bims-almceb Biomed News
on Acute Leukemia Metabolism and Cell Biology
Issue of 2022‒03‒27
fifteen papers selected by
Camila Kehl Dias
Federal University of Rio Grande do Sul
  1. Aldehyde Dehydrogenase Enzyme Functions in Acute Leukemia Stem Cells.
  2. A non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine.
  3. Synergy of Venetoclax and 8-Chloro-Adenosine in AML: The Interplay of rRNA Inhibition and Fatty Acid Metabolism.
  4. Venetoclax-Resistant MV4-11 Leukemic Cells Activate PI3K/AKT Pathway for Metabolic Reprogramming and Redox Adaptation for Survival.
  5. Acute Myeloid Leukemia Cells Educate Mesenchymal Stromal Cells toward an Adipogenic Differentiation Propensity with Leukemia Promotion Capabilities.
  6. Stem Cell Theory of Cancer: Implications for Drug Resistance and Chemosensitivity in Cancer Care.
  7. Editorial: Cellular and Molecular Mechanisms of Immune Checkpoint Blockers in Anti-leukemia/Lymphoma Immune Therapy.
  8. [Cholesterol Metabolism and Tumor Immunity].
  9. Combined Activity of the Redox-Modulating Compound Setanaxib (GKT137831) with Cytotoxic Agents in the Killing of Acute Myeloid Leukemia Cells.
  10. Translating recent advances in the pathogenesis of acute myeloid leukemia to the clinic.
  11. Activation of Drp1 promotes fatty acids-induced metabolic reprograming to potentiate Wnt signaling in colon cancer.
  12. Mechanistic insights into the interplays between neutrophils and other immune cells in cancer development and progression.
  13. Editorial: Metabolism and Cell Adhesion in Cancer.
  14. Reductive TCA cycle catalyzed by wild-type IDH2 promotes acute myeloid leukemia and is a metabolic vulnerability for potential targeted therapy.
  15. The Interplay between Cell-Extracellular Matrix Interaction and Mitochondria Dynamics in Cancer.
  1. Front Biosci (Schol Ed). 2022 Mar 08. 14(1): 8
    Aldehyde Dehydrogenase Enzyme Functions in Acute Leukemia Stem Cells.
    Garrett M Dancik, Ioannis F Voutsas, Spiros Vlahopoulos.
      The enzymes that belong to the aldehyde dehydrogenase family are expressed in a variety of cells; yet activity of their main members characterizes stem cells, both normal and malignant. Several members of this family perform critical functions in stem cells, in general, and a few have been shown to have key roles in malignant tumors and their recurrence. In particular, ALDH1A1, which localizes to the cytosol and the nucleus, is an enzyme critical in cancer stem cells. In acute myeloid leukemia (AML), ALDH1A1 protects leukemia-initiating cells from a number of antineoplastic agents, and proves vital for the establishment of human AML xenografts in mice. ALDH2, which is located in mitochondria, has a major role in alcohol metabolism by clearing ethanol-derived acetaldehyde. Haematopoietic stem cells require ALDH2 for protection against acetaldehyde, which can cause damage to DNA, leading to insertions, deletions, chromosomal rearrangements, and translocations. Mutations compromise stem cell function, and thereby threaten blood homeostasis. We review here the potential of targeting the enzymatic activity of aldehyde dehydrogenases in acute leukemia.
    Keywords:  acute; aldehyde dehydrogenase; biomarker; drug resistance; gene expression; immunosuppression; leukemia; myeloid; neoplastic stem cells
    DOI:  https://doi.org/10.31083/j.fbs1401008
  2. Nat Commun. 2022 Mar 21. 13(1): 1503
    A non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine.
    Carlos Sebastian, Christina Ferrer, Maria Serra, Jee-Eun Choi, Nadia Ducano, Alessia Mira, Manasvi S Shah, Sylwia A Stopka, Andrew J Perciaccante, Claudio Isella, Daniel Moya-Rull, Marianela Vara-Messler, Silvia Giordano, Elena Maldi, Niyati Desai, Diane E Capen, Enzo Medico, Murat Cetinbas, Ruslan I Sadreyev, Dennis Brown, Miguel N Rivera, Anna Sapino, David T Breault, Nathalie Y R Agar, Raul Mostoslavsky.
