Ola Myklebost

ACTIVITIES

The Mesenchymal Cancer Biology Group are studying sarcomas, malignant tumours with mesenchymal characteristics, and focus on osteo- and liposarcomas, as well as normal mesenchymal stem cells as model systems. Our CAST projects involve identification and characterization of stem-like cells in sarcomas, and the involvement of stem cell pathways in sarcoma development.

GROUP MEMBERS

Anna-Berit Wennerström
Technical personnel

Leonardo A. Meza-Zepeda
Senior Scientist

Menaka Sathermugathevan
Technical personnel

Petros Gebregziabher
Technical personnel

Russel Castro
Technical personnel

Stine Kresse
Post doc

Silje Lauvrak
Post doc

STATUS 2013

The microRNA let-7 is considered a tumor suppressor
and a regulator of stemness and differentiation, and is
normally highly expressed in well differentiated tissues.
The expression of let-7 is frequently lost in cancer, which has prognostic value in a wide range of cancers, and
let-7 replacement therapy shows great potential as a cancer therapeutic.

To date let-7 isoforms have not been fully characterized in sarcoma, so we are focused on determining expression level in a panel of liposarcoma cell lines. We are also investigating the effect of introducing let-7 mimics in chosen LPS cell line models to study the effects on growth rate, cell stemness and differentiation, in order to evaluate whether let-7 replacement therapy is also beneficial as therapy for sarcoma. We also examine the role of let-7 miRNAs in aggressive breast cancer cells, and found that they reduce cell growth as well as the cells capacity to generate spheroids in vitro. Furthermore, we have performed global analyses of the transcriptome and the proteome to identify changes that may explain these functional effects. In parallel, we have also analyzed the global effects of reducing the let-7 target gene HMGA2, which is an embryonic gene encoding an architectural transcription factor that is associated with the stemness program.

The comparisons identified some interesting differences that may enlighten processes involved in the balances between cell stemness and differentiation. Wnt/β-catenin signaling is frequently up-regulated in osteosarcoma and is thought to contribute to the disease. We have evaluated the effect of tankyrase inhibitors JW74 and JW55 on osteosarcoma cell lines, both at the molecular level and at the functional level. Interestingly, we have shown that the drug has the ability to induce differentiation in cell lines which have a block towards differentiation, thus enabling poorly differentiated cancer cells to overcome their resistance to differentiation, which may render the cells more susceptible for standard therapies.

SELECTED PUBLICATIONS

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 brain identifies dysregulated Wnt- signaling and a fingerprint associated with clinical outcome
Exp Cell Res (in press)
PubMed 23791939

Stratford EW, Bostad M, Castro R, Skarpen E, Berg K, Høgset A, Myklebost O, Selbo PK (2013)
Photochemical internalization of CD133-targeting immunotoxins efficiently depletes sarcoma cells with stem-like properties and reduces tumorigenicity
Biochim Biophys Acta, 1830 (8), 4235-43
PubMed 23643966

Bianchini L, Birtwisle L, Saâda E, Bazin A, Long E, Roussel JF, Michiels JF, Forest F, Dani C, Myklebost O, Birtwisle-Peyrottes I, Pedeutour F (2013)
Identification of PPAP2B as a novel recurrent translocation partner gene of HMGA2 in lipomas
Genes Chromosomes Cancer, 52 (6), 580-90
PubMed 23508853

Kuijjer ML, Peterse EF, van den Akker BE, Briaire-de Bruijn IH, Serra M, Meza-Zepeda LA, Myklebost O, Hassan AB, Hogendoorn PC, Cleton-Jansen AM (2013)
IR/IGF1R signaling as potential target for treatment of high-grade osteosarcoma
BMC Cancer, 13, 245
PubMed 23688189

Doorn J, Fernandes HA, Le BQ, van de Peppel J, van Leeuwen JP, De Vries MR, Aref Z, Quax PH, Myklebost O, Saris DB, van Blitterswijk CA, de Boer J (2013)
A small molecule approach to engineering vascularized tissue
Biomaterials, 34 (12), 3053-63
PubMed 23369216

Ohnstad HO, Castro R, Sun J, Heintz KM, Vassilev LT, Bjerkehagen B, Kresse SH, Meza-Zepeda LA, Myklebost O (2013)
Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma
Cancer, 119 (5), 1013-22
PubMed 23165797

Skotheim RI, Meza-Zepeda LA, Hovig E, Lønning PE, Lothe RA, Myklebost O (2012)
[Genome sequencing for personalized cancer treatment]
Tidsskr Nor Laegeforen, 132 (21), 2406-8
PubMed 23160594

