bims-myxlip Biomed News
on Myxoid liposarcoma
Issue of 2021‒01‒24
seven papers selected by
Laura Mannarino
Mario Negri Institute

  1. Oncogenesis. 2021 Jan 19. 10(1): 12
      The self-renewal transcription factor Nanog and the phosphoinositide 3-kinase (PI3K)-Akt pathway are known to be essential for maintenance of mesenchymal stem cells. We evaluated their contribution to the maintenance of CD133(+) cancer stem-like cells (CSCs) and spheroid-forming cells in patient-derived cell lines from three human sarcoma subtypes: HT1080 fibrosarcoma, SK-LMS-1 leiomyosarcoma, and DDLS8817 dedifferentiated liposarcoma. Levels of Nanog and activated Akt were significantly higher in sarcoma cells grown as spheroids or sorted for CD133 expression to enrich for CSCs. shRNA knockdown of Nanog decreased spheroid formation 10- to 14-fold, and reversed resistance to both doxorubicin and radiation in vitro and in H1080 flank xenografts. In the HT1080 xenograft model, doxorubicin and Nanog knockdown reduced tumor growth by 34% and 45%, respectively, and the combination reduced tumor growth by 74%. Using a human phospho-kinase antibody array, Akt1/2 signaling, known to regulate Nanog, was found to be highly activated in sarcoma spheroid cells compared with monolayer cells. Pharmacologic inhibition of Akt using LY294002 and Akt1/2 knockdown using shRNA in sarcoma CSCs decreased Nanog expression and spheroid formation and reversed chemotherapy resistance. Akt1/2 inhibition combined with doxorubicin treatment of HT1080 flank xenografts reduced tumor growth by 73%. Finally, in a human sarcoma tumor microarray, expression of CD133, Nanog, and phospho-Akt were 1.8- to 6.8-fold higher in tumor tissue compared with normal tissue. Together, these results indicate that the Akt1/2-Nanog pathway is critical for maintenance of sarcoma CSCs and spheroid-forming cells, supporting further exploration of this pathway as a therapeutic target in sarcoma.
  2. Nat Commun. 2021 01 21. 12(1): 498
    Christian Koelsche, Daniel Schrimpf, Damian Stichel, Martin Sill, Felix Sahm, David E Reuss, Mirjam Blattner, Barbara Worst, Christoph E Heilig, Katja Beck, Peter Horak, Simon Kreutzfeldt, Elke Paff, Sebastian Stark, Pascal Johann, Florian Selt, Jonas Ecker, Dominik Sturm, Kristian W Pajtler, Annekathrin Reinhardt, Annika K Wefers, Philipp Sievers, Azadeh Ebrahimi, Abigail Suwala, Francisco Fernández-Klett, Belén Casalini, Andrey Korshunov, Volker Hovestadt, Felix K F Kommoss, Mark Kriegsmann, Matthias Schick, Melanie Bewerunge-Hudler, Till Milde, Olaf Witt, Andreas E Kulozik, Marcel Kool, Laura Romero-Pérez, Thomas G P Grünewald, Thomas Kirchner, Wolfgang Wick, Michael Platten, Andreas Unterberg, Matthias Uhl, Amir Abdollahi, Jürgen Debus, Burkhard Lehner, Christian Thomas, Martin Hasselblatt, Werner Paulus, Christian Hartmann, Ori Staszewski, Marco Prinz, Jürgen Hench, Stephan Frank, Yvonne M H Versleijen-Jonkers, Marije E Weidema, Thomas Mentzel, Klaus Griewank, Enrique de Álava, Juan Díaz Martín, Miguel A Idoate Gastearena, Kenneth Tou-En Chang, Sharon Yin Yee Low, Adrian Cuevas-Bourdier, Michel Mittelbronn, Martin Mynarek, Stefan Rutkowski, Ulrich Schüller, Viktor F Mautner, Jens Schittenhelm, Jonathan Serrano, Matija Snuderl, Reinhard Büttner, Thomas Klingebiel, Rolf Buslei, Manfred Gessler, Pieter Wesseling, Winand N M Dinjens, Sebastian Brandner, Zane Jaunmuktane, Iben Lyskjær, Peter Schirmacher, Albrecht Stenzinger, Benedikt Brors, Hanno Glimm, Christoph Heining, Oscar M Tirado, Miguel Sáinz-Jaspeado, Jaume Mora, Javier Alonso, Xavier Garcia Del Muro, Sebastian Moran, Manel Esteller, Jamal K Benhamida, Marc Ladanyi, Eva Wardelmann, Cristina Antonescu, Adrienne Flanagan, Uta Dirksen, Peter Hohenberger, Daniel Baumhoer, Wolfgang Hartmann, Christian Vokuhl, Uta Flucke, Iver Petersen, Gunhild Mechtersheimer, David Capper, David T W Jones, Stefan Fröhling, Stefan M Pfister, Andreas von Deimling.
      Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications.
  3. J Biol Chem. 2020 Dec 11. pii: S0021-9258(17)50618-3. [Epub ahead of print]295(50): 17310-17322
      In addition to their well-known role in the control of cellular proliferation and cancer, cell cycle regulators are increasingly identified as important metabolic modulators. Several GWAS have identified SNPs near CDKN2A, the locus encoding for p16INK4a (p16), associated with elevated risk for cardiovascular diseases and type-2 diabetes development, two pathologies associated with impaired hepatic lipid metabolism. Although p16 was recently shown to control hepatic glucose homeostasis, it is unknown whether p16 also controls hepatic lipid metabolism. Using a combination of in vivo and in vitro approaches, we found that p16 modulates fasting-induced hepatic fatty acid oxidation (FAO) and lipid droplet accumulation. In primary hepatocytes, p16-deficiency was associated with elevated expression of genes involved in fatty acid catabolism. These transcriptional changes led to increased FAO and were associated with enhanced activation of PPARα through a mechanism requiring the catalytic AMPKα2 subunit and SIRT1, two known activators of PPARα. By contrast, p16 overexpression was associated with triglyceride accumulation and increased lipid droplet numbers in vitro, and decreased ketogenesis and hepatic mitochondrial activity in vivo. Finally, gene expression analysis of liver samples from obese patients revealed a negative correlation between CDKN2A expression and PPARA and its target genes. Our findings demonstrate that p16 represses hepatic lipid catabolism during fasting and may thus participate in the preservation of metabolic flexibility.
    Keywords:  AMP-activated kinase (AMPK); AMPKα; CDKN2A; PPARα; cell cycle; fatty acid oxidation; lipid metabolism; liver; peroxisome proliferator-activated receptor (PPAR); steatosis
  4. Int J Mol Sci. 2021 Jan 17. pii: E884. [Epub ahead of print]22(2):
      Adiponectin plays multiple critical roles in modulating various physiological processes by binding to its receptors. The functions of PEG-BHD1028, a potent novel peptide agonist to AdipoRs, was evaluated using in vitro and in vivo models based on the reported action spectrum of adiponectin. To confirm the design concept of PEG-BHD1028, the binding sites and their affinities were analyzed using the SPR (Surface Plasmon Resonance) assay. The results revealed that PEG-BHD1028 was bound to two heterogeneous binding sites of AdipoR1 and AdipoR2 with a relatively high affinity. In C2C12 cells, PEG-BHD1028 significantly activated AMPK and subsequent pathways and enhanced fatty acid β-oxidation and mitochondrial biogenesis. Furthermore, it also facilitated glucose uptake by lowering insulin resistance in insulin-resistant C2C12 cells. PEG-BHD1028 significantly reduced the fasting plasma glucose level in db/db mice following a single s.c. injection of 50, 100, and 200 μg/Kg and glucose tolerance at a dose of 50 μg/Kg with significantly decreased insulin production. The animals received 5, 25, and 50 μg/Kg of PEG-BHD1028 for 21 days significantly lost their weight after 18 days in a range of 5-7%. These results imply the development of PEG-BHD1028 as a potential adiponectin replacement therapeutic agent.
