Iver Langmoen group

The Langmoen Lab is a translational research group for neurosurgery at Oslo University Hospital.  We explore the biology underlying neurosurgical conditions. Our research efforts encompass both normal and cancer cells from the human brain. The studies on brain cancer are focused on glioblastoma which is both the most frequent and most deadly brain cancer (median survival in unselected series ≈10 months).

Aims

  • To characterize human brain stem cells and develop cell types for neurodegenerative disorders
  • To characterize glioblastoma stem cells (GSCs)
  • To develop therapeutic strategies against GCSs

 

Ongoing Projects

Development of a stem cell-based vaccine in patients with brain cancer:

We participated in the identification of stem cells in glioblastoma. Following this we developed the first clinical protocol that targeted stem cells in solid tumors by transducing dendritic cells from the patients with their own cancer stem cell mRNA. This significantly improved clinical outcome. Almost one out of four of the patients are still alive. These patients have a median survival of 7 years and are still recurrence free.  A randomized trial of the vaccine has now been certified by all required authorities. In this study we will use an improved version of the vaccine. Our intention in this study is also to clarify why some patients respond and others do not.

 

Individualized systems medicine strategy to target GSCs in patients with recurrent glioblastoma:

In collaboration with our partners at the Finnish Institute for Molecular Medicine, we are combining the novel technical possibilities of high-throughput screening and deep sequencing with our established know-how on patient specific tumor stem cell cultures.  Exploring a panel of 525 drugs established in clinical use, as well as drugs in early-phase development, we are screening individualized tumor stem cells for drug sensitivity. The approach has been coined Individualized Systems Medicine. The preclinical pipelines along with validation of screening results have been established in 2016. We are preparing to translate the strategy of individualized medicine to patient treatment in 2017.

 

Coordinated undermining of survival paths with nine repurposed drugs (CUSP9) and temozolomide in patient-derived GBM samples:

A major barrier to effective treatment in glioblastoma is the simultaneous activity of multiple survival and growth-promoting mechanisms. A conceptually new treatment approach has emerged focusing on coordinated blockade of native survival paths of GBM. The coordinated blockade is undertaken by nine clinically well-known and repurposed drugs concomitant with the cytotoxic and standard of care, temozolomide, in a drug cocktail termed CUSP9. We have evaluated the in vitro efficacy of CUSP9 in patient-derived GBM samples using clinical relative drug concentrations across several different experimental cell assays. The coordinated approach has demonstrated a broad efficacy among several patient samples and experimental cell assays, and as the drugs have well-known safety profiles the results are intriguing for translation to patient treatment.

 

Characterization of invasive GCSs at the single cell level:

Glioblastomas are characterized by diffusely infiltrative growth. To investigate the invasive properties of glioblastoma cells we film cells while they invade into rodent brain slices or 3D-biomatrixes using time-lapse microscopy. We have identified subpopulations of cells with different invasive potentials. These cells display specific movement patterns and morphology. We hypothesize that these cells have diverging activation of signaling pathways and microarray expression analysis show their selective regulation of pathways and genes. We are currently focusing on confirming these findings on a single cell level. 

 

Molecular targeting of cancer stem cells in glioblastoma:

By performing a systematic comparison of gene expression in adult human neural stem cells and GSCs, we have identified differentially expressed genes that may have potential as new and specific targets for treatment of glioblastoma.  Our results from exploring several of these genes and pathways in-depth, suggest a functional role for the Wnt signaling pathway, PBK and NAT12/NAA30 in GBM. As a strategy to more efficiently and directly identify targets that are likely to trigger a therapeutic response, we are currently focusing on genetic high throughput loss-of function screening as tools to identify both individual and shared target hits in patient derived GSC cell cultures.

 

Management and scientific staff

Iver A. Langmoen, Professor, MD, PhD, Leader

Einar O. Vik-Mo, MD, PhD, Deputy Leader

Cecilie Jonsgar Sandberg, MSc, PhD, Lab manager/HR/Daily activities

Artem Fayzullin, MD, PhD-student

Kirsten Strømme Kireulf-Vieira, MD, PhD-student (dissertation February 2017)

Birthe Mikkelsen, BSc, Research Technician

Awais Mughal, MD, PhD-student (dissertation March 2017)

Emily Palmero, BSc, Research Technician

Erlend Skaga, MD, PhD-student

Marit Christensen, MSc, PhD-student

Maria Ewa Walewska, MSc, Research Technician

Zanina Grieg, MSc, Research Technician

  

