), transmission electron microscopy (TEM), and Bradford assay. After incubating MG-63 cell lines with increasing concentrations of the EVs, Trypan-blue and microculture tetrazolium test (MTT) assays were used to evaluate the cell survival, logarithmic growth, and metabolic activity. Finally, the expression levels of OPN, ANGPT-1, and JAG-1 transcripts were evaluated through the qRT-PCR technique.
RESULTS: Here, we report that AML-derived EVs can affect the viability, cell growth, and metabolic activity of the human osteoblasts cell line (MG-63) compared to those that received healthy-derived EVs. We also found that leukemic EVs tend to induce overexpression of OPN but reduce the expression of ANGPT-1 and JAG-1 genes in the osteoblast transcriptome, which may provide a potential context imposing selective suppression of HSC pool size.
CONCLUSION: These findings extend the general concept of a novel mechanism in which leukemic EVs would make it possible to create a specialized pre-metastatic microenvironment in the interest of tumor expansion, allowing leukemic clones to overcome their HSCs counterparts.

Keywords:  Acute myeloid leukemia; Cell adhesion molecule; Extracellular vesicles; Hematopoiesis; Osteoblast

DOI:  https://doi.org/10.1016/j.retram.2022.103375
Front Pharmacol. 2022 ;13 1060359

Editorial: Targeting intra- and extracellular signals contributing to cancer stemness and metastasis in aggressive cancers, Volume II.

Laia Caja, Enza Lonardo, Patricia Sancho.



Keywords:  cancer metabolism; cancer stem cells; glioblastoma; hepatocellular carcinoma; pancreatic ductal adenocarcinoma; tumor microenvironment

DOI:  https://doi.org/10.3389/fphar.2022.1060359
Br J Cancer. 2022 Dec 15.

Evolving landscape of PD-L2: bring new light to checkpoint immunotherapy.

Yuqing Wang, Jiang Du, Zhenyue Gao, Haoyang Sun, Mei Mei, Yu Wang, Yu Ren, Xuan Zhou.

Immune checkpoint blockade therapy targeting programmed cell death protein 1 (PD-1) has revolutionized the landscape of multiple human cancer types, including head and neck squamous carcinoma (HNSCC). Programmed death ligand-2 (PD-L2), a PD-1 ligand, mediates cancer cell immune escape (or tolerance independent of PD-L1) and predicts poor prognosis of patients with HNSCC. Therefore, an in-depth understanding of the regulatory process of PD-L2 expression may stratify patients with HNSCC to benefit from anti-PD-1 immunotherapy. In this review, we summarised the PD-L2 expression and its immune-dependent and independent functions in HNSCC and other solid tumours. We focused on recent findings on the mechanisms that regulate PD-L2 at the genomic, transcriptional, post-transcriptional, translational, and post-translational levels, also in intercellular communication of tumour microenvironment (TME). We also discussed the prospects of using small molecular agents indirectly targeting PD-L2 in cancer therapy. These findings may provide a notable avenue in developing novel and effective PD-L2-targeted therapeutic strategies for immune combination therapy and uncovering biomarkers that improve the clinical efficacy of anti-PD-1 therapies.

DOI: https://doi.org/10.1038/s41416-022-02084-y
Front Oncol. 2022 ;12 1054458

The transcriptomic landscape of elderly acute myeloid leukemia identifies B7H3 and BANP as a favorable signature in high-risk patients.

Sara Villar, Beñat Ariceta, Xabier Agirre, Aura Daniela Urribarri, Rosa Ayala, David Martínez-Cuadrón, Juan Miguel Bergua, Susana Vives, Lorenzo Algarra, Mar Tormo, Pilar Martínez, Josefina Serrano, Catia Simoes, Pilar Herrera, Maria José Calasanz, Ana Alfonso-Piérola, Bruno Paiva, Joaquín Martínez-López, Jesús F San Miguel, Felipe Prósper, Pau Montesinos.

  Acute myeloid leukemia (AML) in the elderly remains a clinical challenge, with a five-year overall survival rate below 10%. The current ELN 2017 genetic risk classification considers cytogenetic and mutational characteristics to stratify fit AML patients into different prognostic groups. However, this classification is not validated for elderly patients treated with a non-intensive approach, and its performance may be suboptimal in this context. Indeed, the transcriptomic landscape of AML in the elderly has been less explored and it might help stratify this group of patients. In the current study, we analyzed the transcriptome of 224 AML patients > 65 years-old at diagnosis treated in the Spanish PETHEMA-FLUGAZA clinical trial in order to identify new prognostic biomarkers in this population. We identified a specific transcriptomic signature for high-risk patients with mutated TP53 or complex karyotype, revealing that low expression of B7H3 gene with high expression of BANP gene identifies a subset of high-risk AML patients surviving more than 12 months. This result was further validated in the BEAT AML cohort. This unique signature highlights the potential of transcriptomics to identify prognostic biomarkers in in elderly AML.

Keywords:  acute myeloid leukemia; biomarkers; elderly; prognosis; transcriptomics

DOI:  https://doi.org/10.3389/fonc.2022.1054458
Best Pract Res Clin Haematol. 2022 Dec;pii: S1521-6926(22)00064-0. [Epub ahead of print]35(4): 101409

How can we design a better care model to address the acute distress of an acute leukemia diagnosis? Care models to address the acute distress of an acute leukemia diagnosis.

Areej El-Jawahri.



Keywords:  AML; Acute myeloid leukemia; Distress; Hospitalization; QOL; Quality of life

DOI:  https://doi.org/10.1016/j.beha.2022.101409