      Although reprogramming of cellular metabolism is a hallmark of cancer, little is known about how metabolic reprogramming contributes to early stages of transformation. Here, we show that the histone deacetylase SIRT6 regulates tumor initiation during intestinal cancer by controlling glucose metabolism. Loss of SIRT6 results in an increase in the number of intestinal stem cells (ISCs), which translates into enhanced tumor initiating potential in APCmin mice. By tracking down the connection between glucose metabolism and tumor initiation, we find a metabolic compartmentalization within the intestinal epithelium and adenomas, where a rare population of cells exhibit features of Warburg-like metabolism characterized by high pyruvate dehydrogenase kinase (PDK) activity. Our results show that these cells are quiescent cells expressing +4 ISCs and enteroendocrine markers. Active glycolysis in these cells suppresses ROS accumulation and enhances their stem cell and tumorigenic potential. Our studies reveal that aerobic glycolysis represents a heterogeneous feature of cancer, and indicate that this metabolic adaptation can occur in non-dividing cells, suggesting a role for the Warburg effect beyond biomass production in tumors.
    DOI:  https://doi.org/10.1038/s41467-022-29085-y
  3. Cancers (Basel). 2022 Mar 11. pii: 1446. [Epub ahead of print]14(6):
    Synergy of Venetoclax and 8-Chloro-Adenosine in AML: The Interplay of rRNA Inhibition and Fatty Acid Metabolism.
    Dinh Hoa Hoang, Corey Morales, Ivan Rodriguez Rodriguez, Melissa Valerio, Jiamin Guo, Min-Hsuan Chen, Xiwei Wu, David Horne, Varsha Gandhi, Lisa S Chen, Bin Zhang, Vinod Pullarkat, Steven T Rosen, Guido Marcucci, Ralf Buettner, Le Xuan Truong Nguyen.
      It is known that 8-chloro-adenosine (8-Cl-Ado) is a novel RNA-directed nucleoside analog that targets leukemic stem cells (LSCs). In a phase I clinical trial with 8-Cl-Ado in patients with refractory or relapsed (R/R) AML, we observed encouraging but short-lived clinical responses, likely due to intrinsic mechanisms of LSC resistance. LSC homeostasis depends on amino acid-driven and/or fatty acid oxidation (FAO)-driven oxidative phosphorylation (OXPHOS) for survival. We recently reported that 8-Cl-Ado and the BCL-2-selective inhibitor venetoclax (VEN) synergistically inhibit FAO and OXPHOS in LSCs, thereby suppressing acute myeloid leukemia (AML) growth in vitro and in vivo. Herein, we report that 8-Cl-Ado inhibits ribosomal RNA (rRNA) synthesis through the downregulation of transcription initiation factor TIF-IA that is associated with increasing levels of p53. Paradoxically, 8-Cl-Ado-induced p53 increased FAO and OXPHOS, thereby self-limiting the activity of 8-Cl-Ado on LSCs. Since VEN inhibits amino acid-driven OXPHOS, the addition of VEN significantly enhanced the activity of 8-Cl-Ado by counteracting the self-limiting effect of p53 on FAO and OXPHOS. Overall, our results indicate that VEN and 8-Cl-Ado can cooperate in targeting rRNA synthesis and OXPHOS and in decreasing the survival of the LSC-enriched cell population, suggesting the VEN/8-Cl-Ado regimen as a promising therapeutic approach for patients with R/R AML.
    Keywords:  8-chloro-adenosine; acute myeloid leukemia; metabolism; rRNA synthesis; venetoclax
    DOI:  https://doi.org/10.3390/cancers14061446
  4. Antioxidants (Basel). 2022 Feb 25. pii: 461. [Epub ahead of print]11(3):
    Venetoclax-Resistant MV4-11 Leukemic Cells Activate PI3K/AKT Pathway for Metabolic Reprogramming and Redox Adaptation for Survival.
    Hind A Alkhatabi, Samir F Zohny, Mohammed Razeeth Shait Mohammed, Hani Choudhry, Mohd Rehan, Aamir Ahmad, Farid Ahmed, Mohammad Imran Khan.