Collaborators

  • Gunnar Kvalheim
  • Steven Wilson
  • Stefan Krauss
  • Krishna Bhat and Frederick Lang , MD Anderson Cancer Center, Houton, USA
  • Krister Wennerberg and Markus Perola, Institute for Molecular Medicine Finland (FIMM), University of Helsinki
  • Aki Laakso and Emilia Gaàl-Paavola, Helsinki University Hospital, Finland
  • Deni Galileo, University of Delaware, USA
  • Charles Liu, University of Southern California, Los Angeles, USA
  • Yasuhiro Watanabe, Tottori University, Japan
  • Winston Hide, Harvard University, MA, USA
  • Rainer Glass, Klinik der Universität München, Germany

 

 Selected Publications

Fayzullin A, Tuvnes FA, Skjellegrind HK, Behnan J, Mughal AA, Langmoen IA, Vik-Mo EO. Time-lapse phenotyping of invasive glioma cells ex vivo reveals subtype-specific movement patterns guided by tumor core signaling. Exp Cell Res. 2016 Dec 10;349(2):199-213

Skjellegrind HK, Fayzullin A, Johnsen EO, Eide L, Langmoen IA, Moe MC, Vik-Mo EO. Short-Term Differentiation of Glioblastoma Stem Cells Induces Hypoxia Tolerance. Neurochem Res. 2016 Jul;41(7):1545-58

Kierulf-Vieira KS, Sandberg CJ, Grieg Z, Günther CC, Langmoen IA, Vik-Mo EO. Wnt inhibition is dysregulated in gliomas and its
re-establishment inhibits proliferation and tumor sphere formation. Exp Cell Res. 2016 Jan 1;340(1):53-61

Stangeland B, Mughal AA, Grieg Z, Sandberg CJ, Joel M, Nygård S, Meling T,Murrell W, Vik Mo EO, Langmoen IA. Combined expressional analysis, bioinformatics and targeted proteomics identify new potential therapeutic targets in glioblastoma stem cells. Oncotarget. 2015 Sep 22;6(28):26192-215

Mughal AA, Grieg Z, Skjellegrind H, Fayzullin A, Lamkhannat M, Joel M, Ahmed MS, Murrell W, Vik-Mo EO, Langmoen IA, Stangeland B. Knockdown of NAT12/NAA30reduces tumorigenic features of glioblastoma-initiating cells. Mol Cancer. 2015 Aug 21;14:160

Sandberg CJ, Vik-Mo EO, Behnan J, Helseth E, Langmoen IA. Transcriptional profiling of adult neural stem-like cells from the human brain. PLoS One. 2014 Dec 16;9(12)

Behnan J, Isakson P, Joel M, Cilio C, Langmoen IA, Vik-Mo EO, Badn W. Recruited brain tumor-derived mesenchymal stem cells contribute to brain tumor progression. Stem Cells. 2014 May;32(5):1110-23

Murrell W, Palmero E, Bianco J, Stangeland B, Joel M, Paulson L, Thiede B, Grieg Z, Ramsnes I, Skjellegrind HK, Nygård S, Brandal P, Sandberg C, Vik-Mo E,Palmero S, Langmoen IA. Expansion of multipotent stem cells from the adult human brain. PLoS One. 2013 Aug 14;8(8):e71334

Vik-Mo EO, Nyakas M, Mikkelsen BV, Moe MC, Due-Tønnesen P, Suso EM, Sæbøe-Larssen S, Sandberg C, Brinchmann JE, Helseth E, Rasmussen AM, Lote K, Aamdal S, Gaudernack G, Kvalheim G, Langmoen IA. Therapeutic vaccination against autologous cancer stem cells with mRNA-transfected dendritic cells in patientswith glioblastoma. Cancer Immunol Immunother. 2013 Sep;62(9):1499-509

Sandberg CJ, Altschuler G, Jeong J, Strømme KK, Stangeland B, Murrell W,Grasmo-Wendler UH, Myklebost O, Helseth E, Vik-Mo EO, Hide W, Langmoen IA.Comparison of glioma stem cells to neural stem cells from the adult human brainidentifies dysregulated Wnt- signaling and a fingerprint associated with clinicaloutcome. Exp Cell Res. 2013 Aug 15;319(14):2230-43

Moe MC, Varghese M, Danilov AI, Westerlund U, Ramm-Pettersen J, Brundin L, Svensson M, Berg-Johnsen J, Langmoen IA. Multipotent progenitor cells from the adult human brain: neurophysiological differentiation to mature neurons. Brain.2005 Sep;128(Pt 9):2189-99

Moe MC, Westerlund U, Varghese M, Berg-Johnsen J, Svensson M, Langmoen IA. Development of neuronal networks from single stem cells harvested from the adult human brain. Neurosurgery. 2005 Jun;56(6):1182-8

 

 
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