bims-almceb 2022-08-14 papers

bims-almceb

Biomed News

on Acute Leukemia Metabolism and Cell Biology

Issue of 2022–08–14
twelve papers selected by
Camila Kehl Dias, Federal University of Rio Grande do Sul

The metabolic addiction of cancer stem cells.
c-Myc plays a critical role in the antileukemic activity of the Mcl-1-selective inhibitor AZD5991 in acute myeloid leukemia.
Editorial: New insights into the mechanisms of resistance to anti-cancer drugs.
Metabolic profiles of regulatory T cells and their adaptations to the tumor microenvironment: implications for antitumor immunity.
Miro proteins and their role in mitochondrial transfer in cancer and beyond.
Balanced mitochondrial and cytosolic translatomes underlie the biogenesis of human respiratory complexes.
Multiple gene knockdown strategies for investigating the properties of human leukemia stem cells and exploring new therapies.
Mitochondrial pyruvate carrier: a metabolic-epigenetic checkpoint orchestrating T cell differentiation.
The adipocyte microenvironment and cancer.
Precision medicine in AML: Function plus -omics is better than either alone.
Stressed to death: Mitochondrial stress responses connect respiration and apoptosis in cancer.
Connections between metabolism and epigenetics: mechanisms and novel anti-cancer strategy.

Front Oncol. 2022 ;12 955892

The metabolic addiction of cancer stem cells.

Om Saswat Sahoo, Karthikeyan Pethusamy, Tryambak P Srivastava, Joyeeta Talukdar, Mohammed S Alqahtani, Mohamed Abbas, Ruby Dhar, Subhradip Karmakar.

  Cancer stem cells (CSC) are the minor population of cancer originating cells that have the capacity of self-renewal, differentiation, and tumorigenicity (when transplanted into an immunocompromised animal). These low-copy number cell populations are believed to be resistant to conventional chemo and radiotherapy. It was reported that metabolic adaptation of these elusive cell populations is to a large extent responsible for their survival and distant metastasis. Warburg effect is a hallmark of most cancer in which the cancer cells prefer to metabolize glucose anaerobically, even under normoxic conditions. Warburg's aerobic glycolysis produces ATP efficiently promoting cell proliferation by reprogramming metabolism to increase glucose uptake and stimulating lactate production. This metabolic adaptation also seems to contribute to chemoresistance and immune evasion, a prerequisite for cancer cell survival and proliferation. Though we know a lot about metabolic fine-tuning in cancer, what is still in shadow is the identity of upstream regulators that orchestrates this process. Epigenetic modification of key metabolic enzymes seems to play a decisive role in this. By altering the metabolic flux, cancer cells polarize the biochemical reactions to selectively generate "onco-metabolites" that provide an added advantage for cell proliferation and survival. In this review, we explored the metabolic-epigenetic circuity in relation to cancer growth and proliferation and establish the fact how cancer cells may be addicted to specific metabolic pathways to meet their needs. Interestingly, even the immune system is re-calibrated to adapt to this altered scenario. Knowing the details is crucial for selective targeting of cancer stem cells by choking the rate-limiting stems and crucial branch points, preventing the formation of onco-metabolites.

Keywords:  cancer stem cells; cross talks; epigenetics; metabolism; oncometabolites

DOI:  https://doi.org/10.3389/fonc.2022.955892
Apoptosis. 2022 Aug 09.

c-Myc plays a critical role in the antileukemic activity of the Mcl-1-selective inhibitor AZD5991 in acute myeloid leukemia.

Shuang Liu, Xinan Qiao, Shuangshuang Wu, Yuqinq Gai, Yongwei Su, Holly Edwards, Yue Wang, Hai Lin, Jeffrey W Taub, Guan Wang, Yubin Ge.

  Acute myeloid leukemia (AML) is an aggressive disease with a low 5-year overall survival rate of 29.5%. Thus, more effective therapies are in need to prolong survival of AML patients. Mcl-1 is overexpressed in AML and is associated with poor prognosis, representing a promising therapeutic target. The oncoprotein c-Myc is also overexpressed in AML and is a significant prognostic factor. In addition, Mcl-1 is required for c-Myc induced AML, indicating that c-Myc-driven AML harbors a Mcl-1 dependency and co-targeting of Mcl-1 and c-Myc represents a promising strategy to eradicate AML. In this study, we investigated the role of c-Myc in the antileukemic activity of Mcl-1 selective inhibitor AZD5991 and the antileukemic activity of co-targeting of Mcl-1 and c-Myc in preclinical models of AML. We found that c-Myc protein levels negatively correlated with AZD5991 EC50s in AML cell lines and primary patient samples. AZD5991 combined with inhibition of c-Myc synergistically induced apoptosis in AML cell lines and primary patient samples, and cooperatively targeted leukemia progenitor cells. AML cells with acquired resistance to AZD5991 were resensitized to AZD5991 when c-Myc was inhibited. The combination also showed promising and synergistic antileukemic activity in vitro against AML cell lines with acquired resistance to the main chemotherapeutic drug AraC and primary AML cells derived from a patient at relapse post chemotherapy. The oncoprotein c-Myc represents a potential biomarker of AZD5991 sensitivity and inhibition of c-Myc synergistically enhances the antileukemic activity of AZD5991 against AML.