      Venetoclax (ABT199) is a selective B-cell lymphoma 2 (BCL-2) inhibitor. The US FDA recently approved it to be used in combination with low-dose cytarabine or hypomethylating agents in acute myeloid leukemia (AML) or elderly patients non-eligible for chemotherapy. However, acquiring resistance to venetoclax in AML patients is the primary cause of treatment failure. To understand the molecular mechanisms inherent in the resistance to BCL-2 inhibitors, we generated a venetoclax-resistant cell line model and assessed the consequences of this resistance on its metabolic pathways. Untargeted metabolomics data displayed a notable impact of resistance on the PI3K/AKT pathway, the Warburg effect, glycolysis, the TCA cycle, and redox metabolism. The resistant cells showed increased NADPH and reduced glutathione levels, switching their energy metabolism towards glycolysis. PI3K/AKT pathway inhibition shifted resistant cells towards oxidative phosphorylation (OXPHOS). Our results provide a metabolic map of resistant cells that can be used to design novel metabolic targets to challenge venetoclax resistance in AML.
    Keywords:  MV4-11; OXPHOS; PI3K/AKT pathway; acute myeloid leukemia; glycolysis; metabolomics; redox metabolism; venetoclax; venetoclax resistance model
    DOI:  https://doi.org/10.3390/antiox11030461
  5. Adv Sci (Weinh). 2022 Mar 20. e2105811
    Acute Myeloid Leukemia Cells Educate Mesenchymal Stromal Cells toward an Adipogenic Differentiation Propensity with Leukemia Promotion Capabilities.
    Luwen Zhang, Qiong Zhao, Hui Cang, Ziqiang Wang, Xiaojia Hu, Ruolang Pan, Yang Yang, Ye Chen.
      Mesenchymal stromal cells (MSCs) are essential elements of the bone marrow (BM) microenvironment, which have been widely implicated in pathways that contribute to leukemia growth and resistance. Recent reports showed genotypic and phenotypic alterations in leukemia patient-derived MSCs, indicating that MSCs might be educated/reprogrammed. However, the results have been inconclusive, possibly due to the heterogeneity of leukemia. Here, the authors report that acute myeloid leukemia (AML) induces MSCs towards an adipogenic differentiation propensity. RNAseq analysis reveal significant upregulation of gene expression enriched in the adipocyte differentiation process and reduction in osteoblast differentiation. The alteration is accompanied by a metabolic switch from glycolysis to a more oxidative phosphorylation-dependent manner. Mechanistic studies identify that AML cell-derived exosomes play a vital role during the AML cell-mediated MSCs education/reprogramming process. Pre-administration of mice BM microenvironment with AML-derived exosomes greatly enhance leukemia engraftment in vivo. The quantitative proteomic analysis identified a list of exosomal protein components that are differently expressed in AML-derived exosomes, which represent an opportunity for novel therapeutic strategies based on the targeting of exosome-based AML cells-MSCs communication. Collectively, the data show that AML-educated MSCs tend to differentiate into adipocytes contributing to disease progression, which suggests complex interactions of leukemia with microenvironment components.
    Keywords:  acute myeloid leukemia (AML); cell-derived exosomes; mesenchymal stromal cells (MSCs)
    DOI:  https://doi.org/10.1002/advs.202105811
  6. Cancers (Basel). 2022 Mar 18. pii: 1548. [Epub ahead of print]14(6):
    Stem Cell Theory of Cancer: Implications for Drug Resistance and Chemosensitivity in Cancer Care.
    Shi-Ming Tu, Charles C Guo, Diana S-L Chow, Niki M Zacharias.
      When it concerns cancer care and cancer therapy, drug resistance is more than an obstacle to successful treatment; it is a major cause of frustration in our attempts to optimize drug development versus therapy development. Importantly, overcoming the challenges of drug resistance may provide invaluable clues about the origin and nature of cancer. From this perspective, we discuss how chemoresistance and chemosensitivity in cancer therapy could be directly linked to the stem cell origin of cancer. A stem cell theory of cancer stipulates that both normal stem cells and cancer stem cells are similarly endowed with robust efflux pumps, potent antiapoptotic mechanisms, redundant DNA repair systems, and abundant antioxidation reserves. Cancer stem cells, like their normal stem cell counterparts, are equipped with the same drug resistance phenotypes (e.g., ABC transporters, anti-apoptotic pathways, and DNA repair mechanisms). Drug resistance, like other cancer hallmarks (e.g., tumor heterogeneity and cancer dormancy), could be intrinsically ingrained and innately embedded within malignancy. We elaborate that cellular context and the microenvironment may attenuate the effects of cancer treatments. We examine the role of circadian rhythms and the value of chronotherapy to maximize efficacy and minimize toxicity. We propose that a stem cell theory of drug resistance and drug sensitivity will ultimately empower us to enhance drug development and enable us to improve therapy development in patient care.
