Gunhild Mælandsmo

Dr. Gunhild Mælandsmo
Metastasis: biology and therapy 
Dept. of Tumor Biology
Oslo University Hospital,
The Norwegian Radium Hospital
gunhildm@rr-research.no
Tel +47 22 78 18 79

 


ACTIVITIES

The group is studying the impact of stem or progenitor cells for initiation and progression of breast cancer and malignant melanoma. In our studies we are utilizing either clinical material obtained directly from the patients, or human tumors grown as xenografts in nude mice. We are in the process of establishing optimized methods for preparing the tissue, isolating the tumor-initiating cell populations and cultivating the cells for maintenance of stemness characteristics and differentiation capability. 

In the breast cancer project we utilize models representative for basal-like and luminal A subtype of human breast cancer grown orthotopically in nude mice. The primary purpose of the project is to investigate whether any of the two subtypes of breast cancer originate from cells with stem cell-like properties, and furthermore to study whether the ER negative basal-like subtype descend from a more primitive/less differentiated, potential pluripotent, stem cell compared to the ER positive luminal A subtype. We are isolating cell populations based on cell surface markers and have established several in vitro assays for measuring stem cell characteristics; mammosphere assay, soft agar and cultivation as 3D structures in collagen or Matrigel matrixes.

 

In the melanoma projects we obtain material from lymph node resections. The samples are easily disaggregated to obtain single cell suspensions which are seeded in specialized media. We are at present evaluating whether growth as monolayer compared to 3D structures might select for stem cell-like properties. 

 

GROUP MEMBERS
active in CAST

Ingrid Johanne Bettum
PhD student

 

Lina Prasmickaite
Senior scientist

 

Kristin Andersen
Post doc 

 

 

STATUS 2013

BREAST CANCER PROJECT

Intratumoral heterogeneity: We have isolated tumor cell populations from two orthotopically growing patientderived breast cancer xenograft models (PDBCX) and characterized their intracellular heterogeneity. In both cancer subtypes (luminal and basal-like) all tumor cells expressed EpCAM, and in vivo experiments showed that the luminal like EpCAM subpopulation had the highest tumor initiating potential. Further analysis of this population revealed intracellular heterogeneity with respect to in vivo tumorigenicity. In collaboration with T. Sørlie, whole genome expression analysis and mass spectrometry based proteome analysis were performed. Studies of the differences in miRNA and epigenetic patterns between the populations have also been initiated. To unravel the general value in the identified molecular patterns five new ortothopically growing PDBCX models from Curie Institute, Paris, has been established, and included in the studies. The PDBCX has been used for testing subpopulation
specific effects of estrogen withdrawel. In addition will Wnt inhibitors and CSGP4-targeted PCI therapy be tested. S100A4 in EMT and stemness: To study the importance of the mesenchymal marker S100A4 during EMT, HMLE cells with shRNA knockdown of endogenous expression has been established. Epithelial HMLE-S100A4-knock down cells has the ability to undergo TGF-β induced EMT. We are currently investigating whether S100A4 acts as a stabilizer of the mesenchymal phenotype, thereby contributing to both EMT and MET. It is well known that MMPs can induce EMT and an invasive phenotype in mammary epithelial cells and furthermore that S100A4 induce expression of MMPs in various cell systems. We are currently characterizing extracellular S100A4 mediated signaling programs responsible for inducing MMP expression. Three different model systems, have been characterized and S100A4-mediated MMP transcription was induced in all cell systems. Preliminary data suggest that S100A4 mediated MMP induction involve activation and internalization of EGFR and activation of ERK.

MELANOMA PROJECT

Melanoma seems not to follow the “classical” CSC model, which suggests the presence of an exclusive “stable” small cell subpopulation distinguishable by specific markers. Rather, our data suggests that most of melanoma cells have the potential to exhibit “stemcellness”. This is in agreement with the new theory, which proposes that acquisition of CSC characteristics in melanoma might be a dynamic process and most of melanoma cells can switch into transient CSC-like phenotype given appropriate signals from the microenvironment. This signifies the importance of better understanding the microenvironment-driven signals that might regulate phenotype-switching i.e. generation of invasive/metastatic, therapy-resistant, stem-like subpopulations. We have developed in vitro and in vivo melanoma models allowing investigation of tumor-microenvironment interaction and its role on the phenotype and functional properties of melanoma cells.