Keywords:  10058-F4; AZD5991; Acute myeloid leukemia; Mcl-1; c-Myc

DOI:  https://doi.org/10.1007/s10495-022-01756-7
Front Oncol. 2022 ;12 990144

Editorial: New insights into the mechanisms of resistance to anti-cancer drugs.

Francesco Bertoni, Simona Rapposelli.



Keywords:  anti-cancer drugs; chemoresistance; combination therapy; drug resistance; targeted-therapy

DOI:  https://doi.org/10.3389/fonc.2022.990144
J Hematol Oncol. 2022 Aug 10. 15(1): 104

Metabolic profiles of regulatory T cells and their adaptations to the tumor microenvironment: implications for antitumor immunity.

Yuheng Yan, Lan Huang, Yiming Liu, Ming Yi, Qian Chu, Dechao Jiao, Kongming Wu.

  Characterized by the expression of the critical transcription factor forkhead box protein P3, regulatory T (Treg) cells are an essential part of the immune system, with a dual effect on the pathogenesis of autoimmune diseases and cancer. Targeting Tregs to reestablish the proinflammatory and immunogenic tumor microenvironment (TME) is an increasingly attractive strategy for cancer treatment and has been emphasized in recent years. However, attempts have been significantly hindered by the subsequent autoimmunity after Treg ablation owing to systemic loss of their suppressive capacity. Cellular metabolic reprogramming is acknowledged as a hallmark of cancer, and emerging evidence suggests that elucidating the underlying mechanisms of how intratumoral Tregs acquire metabolic fitness and superior immunosuppression in the TME may contribute to clinical benefits. In this review, we discuss the common and distinct metabolic profiles of Tregs in peripheral tissues and the TME, as well as the differences between Tregs and other conventional T cells in their metabolic preferences. By focusing on the critical roles of different metabolic programs, such as glycolysis, oxidative phosphorylation, fatty acid oxidation, fatty acid synthesis, and amino acid metabolism, as well as their essential regulators in modulating Treg proliferation, migration, and function, we hope to provide new insights into Treg cell-targeted antitumor immunotherapies.

Keywords:  Amino acid metabolism; Fatty acid oxidation; Fatty acid synthesis; Glycolysis; Immunotherapy; Oxidative phosphorylation; Regulatory T cell; Tumor microenvironment

DOI:  https://doi.org/10.1186/s13045-022-01322-3
Front Cell Dev Biol. 2022 ;10 937753

Miro proteins and their role in mitochondrial transfer in cancer and beyond.

Zuzana Nahacka, Jaromir Novak, Renata Zobalova, Jiri Neuzil.

  Mitochondria are organelles essential for tumor cell proliferation and metastasis. Although their main cellular function, generation of energy in the form of ATP is dispensable for cancer cells, their capability to drive their adaptation to stress originating from tumor microenvironment makes them a plausible therapeutic target. Recent research has revealed that cancer cells with damaged oxidative phosphorylation import healthy (functional) mitochondria from surrounding stromal cells to drive pyrimidine synthesis and cell proliferation. Furthermore, it has been shown that energetically competent mitochondria are fundamental for tumor cell migration, invasion and metastasis. The spatial positioning and transport of mitochondria involves Miro proteins from a subfamily of small GTPases, localized in outer mitochondrial membrane. Miro proteins are involved in the structure of the MICOS complex, connecting outer and inner-mitochondrial membrane; in mitochondria-ER communication; Ca2+ metabolism; and in the recycling of damaged organelles via mitophagy. The most important role of Miro is regulation of mitochondrial movement and distribution within (and between) cells, acting as an adaptor linking organelles to cytoskeleton-associated motor proteins. In this review, we discuss the function of Miro proteins in various modes of intercellular mitochondrial transfer, emphasizing the structure and dynamics of tunneling nanotubes, the most common transfer modality. We summarize the evidence for and propose possible roles of Miro proteins in nanotube-mediated transfer as well as in cancer cell migration and metastasis, both processes being tightly connected to cytoskeleton-driven mitochondrial movement and positioning.