    Keywords:  cancer stem cells; chemosensitivity; chronotherapy; circadian rhythm; clonal origin; drug development; drug resistance; therapy development; unified theory
    DOI:  https://doi.org/10.3390/cancers14061548
  7. Front Oncol. 2022 ;12 872300
    Editorial: Cellular and Molecular Mechanisms of Immune Checkpoint Blockers in Anti-leukemia/Lymphoma Immune Therapy.
    Mazdak Ganjalikhani-Hakemi, Ling Xu, Andrey A Zamyatnin, Alexandr V Bazhin.
      
    Keywords:  immune checkpoint (ICP); immune checkpoint blockers (ICBs); immune therapy; leukemia; lymphoma
    DOI:  https://doi.org/10.3389/fonc.2022.872300
  8. Sichuan Da Xue Xue Bao Yi Xue Ban. 2022 Mar;53(2): 335-341
    [Cholesterol Metabolism and Tumor Immunity].
    Na Luo, Rong-Chen Shi, Rong-Yang Dai, Hong-Ming Miao.
      Cholesterol, an important lipid molecule of organisms, is involved in the formation of cell membrane structure, bile acid metabolism and steroid hormone synthesis, playing an important role in the regulation of cell structure and functions. In recent years, a large number of studies have shown that cholesterol metabolism is reprogrammed during tumor formation and development. In addition to directly affecting the biological behavior of tumor cells, cholesterol metabolic reprogramming also regulates the antitumor activity of immune cells in the tumor microenvironment. We reviewed herein the cholesterol metabolism reprogramming of and interactions among immune cells including myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), dendritic cells (DCs), and T cells in the tumor microenvironment. However, the relationship between cholesterol metabolism and tumor immunity in tumor microenvironment is complex and diversified. The differences and similarities of cholesterol metabolism reprogramming in tumor microenvironment in regulating immune cell activity and the specific regulatory mechanism are still unresolved issues. Targeted intervention of the cholesterol metabolism pathway of immune cells is expected to become a new strategy of cholesterol metabolism in tumor immunotherapy.
    Keywords:  Cholesterol; Immune regulation; Metabolism; Tumor; Tumor microenvironment
    DOI:  https://doi.org/10.12182/20220360202
  9. Antioxidants (Basel). 2022 Mar 08. pii: 513. [Epub ahead of print]11(3):
    Combined Activity of the Redox-Modulating Compound Setanaxib (GKT137831) with Cytotoxic Agents in the Killing of Acute Myeloid Leukemia Cells.
    Muhammed Burak Demircan, Peter C Mgbecheta, Anne Kresinsky, Tina M Schnoeder, Katrin Schröder, Florian H Heidel, Frank D Böhmer.
      Acute myeloid leukemia (AML) cells harbor elevated levels of reactive oxygen species (ROS), which promote cell proliferation and cause oxidative stress. Therefore, the inhibition of ROS formation or elevation beyond a toxic level have been considered as therapeutic strategies. ROS elevation has recently been linked to enhanced NADPH oxidase 4 (NOX4) activity. Therefore, the compound Setanaxib (GKT137831), a clinically advanced ROS-modulating substance, which has initially been identified as a NOX1/4 inhibitor, was tested for its inhibitory activity on AML cells. Setanaxib showed antiproliferative activity as single compound, and strongly enhanced the cytotoxic action of anthracyclines such as daunorubicin in vitro. Setanaxib attenuated disease in a mouse model of FLT3-ITD driven myeloproliferation in vivo. Setanaxib did not significantly inhibit FLT3-ITD signaling, including FLT3 autophosphorylation, activation of STAT5, AKT, or extracellular signal regulated kinase 1 and 2 (ERK1/2). Surprisingly, the effects of Setanaxib on cell proliferation appeared to be independent of the presence of NOX4 and were not associated with ROS quenching. Instead, Setanaxib caused elevation of ROS levels in the AML cells and importantly, enhanced anthracycline-induced ROS formation, which may contribute to the combined effects. Further assessment of Setanaxib as potential enhancer of cytotoxic AML therapy appears warranted.
    Keywords:  CRISPR/Cas9-mediated deletion; GKT137831; NADPH oxidase 4 (NOX4); Setanaxib; acute myeloid leukemia (AML); inhibitor; reactive oxygen species (ROS)
    DOI:  https://doi.org/10.3390/antiox11030513
  10. Genes Dev. 2022 Mar 01. 36(5-6): 259-277
    Translating recent advances in the pathogenesis of acute myeloid leukemia to the clinic.