 

SELECTED PUBLICATIONS 

Esmaeili MBathen TFEngebråten OMaelandsmo GMGribbestad ISMoestue SA
Quantitative (31) P HR-MAS MR spectroscopy for detection of response to PI3K/mTOR inhibition in breast cancer xenografts
Magn Reson Med (in press)
PubMed 23878023

Moestue SAHuuse EMLindholm EMBofin AEngebraaten OMaelandsmo GMAkslen LAGribbestad IS
Low-molecular contrast agent dynamic contrast-enhanced (DCE)-MRI and diffusion-weighted (DW)-MRI in early assessment of bevacizumab treatment in breast cancer xenografts
J Magn Reson Imaging (in press)
PubMed 23908122

Rud AKBorgen EMælandsmo GMFlatmark KLe HJosefsen DSolvoll ISchirmer CBHelland AJørgensen L,Brustugun OTFodstad OBoye K
Clinical significance of disseminated tumour cells in non-small cell lung cancer
Br J Cancer (in press)
PubMed 23942067

Borgan ELindholm EMMoestue SMælandsmo GMLingjærde OCGribbestad ISBørresen-Dale ALEngebraaten O,Sørlie T (2013)
Subtype-specific response to bevacizumab is reflected in the metabolome and transcriptome of breast cancer xenografts
Mol Oncol7 (1)130-42
PubMed 23142657

Haugen MHJohansen HTPettersen SJSolberg RBrix KFlatmark KMaelandsmo GM (2013)
Nuclear legumain activity in colorectal cancer
PLoS One8 (1)e52980
PubMed 23326369

Jin YQu STesikova MWang LKristian AMælandsmo GMKong HZhang TJerónimo CTeixeira MRYuca ETekedereli IGorgulu KAlpay NSood AKLopez-Berestein GDanielsen HEOzpolat BSaatcioglu F (2013)
Molecular circuit involving KLK4 integrates androgen and mTOR signaling in prostate cancer
Proc Natl Acad Sci U S A110 (28)E2572-81
PubMed 23798432

Moestue SADam CGGorad SSKristian ABofin AMælandsmo GMEngebråten OGribbestad ISBjørkøy G (2013)
Metabolic biomarkers for response to PI3K inhibition in basal-like breast cancer
Breast Cancer Res15 (1)R16
PubMed 23448424

Borgan ELindholm EMMoestue SMælandsmo GMLingjærde OCGribbestad ISBørresen-Dale ALEngebraaten OSørlie T (2013)
Subtype-specific response to bevacizumab is reflected in the metabolome and transcriptome of breast cancer xenografts
Mol Oncol7 (1)130-42
PubMed 23142657

Slipicevic AØy GFRosnes AKStakkestad ØEmilsen EEngesæter BMælandsmo GMFlørenes VA (2013)
Low-dose anisomycin sensitizes melanoma cells to TRAIL induced apoptosis
Cancer Biol Ther14 (2)146-54
PubMed 23192275

Haugen MHJohansen HTPettersen SJSolberg RBrix KFlatmark KMaelandsmo GM (2013)
Nuclear legumain activity in colorectal cancer
PLoS One8 (1)e52980
PubMed 23326369

Smith RJohansen HTNilsen HHaugen MHPettersen SJMælandsmo GMAbrahamson MSolberg R (2012)
Intra- and extracellular regulation of activity and processing of legumain by cystatin E/M
Biochimie94 (12)2590-9
PubMed 22902879

Engesæter BEngebraaten OFlørenes VAMælandsmo GM (2012)
Dacarbazine and the agonistic TRAIL receptor-2 antibody lexatumumab induce synergistic anticancer effects in melanoma
PLoS One7 (9)e45492
PubMed 23029050

Kernstock SDavydova EJakobsson MMoen APettersen SMælandsmo GMEgge-Jacobsen WFalnes PØ (2012)
Lysine methylation of VCP by a member of a novel human protein methyltransferase family
Nat Commun31038
PubMed 22948820

Boye KNesland JMSandstad BHaugland Haugen MMælandsmo GMFlatmark K (2012)
EMMPRIN is associated with S100A4 and predicts patient outcome in colorectal cancer
Br J Cancer107 (4)667-74
PubMed 22782346

Rud AKLund-Iversen MBerge GBrustugun OTSolberg SKMælandsmo GMBoye K (2012)
Expression of S100A4, ephrin-A1 and osteopontin in non-small cell lung cancer
BMC Cancer12333
PubMed 22853000