Kresse SH, Rydbeck H, Skårn M, Namløs HM, Barragan-Polania AH, Cleton-Jansen AM, Serra M, Liestøl K, Hogendoorn PC, Hovig E, Myklebost O, Meza-Zepeda LA(2012)
Integrative analysis reveals relationships of genetic and epigenetic alterations in osteosarcoma
PLoS One, 7 (11), e48262
PubMed 23144859

Namløs HM, Meza-Zepeda LA, Barøy T, Østensen IH, Kresse SH, Kuijjer ML, Serra M, Bürger H, Cleton-Jansen AM, Myklebost O (2012)
Modulation of the osteosarcoma expression phenotype by microRNAs
PLoS One, 7 (10), e48086
PubMed 23133552

Stratford EW, Castro R, Daffinrud J, Skårn M, Lauvrak S, Munthe E, Myklebost O (2012)
Characterization of liposarcoma cell lines for preclinical and biological studies
Sarcoma, 2012, 148614
PubMed 22911243

Kuijjer ML, Rydbeck H, Kresse SH, Buddingh EP, Lid AB, Roelofs H, Bürger H, Myklebost O, Hogendoorn PC, Meza-Zepeda LA, Cleton-Jansen AM (2012)
Identification of osteosarcoma driver genes by integrative analysis of copy number and gene expression data
Genes Chromosomes Cancer, 51 (7), 696-706
PubMed 22454324

Skårn M, Namløs HM, Noordhuis P, Wang MY, Meza-Zepeda LA, Myklebost O (2012)
Adipocyte differentiation of human bone marrow-derived stromal cells is modulated by microRNA-155, microRNA-221, and microRNA-222
Stem Cells Dev, 21 (6), 873-83
PubMed 21756067

Namløs HM, Kresse SH, Müller CR, Henriksen J, Holdhus R, Sæter G, Bruland OS, Bjerkehagen B, Steen VM, Myklebost O (2012)
Global gene expression profiling of human osteosarcomas reveals metastasis-associated chemokine pattern
Sarcoma, 2012, 639038
PubMed 22518090

Kresse SH, Meza-Zepeda LA, Machado I, Llombart-Bosch A, Myklebost O (2012)
Preclinical xenograft models of human sarcoma show nonrandom loss of aberrations
Cancer, 118 (2), 558-70
PubMed 21713766

Hjortland GO, Meza-Zepeda LA, Beiske K, Ree AH, Tveito S, Hoifodt H, Bohler PJ, Hole KH, Myklebost O, Fodstad O, Smeland S, Hovig E (2011)
Genome wide single cell analysis of chemotherapy resistant metastatic cells in a case of gastroesophageal adenocarcinoma
BMC Cancer, 11, 455
PubMed 22014070

Kuijjer ML, Namløs HM, Hauben EI, Machado I, Kresse SH, Serra M, Llombart-Bosch A, Hogendoorn PC, Meza-Zepeda LA, Myklebost O, Cleton-Jansen AM (2011)
mRNA expression profiles of primary high-grade central osteosarcoma are preserved in cell lines and xenografts
BMC Med Genomics, 4, 66
PubMed 21933437

Stratford EW, Castro R, Wennerstrom A, Holm R, Munthe E, Lauvrak S, Bjerkehagen B, Myklebost O (2011)
Liposarcoma Cells with Aldefluor and CD133 Activity have a Cancer Stem Cell Potential
Clin Sarcoma Res, 1 (1), 8
PubMed 22612877

Ohnstad HO, Paulsen EB, Noordhuis P, Berg M, Lothe RA, Vassilev LT, Myklebost O (2011)
MDM2 antagonist Nutlin-3a potentiates antitumour activity of cytotoxic drugs in sarcoma cell lines
BMC Cancer, 11, 211:1-11
PubMed 21624110

Buddingh EP, Kuijjer ML, Duim RA, Bürger H, Agelopoulos K, Myklebost O, Serra M, Mertens F, Hogendoorn PC, Lankester AC, Cleton-Jansen AM (2011)
Tumor-infiltrating macrophages are associated with metastasis suppression in high-grade osteosarcoma: a rationale for treatment with macrophage activating agents
Clin Cancer Res, 17 (8), 2110-9
PubMed 21372215

Kresse SH, Ohnstad HO, Bjerkehagen B, Myklebost O, Meza-Zepeda LA (2010)
DNA copy number changes in human malignant fibrous histiocytomas by array comparative genomic hybridisation
PLoS One, 5 (11), e15378
PubMed 21085701

Mayordomo E, Machado I, Giner F, Kresse SH, Myklebost O, Carda C, Navarro S, Llombart-Bosch A (2010)
A tissue microarray study of osteosarcoma: histopathologic and immunohistochemical validation of xenotransplanted tumors as preclinical models
Appl Immunohistochem Mol Morphol, 18 (5), 453-61
PubMed 20436344