    Jan Philipp Bewersdorf, Omar Abdel-Wahab.
      Despite FDA approval of nine new drugs for patients with acute myeloid leukemia (AML) in the United States over the last 4 years, AML remains a major area of unmet medical need among hematologic malignancies. In this review, we discuss the development of promising new molecular targeted approaches for AML, including menin inhibition, novel IDH1/2 inhibitors, and preclinical means to target TET2, ASXL1, and RNA splicing factor mutations. In addition, we review progress in immune targeting of AML through anti-CD47, anti-SIRPα, and anti-TIM-3 antibodies; bispecific and trispecific antibodies; and new cellular therapies in development for AML.
    Keywords:  ASXL1; IDH1; IDH2; RNA splicing; TET2; acute myeloid leukemia; menin; myelodysplastic syndromes
    DOI:  https://doi.org/10.1101/gad.349368.122
  11. Cell Death Differ. 2022 Mar 24.
    Activation of Drp1 promotes fatty acids-induced metabolic reprograming to potentiate Wnt signaling in colon cancer.
    Xiaopeng Xiong, Sumati Hasani, Lyndsay E A Young, Dylan R Rivas, Ashley T Skaggs, Rebecca Martinez, Chi Wang, Heidi L Weiss, Matthew S Gentry, Ramon C Sun, Tianyan Gao.
      Cancer cells are known for their ability to adapt variable metabolic programs depending on the availability of specific nutrients. Our previous studies have shown that uptake of fatty acids alters cellular metabolic pathways in colon cancer cells to favor fatty acid oxidation. Here, we show that fatty acids activate Drp1 to promote metabolic plasticity in cancer cells. Uptake of fatty acids (FAs) induces mitochondrial fragmentation by promoting ERK-dependent phosphorylation of Drp1 at the S616 site. This increased phosphorylation of Drp1 enhances its dimerization and interaction with Mitochondrial Fission Factor (MFF) at the mitochondria. Consequently, knockdown of Drp1 or MFF attenuates fatty acid-induced mitochondrial fission. In addition, uptake of fatty acids triggers mitophagy via a Drp1- and p62-dependent mechanism to protect mitochondrial integrity. Moreover, results from metabolic profiling analysis reveal that silencing Drp1 disrupts cellular metabolism and blocks fatty acid-induced metabolic reprograming by inhibiting fatty acid utilization. Functionally, knockdown of Drp1 decreases Wnt/β-catenin signaling by preventing fatty acid oxidation-dependent acetylation of β-catenin. As a result, Drp1 depletion inhibits the formation of tumor organoids in vitro and xenograft tumor growth in vivo. Taken together, our study identifies Drp1 as a key mediator that connects mitochondrial dynamics with fatty acid metabolism and cancer cell signaling.
    DOI:  https://doi.org/10.1038/s41418-022-00974-5
  12. Cancer Metastasis Rev. 2022 Mar 21.
    Mechanistic insights into the interplays between neutrophils and other immune cells in cancer development and progression.
    Zimam Mahmud, Atiqur Rahman, Israt Dilruba Mishu, Yearul Kabir.
      Cancer is considered a major public health concern worldwide and is characterized by an uncontrolled division of abnormal cells. The human immune system recognizes cancerous cells and induces innate immunity to destroy those cells. However, sustained tumors may protect themselves by developing immune escape mechanisms through multiple soluble and cellular mediators. Neutrophils are the most plenteous leukocytes in the human blood and are crucial for immune defense in infection and inflammation. Besides, neutrophils emancipate the antimicrobial contents, secrete different cytokines or chemokines, and interact with other immune cells to combat and successfully kill cancerous cells. Conversely, many clinical and experimental studies signpost that being a polarized and heterogeneous population with plasticity, neutrophils, particularly their subpopulations, act as a modulator of cancer development by promoting tumor metastasis, angiogenesis, and immunosuppression. Studies also suggest that tumor infiltrating macrophages, neutrophils, and other innate immune cells support tumor growth and survival. Additionally, neutrophils promote tumor cell invasion, migration and intravasation, epithelial to mesenchymal transition, survival of cancer cells in the circulation, seeding, and extravasation of tumor cells, and advanced growth and development of cancer cells to form metastases. In this manuscript, we describe and review recent studies on the mechanisms for neutrophil recruitment, activation, and their interplay with different immune cells to promote their pro-tumorigenic functions. Understanding the detailed mechanisms of neutrophil-tumor cell interactions and the concomitant roles of other immune cells will substantially improve the clinical utility of neutrophils in cancer and eventually may aid in the identification of biomarkers for cancer prognosis and the development of novel therapeutic approaches for cancer treatment.