Lindholm EMKristian ANalwoga HKrüger KNygård SAkslen LAMælandsmo GMEngebraaten O (2012)
Effect of antiangiogenic therapy on tumor growth, vasculature and kinase activity in basal- and luminal-like breast cancer xenografts
Mol Oncol6 (4)418-27
PubMed 22521242

Tekle CNygren MKChen YWDybsjord INesland JMMaelandsmo GMFodstad O (2012)
B7-H3 contributes to the metastatic capacity of melanoma cells by modulation of known metastasis-associated genes
Int J Cancer130 (10)2282-90
PubMed 21671471

Huuse EMMoestue SALindholm EMBathen TFNalwoga HKrüger KBofin AMaelandsmo GMAkslen LAEngebraaten OGribbestad IS (2012)
In vivo MRI and histopathological assessment of tumor microenvironment in luminal-like and basal-like breast cancer xenografts
J Magn Reson Imaging35 (5)1098-107
PubMed 22170753

Selbo PKWeyergang AEng MSBostad MMælandsmo GMHøgset ABerg K (2012)
Strongly amphiphilic photosensitizers are not substrates of the cancer stem cell marker ABCG2 and provides specific and efficient light-triggered drug delivery of an EGFR-targeted cytotoxic drug
J Control Release159 (2)197-203
PubMed 22349185

Slipicevic AHolm REmilsen ERee Rosnes AKWelch DRMælandsmo GMFlørenes VA (2012)
Cytoplasmic BRMS1 expression in malignant melanoma is associated with increased disease-free survival
BMC Cancer1273
PubMed 22356677

Berge GCostea DEBerg MRasmussen HGrotterød ILothe RAMælandsmo GMFlatmark K (2011)
Coexpression and nuclear colocalization of metastasis-promoting protein S100A4 and p53 without mutual regulation in colorectal carcinoma
Amino Acids41 (4)875-84
PubMed 20191297

Berge GPettersen SGrotterød IBettum IJBoye KMælandsmo GM (2011)
Osteopontin--an important downstream effector of S100A4-mediated invasion and metastasis
Int J Cancer129 (4)780-90
PubMed 20957651

Engesæter BOSathermugathevan MHellenes TEngebråten OHolm RFlørenes VAMælandsmo GM (2011)
Targeting inhibitor of apoptosis proteins in combination with dacarbazine or TRAIL in melanoma cells
Cancer Biol Ther12 (1)47-58
PubMed 21508672

Liu HTekle CChen YWKristian AZhao YZhou MLiu ZDing YWang BMælandsmo GMNesland JMFodstad OTan M (2011)
B7-H3 silencing increases paclitaxel sensitivity by abrogating Jak2/Stat3 phosphorylation
Mol Cancer Ther10 (6)960-71
PubMed 21518725

Andersen KMori HFata JBascom JOyjord TMælandsmo GMBissell M (2011)
The metastasis-promoting protein S100A4 regulates mammary branching morphogenesis
Dev Biol352 (2)181-90
PubMed 21195708

Paus EHaugen MHOlsen KHFlatmark KMaelandsmo GMNilsson ORöijer ELundin MFermér CSamsonova MLebedin YStigbrand T (2011)
TD-11 workshop report: characterization of monoclonal antibodies to S100 proteins
Tumour Biol32 (1)1-12
PubMed 20652782

Boye KNesland JMSandstad BMælandsmo GMFlatmark K (2010)
Nuclear S100A4 is a novel prognostic marker in colorectal cancer
Eur J Cancer46 (16)2919-25
PubMed 20719498

Wiiger MTGehrken HBFodstad ØMaelandsmo GMAndersson Y (2010)
A novel human recombinant single-chain antibody targeting CD166/ALCAM inhibits cancer cell invasion in vitro and in vivo tumour growth
Cancer Immunol Immunother59 (11)1665-74
PubMed 20635083

Røe KSeierstad TKristian AMikalsen LTMælandsmo GMvan der Kogel AJRee AHOlsen DR (2010)
Longitudinal magnetic resonance imaging-based assessment of vascular changes and radiation response in androgen-sensitive prostate carcinoma xenografts under androgen-exposed and androgen-deprived conditions
Neoplasia12 (10)818-25
PubMed 20927320

Moestue SABorgan EHuuse EMLindholm EMSitter BBørresen-Dale ALEngebraaten OMaelandsmo GMGribbestad IS (2010)
Distinct choline metabolic profiles are associated with differences in gene expression for basal-like and luminal-like breast cancer xenograft models
BMC Cancer10433
PubMed 20716336