Eide MB, Liestøl K, Lingjaerde OC, Hystad ME, Kresse SH, Meza-Zepeda L, Myklebost O, Trøen G, Aamot HV, Holte H, Smeland EB, Delabie J (2010)
Genomic alterations reveal potential for higher grade transformation in follicular lymphoma and confirm parallel evolution of tumor cell clones
Blood, 116 (9), 1489-97
PubMed 20505157

Kresse SH, Szuhai K, Barragan-Polania AH, Rydbeck H, Cleton-Jansen AM, Myklebost O, Meza-Zepeda LA (2010)
Evaluation of high-resolution microarray platforms for genomic profiling of bone tumours
BMC Res Notes, 3, 223
PubMed 20691109

Henriksen J, Stabell M, Meza-Zepeda LA, Lauvrak SA, Kassem M, Myklebost O (2010)
Identification of target genes for wild type and truncated HMGA2 in mesenchymal stem-like cells
BMC Cancer, 10, 329
PubMed 20576167

Tenstad E, Tourovskaia A, Folch A, Myklebost O, Rian E (2010)
Extensive adipogenic and osteogenic differentiation of patterned human mesenchymal stem cells in a microfluidic device
Lab Chip, 10 (11), 1401-1409
PubMed 20386793

Ottaviano L, Schaefer KL, Gajewski M, Huckenbeck W, Baldus S, Rogel U, Mackintosh C, de Alava E, Myklebost O, Kresse SH, Meza-Zepeda LA, Serra M, Cleton-Jansen AM, Hogendoorn PC, Buerger H, Aigner T, Gabbert HE, Poremba C (2010)
Molecular characterization of commonly used cell lines for bone tumor research: a trans-European EuroBoNet effort
Genes Chromosomes Cancer, 49 (1), 40-51
PubMed 19787792

Lehne G, Grasmo-Wendler UH, Berner JM, Meza-Zepeda LA, Adamsen BL, Flack A, Reiner A, Clausen OP, Hovig E, Myklebost O (2009)
Upregulation of stem cell genes in multidrug resistant K562 leukemia cells
Leuk Res, 33 (10), 1379-85
PubMed 19394083

Kresse SH, Ohnstad HO, Paulsen EB, Bjerkehagen B, Szuhai K, Serra M, Schaefer KL, Myklebost O, Meza-Zepeda LA (2009)
LSAMP, a novel candidate tumor suppressor gene in human osteosarcomas, identified by array comparative genomic hybridization
Genes Chromosomes Cancer, 48 (8), 679-93
PubMed 19441093

Roman E, Meza-Zepeda LA, Kresse SH, Myklebost O, Vasstrand EN, Ibrahim SO (2008)
Chromosomal aberrations in head and neck squamous cell carcinomas in Norwegian and Sudanese populations by array comparative genomic hybridization
Oncol Rep, 20 (4), 825-43
PubMed 18813824

Kresse SH, Skårn M, Ohnstad HO, Namløs HM, Bjerkehagen B, Myklebost O, Meza-Zepeda LA (2008)
DNA copy number changes in high-grade malignant peripheral nerve sheath tumors by array CGH
Mol Cancer, 7, 48
PubMed 18522746

Lyng H, Lando M, Brøvig RS, Svendsrud DH, Johansen M, Galteland E, Brustugun OT, Meza-Zepeda LA, Myklebost O, Kristensen GB, Hovig E, Stokke T (2008)
GeneCount: genome-wide calculation of absolute tumor DNA copy numbers from array comparative genomic hybridization data
Genome Biol, 9 (5), R86
PubMed 18500990

Meza-Zepeda LA, Noer A, Dahl JA, Micci F, Myklebost O, Collas P (2008)
High-resolution analysis of genetic stability of human adipose tissue stem cells cultured to senescence
J Cell Mol Med, 12 (2), 553-63
PubMed 18419597

Müller CR, Paulsen EB, Noordhuis P, Pedeutour F, Saeter G, Myklebost O (2007)
Potential for treatment of liposarcomas with the MDM2 antagonist Nutlin-3A
Int J Cancer, 121 (1), 199-205
PubMed 17354236

Francis P, Namløs HM, Müller C, Edén P, Fernebro J, Berner JM, Bjerkehagen B, Akerman M, Bendahl PO, Isinger A, Rydholm A, Myklebost O, Nilbert M (2007)
Diagnostic and prognostic gene expression signatures in 177 soft tissue sarcomas: hypoxia-induced transcription profile signifies metastatic potential
BMC Genomics, 8, 73
PubMed 17359542

Kleivi K, Lind GE, Diep CB, Meling GI, Brandal LT, Nesland JM, Myklebost O, Rognum TO, Giercksky KE, Skotheim RI, Lothe RA (2007)
Gene expression profiles of primary colorectal carcinomas, liver metastases, and carcinomatoses
Mol Cancer, 6, 2
PubMed 17201907

Ola Myklebost laboratory