Keywords:  Miro; cancer; intercellular transfer; metastasis; migration; mitochondria; respiration

DOI:  https://doi.org/10.3389/fcell.2022.937753
Genome Biol. 2022 Aug 09. 23(1): 170

Balanced mitochondrial and cytosolic translatomes underlie the biogenesis of human respiratory complexes.

Iliana Soto, Mary Couvillion, Katja G Hansen, Erik McShane, J Conor Moran, Antoni Barrientos, L Stirling Churchman.

BACKGROUND: Oxidative phosphorylation (OXPHOS) complexes consist of nuclear and mitochondrial DNA-encoded subunits. Their biogenesis requires cross-compartment gene regulation to mitigate the accumulation of disproportionate subunits. To determine how human cells coordinate mitochondrial and nuclear gene expression processes, we tailored ribosome profiling for the unique features of the human mitoribosome.
RESULTS: We resolve features of mitochondrial translation initiation and identify a small ORF in the 3' UTR of MT-ND5. Analysis of ribosome footprints in five cell types reveals that average mitochondrial synthesis levels correspond precisely to cytosolic levels across OXPHOS complexes, and these average rates reflect the relative abundances of the complexes. Balanced mitochondrial and cytosolic synthesis does not rely on rapid feedback between the two translation systems, and imbalance caused by mitochondrial translation deficiency is associated with the induction of proteotoxicity pathways.
CONCLUSIONS: Based on our findings, we propose that human OXPHOS complexes are synthesized proportionally to each other, with mitonuclear balance relying on the regulation of OXPHOS subunit translation across cellular compartments, which may represent a proteostasis vulnerability.

DOI: https://doi.org/10.1186/s13059-022-02732-9
Methods Cell Biol. 2022 ;pii: S0091-679X(22)00049-8. [Epub ahead of print]171 1-22

Multiple gene knockdown strategies for investigating the properties of human leukemia stem cells and exploring new therapies.

Andrew Wu, Aysha S Ansari, Hasan Uludaǧ, Xiaoyan Jiang.

  The past two decades have witnessed significant strides in leukemia therapies through approval of therapeutic inhibitors targeting oncogene-driving dysregulated tyrosine kinase activities and key epigenetic and apoptosis regulators. Although these drugs have brought about complete remission in the majority of patients, many patients face relapse or have refractory disease. The main factor contributing to relapse is the presence of a small subpopulation of dormant drug-resistant leukemia cells that possess stem cell features (termed as leukemia stem cells or LSCs). Thus, overcoming drug resistance and targeting LSCs remain major challenges for curative treatment of human leukemia. Chronic myeloid leukemia (CML) is a good example, with rare, propagating LSCs and drug-resistant cells that cannot be eradicated by BCR-ABL-directed tyrosine kinase inhibitor (TKI) monotherapy and that are responsible for disease relapse/progression. Therefore, it is imperative to identify key players in regulating BCR-ABL1-dependent and independent drug-resistance mechanisms, and their key pathways, so that CML LSCs can be selectively targeted or sensitized to TKIs. Here, we describe several easily adaptable gene knockdown approaches in CD34+ CML stem/progenitor cells that can be used to investigate the biological properties of LSCs and molecular effects of genes of interest (GOI), which can be further explored as therapeutic modalities against LSCs in the context of human leukemia.

Keywords:  AML; CD34(+) stem/progenitor cells; CML; CRISPR-Cas9; FACS; Gene knockdown; LTC-IC; Lentiviral-mediated shRNA; Leukemic stem cells; Lipopolymer/siRNA nanoparticles

DOI:  https://doi.org/10.1016/bs.mcb.2022.04.002
Signal Transduct Target Ther. 2022 Aug 12. 7(1): 280

Mitochondrial pyruvate carrier: a metabolic-epigenetic checkpoint orchestrating T cell differentiation.

Yu Chen, Jingchun Wang, Yongsheng Li.

DOI: https://doi.org/10.1038/s41392-022-01101-z
Cancer Metastasis Rev. 2022 Aug 08.

The adipocyte microenvironment and cancer.

Abir Mukherjee, Agnes J Bilecz, Ernst Lengyel.