    Keywords:  AdipoR1; AdipoR2; PEG-BHD1028; adiponectin; fatty acid β-oxidation; glucose tolerance; glucose uptake; insulin resistance; mitochondrial biogenesis; peptide drug
  5. J Diabetes Investig. 2021 Jan 21.
      AIMS/INTRODUCTION: Brown adipose tissue (BAT) utilizes large amounts of fuel for thermogenesis, but the mechanism by which fuel substrates are switched in response to changes in energy status is poorly understood. We have now investigated the role of KLF15, a transcription factor expressed at a high level in adipose tissue, in the regulation of fuel utilization in BAT.MATERIALS AND METHODS: Depletion or overexpression of KLF15 in HB2 differentiated brown adipocytes was achieved by adenoviral infection. Glucose and fatty acid oxidation were measured with radioactive substrates, pyruvate dehydrogenase complex (PDC) activity was determined with a colorimetric assay, and gene expression was examined by reverse transcription and real-time PCR analysis.
    RESULTS: Knockdown of KLF15 in HB2 cells attenuated fatty acid oxidation in association with down-regulation of the expression of genes related to this process including Acox1 and Fatp1, whereas it increased glucose oxidation. Expression of the gene for pyruvate dehydrogenase kinase 4 (PDK4), a negative regulator of PDC, was increased or decreased by KLF15 overexpression or knockdown, respectively, in HB2 cells, with these changes being accompanied by a respective decrease or increase in PDC activity. Chromatin immunoprecipitation showed that Pdk4 is a direct target of KLF15 in HB2 cells. Finally, fasting increased expression of KLf15, Pdk4, and genes involved in fatty acid utilization in BAT of mice, whereas refeeding suppressed Klf15 and Pdk4 expression.
    CONCLUSIONS: Our results implicate KLF15 in the regulation of fuel switching between glucose and fatty acids in response to changes in energy status in BAT.
    Keywords:  Brown adipose tissue; Fuel switching; KLF15
  6. Biomedicines. 2021 Jan 05. pii: E40. [Epub ahead of print]9(1):
      Adipose tissue resides in specific depots scattered in peripheral or deeper locations all over the body and it enwraps most of the organs. This tissue is always in a dynamic evolution as it must adapt to the metabolic demand and constraints. It exhibits also endocrine functions important to regulate energy homeostasis. This complex organ is composed of depots able to produce opposite functions to monitor energy: the so called white adipose tissue acts to store energy as triglycerides preventing ectopic fat deposition while the brown adipose depots dissipate it. It is composed of many cell types. Different types of adipocytes constitute the mature cells specialized to store or burn energy. Immature adipose progenitors (AP) presenting stem cells properties contribute not only to the maintenance but also to the expansion of this tissue as observed in overweight or obese individuals. They display a high regeneration potential offering a great interest for cell therapy. In this review, we will depict the attributes of the distinct types of adipocytes and their contribution to the function and metabolic features of adipose tissue. We will examine the specific role and properties of distinct depots according to their location. We will consider their cellular heterogeneity to present an updated picture of this sophisticated tissue. We will also introduce new trends pointing out a rational targeting of adipose tissue for medical applications.
    Keywords:  adipocytes; adipose progenitors; breast adipose tissue; brown/beige adipose tissue; cancer; epicardial adipose tissue; regenerative medicine; thermogenesis; white adipose tissue
  7. Diabetol Metab Syndr. 2021 Jan 22. 13(1): 10
      Obesity and Metabolic Syndrome have been associated with cardiovascular, diabetes and cancer incidence. Obesity is a state of inflammation. There are cross-talks between adipocyte, adipokines, pro-inflammatory cytokines, insulin, leptin, and other growth factors to initiate signals for proliferation, anti-apoptosis, and angiogenesis. Those networks lead to cancer initiation, promotion, progression, and metastasis. Post menopause women with breast cancer commonly have overweight, obesity, and metabolic syndrome, which are previously reported as conditions to be associated with breast cancer prognosis. MicroRNAs (miRNAs), small non-coding RNA that regulate gene expression, are known to play important roles either in metabolic or carcinogenesis process in patients with breast cancer. Some miRNAs expressions are deregulated in persons either with obesity, breast cancer, or breast cancer with co-morbid obesity. This literature review aimed at reviewing recent publications on the role of obesity, leptin, and microRNA deregulation in adverse prognosis of breast cancer. Understanding the influence of deregulated miRNAs and their target genes in patients with breast cancer and obesity will direct more studies to explore the potential prognostic role of obesity in breast cancer from epigenetic points of view.
    Keywords:  Breast cancer; Lipid metabolism; Obesity; Prognosis; microRNA