    Keywords:  Angiogenesis; Cancer growth; Immunosuppression; Metastasis; N1 and N2 neutrophils; NETosis; Neutrophils
    DOI:  https://doi.org/10.1007/s10555-022-10024-8
  13. Front Cell Dev Biol. 2022 ;10 871471
    Editorial: Metabolism and Cell Adhesion in Cancer.
    Tanja Nicole Hartmann.
      
    Keywords:  AMPK; FAK; adhesion; integrin; mTOR; metabolism; migration; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2022.871471
  14. J Hematol Oncol. 2022 Mar 21. 15(1): 30
    Reductive TCA cycle catalyzed by wild-type IDH2 promotes acute myeloid leukemia and is a metabolic vulnerability for potential targeted therapy.
    Peiting Zeng, Wenhua Lu, Jingyu Tian, Shuang Qiao, Jiangjiang Li, Christophe Glorieux, Shijun Wen, Hui Zhang, Yiqing Li, Peng Huang.
      BACKGROUND: Isocitrate dehydrogenase-2 (IDH2) is a mitochondrial enzyme that catalyzes the metabolic conversion between isocitrate and alpha-ketoglutarate (α-KG) in the TCA cycle. IDH2 mutation is an oncogenic event in acute myeloid leukemia (AML) due to the generation of 2-hydroxyglutarate. However, the role of wild-type IDH2 in AML remains unknown, despite patients with it suffer worse clinical outcome than those harboring mutant type.METHODS: IDH2 expression in AML cell lines and patient samples was evaluated by RT-qPCR, western blotting and database analyses. The role of wild-type IDH2 in AML cell survival and proliferation was tested using genetic knockdown and pharmacological inhibition in AML cells and animal models. LC-MS, GC-MS, isotope metabolic tracing, and molecular analyses were performed to reveal the underlying mechanisms.
    RESULTS: We found that wild-type IDH2 was overexpressed in AML and played a major role in promoting leukemia cell survival and proliferation in vitro and in vivo. Metabolomic analyses revealed an active IDH2-mediated reductive TCA cycle that promoted the conversion of α-KG to isocitrate/citrate to facilitate glutamine utilization for lipid synthesis in AML cells. Suppression of wild-type IDH2 by shRNA resulted in elevated α-KG and decreased isocitrate/citrate, leading to reduced lipid synthesis, a significant decrease in c-Myc downregulated by α-KG, and an inhibition of AML viability and proliferation. Importantly, pharmacological inhibition of IDH2 showed significant therapeutic effect in mice inoculated with AML cells with wt-IDH2 and induced a downregulation of C-MYC in vivo.
    CONCLUSIONS: Wt-IDH2 is an essential molecule for AML cell survival and proliferation by promoting conversion of α-KG to isocitrate for lipid synthesis and by upregulating c-Myc expression and could be a potential therapeutic target in AML.
    Keywords:  Acute myeloid leukemia; Alpha-ketoglutarate; Lipid synthesis; TCA cycle; Wild-type IDH2; c-Myc
    DOI:  https://doi.org/10.1186/s13045-022-01245-z
  15. Cancers (Basel). 2022 Mar 10. pii: 1433. [Epub ahead of print]14(6):
    The Interplay between Cell-Extracellular Matrix Interaction and Mitochondria Dynamics in Cancer.
    Bian Yanes, Elena Rainero.
      The tumor microenvironment, in particular the extracellular matrix (ECM), plays a pivotal role in controlling tumor initiation and progression. In particular, the interaction between cancer cells and the ECM promotes cancer cell growth and invasion, leading to the formation of distant metastasis. Alterations in cancer cell metabolism is a key hallmark of cancer, which is often associated with alterations in mitochondrial dynamics. Recent research highlighted that, changes in mitochondrial dynamics are associated with cancer migration and metastasis-these has been extensively reviewed elsewhere. However, less is known about the interplay between the extracellular matrix and mitochondria functions. In this review, we will highlight how ECM remodeling associated with tumorigenesis contribute to the regulation of mitochondrial function, ultimately promoting cancer cell metabolic plasticity, able to fuel cancer invasion and metastasis.
    Keywords:  extracellular matrix; mitochondria dynamics; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers14061433
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