  Many epithelial tumors grow in the vicinity of or metastasize to adipose tissue. As tumors develop, crosstalk between adipose tissue and cancer cells leads to changes in adipocyte function and paracrine signaling, promoting a microenvironment that supports tumor growth. Over the last decade, it became clear that tumor cells co-opt adipocytes in the tumor microenvironment, converting them into cancer-associated adipocytes (CAA). As adipocytes and cancer cells engage, a metabolic symbiosis ensues that is driven by bi-directional signaling. Many cancers (colon, breast, prostate, lung, ovarian cancer, and hematologic malignancies) stimulate lipolysis in adipocytes, followed by the uptake of fatty acids (FA) from the surrounding adipose tissue. The FA enters the cancer cell through specific fatty acid receptors and binding proteins (e.g., CD36, FATP1) and are used for membrane synthesis, energy metabolism (β-oxidation), or lipid-derived cell signaling molecules (derivatives of arachidonic and linolenic acid). Therefore, blocking adipocyte-derived lipid uptake or lipid-associated metabolic pathways in cancer cells, either with a single agent or in combination with standard of care chemotherapy, might prove to be an effective strategy against cancers that grow in lipid-rich tumor microenvironments.

Keywords:  Adipose tissue; Cancer; Immune cells; Lipids; Metabolism; Metastasis

DOI:  https://doi.org/10.1007/s10555-022-10059-x
Cancer Cell. 2022 Aug 08. pii: S1535-6108(22)00322-1. [Epub ahead of print]40(8): 804-806

Precision medicine in AML: Function plus -omics is better than either alone.

Anthony Letai.

Morphology, immunophenotype, cytogenetics, and genomics have long dominated diagnostics in acute myelogenous leukemia (AML). In this issue of Cancer Cell, Bottomly et al. demonstrate that combining the above with transcriptomics and ex vivo drug testing of patient myeloblasts yields novel diagnostic and therapeutic insights with the potential for clinical translation.

DOI: https://doi.org/10.1016/j.ccell.2022.07.009
Mol Cell. 2022 Aug 09. pii: S1097-2765(22)00708-0. [Epub ahead of print]

Stressed to death: Mitochondrial stress responses connect respiration and apoptosis in cancer.

Jacob M Winter, Tarun Yadav, Jared Rutter.

  Mitochondrial energetics and respiration have emerged as important factors in how cancer cells respond to or evade apoptotic signals. The study of the functional connection between these two processes may provide insight into following questions old and new: how might we target respiration or downstream signaling pathways to amplify apoptotic stress in the context of cancer therapy? Why are respiration and apoptotic regulation housed in the same organelle? Here, we briefly review mitochondrial respiration and apoptosis and then focus on how the intersection of these two processes is regulated by cytoplasmic signaling pathways such as the integrated stress response.

Keywords:  CRISPR; apoptosis; cancer; electron transport chain; integrated stress response; leukemia; mitochondria; oncology; oxidative phosphorylation; respiration; stress; venetoclax

DOI:  https://doi.org/10.1016/j.molcel.2022.07.012
Front Pharmacol. 2022 ;13 935536

Connections between metabolism and epigenetics: mechanisms and novel anti-cancer strategy.

Chen Chen, Zehua Wang, Yanru Qin.

  Cancer cells undergo metabolic adaptations to sustain their growth and proliferation under several stress conditions thereby displaying metabolic plasticity. Epigenetic modification is known to occur at the DNA, histone, and RNA level, which can alter chromatin state. For almost a century, our focus in cancer biology is dominated by oncogenic mutations. Until recently, the connection between metabolism and epigenetics in a reciprocal manner was spotlighted. Explicitly, several metabolites serve as substrates and co-factors of epigenetic enzymes to carry out post-translational modifications of DNA and histone. Genetic mutations in metabolic enzymes facilitate the production of oncometabolites that ultimately impact epigenetics. Numerous evidences also indicate epigenome is sensitive to cancer metabolism. Conversely, epigenetic dysfunction is certified to alter metabolic enzymes leading to tumorigenesis. Further, the bidirectional relationship between epigenetics and metabolism can impact directly and indirectly on immune microenvironment, which might create a new avenue for drug discovery. Here we summarize the effects of metabolism reprogramming on epigenetic modification, and vice versa; and the latest advances in targeting metabolism-epigenetic crosstalk. We also discuss the principles linking cancer metabolism, epigenetics and immunity, and seek optimal immunotherapy-based combinations.

Keywords:  cancer metabolism; epigenetics; immunity; novel anti-cancer strategy; oncology

DOI:  https://doi.org/10.3389/fphar.2022.935536