Wang LJin YArnoldussen YJJonson IQu SMaelandsmo GMKristian ARisberg BWaehre HDanielsen HESaatcioglu F (2010)
STAMP1 is both a proliferative and an antiapoptotic factor in prostate cancer
Cancer Res70 (14)5818-28
PubMed 20587517

Grotterød IMaelandsmo GMBoye K (2010)
Signal transduction mechanisms involved in S100A4-induced activation of the transcription factor NF-kappaB
BMC Cancer10241
PubMed 20507646

Prasmickaite LEngesaeter BØSkrbo NHellenes TKristian AOliver NKSuo ZMaelandsmo GM (2010)
Aldehyde dehydrogenase (ALDH) activity does not select for cells with enhanced aggressive properties in malignant melanoma
PLoS One5 (5)e10731
PubMed 20505780

Kaarbø MMikkelsen OLMalerød LQu SLobert VHAkgul GHalvorsen TMaelandsmo GMSaatcioglu F (2010)
PI3K-AKT-mTOR pathway is dominant over androgen receptor signaling in prostate cancer cells
Cell Oncol32 (1-2)11-27
PubMed 20203370

Briggs JJHaugen MHJohansen HTRiker AIAbrahamson MFodstad ØMaelandsmo GMSolberg R (2010)
Cystatin E/M suppresses legumain activity and invasion of human melanoma
BMC Cancer1017
PubMed 20074384

Oy GFSlipicevic ADavidson BSolberg Faye RMaelandsmo GMFlørenes VA (2010)
Biological effects induced by insulin-like growth factor binding protein 3 (IGFBP-3) in malignant melanoma
Int J Cancer126 (2)350-61
PubMed 19588500

Bergamaschi AHjortland GOTriulzi TSørlie TJohnsen HRee AHRussnes HGTronnes SMaelandsmo GMFodstad OBorresen-Dale ALEngebraaten O (2009)
Molecular profiling and characterization of luminal-like and basal-like in vivo breast cancer xenograft models
Mol Oncol3 (5-6)469-82
PubMed 19713161

Høyem SBruheim SMaelandsmo GOlberg DEBrudeli BAsberg AKlaveness JRongved P (2009)
Didanosine ester prodrugs: synthesis, albumin binding properties and pharmacokinetic studies in rats
Eur J Med Chem44 (10)3874-9
PubMed 19433342

Elenjord RAllen JBJohansen HTKildalsen HSvineng GMaelandsmo GMLoennechen TWinberg JO (2009)
Collagen I regulates matrix metalloproteinase-2 activation in osteosarcoma cells independent of S100A4
FEBS J276 (18)5275-86
PubMed 19682073

Cedervall JJamil SPrasmickaite LCheng YEskandarpour MHansson JMaelandsmo GMRingborg UGulyas MZhen HSKanter LAhrlund-Richter L (2009)
Species-specific in vivo engraftment of the human BL melanoma cell line results in an invasive dedifferentiated phenotype not present in xenografts
Cancer Res69 (9)3746-54
PubMed 19383913

Maelandsmo GMFlørenes VANguyen MTFlatmark KDavidson B (2009)
Different expression and clinical role of S100A4 in serous ovarian carcinoma at different anatomic sites
Tumour Biol30 (1)15-25
PubMed 19194111

Arnoldussen YJLorenzo PIPretorius MEWaehre HRisberg BMaelandsmo GMDanielsen HESaatcioglu F (2008)
The mitogen-activated protein kinase phosphatase vaccinia H1-related protein inhibits apoptosis in prostate cancer cells and is overexpressed in prostate cancer
Cancer Res68 (22)9255-64
PubMed 19010898

Boye KGrotterød IAasheim HCHovig EMaelandsmo GM (2008)
Activation of NF-kappaB by extracellular S100A4: analysis of signal transduction mechanisms and identification of target genes
Int J Cancer123 (6)1301-10
PubMed 18548584

Haugen MHFlatmark KMikalsen SOMalandsmo GM (2008)
The metastasis-associated protein S100A4 exists in several charged variants suggesting the presence of posttranslational modifications
BMC Cancer8172
PubMed 18554396

Faye RSPaus EMaelandsmo GMBerner AHøifødt HKFodstad ØAamdal S (2008)
S100B in bone marrow aspirates in healthy individuals and malignant melanoma patients
Melanoma Res18 (2)134-40
PubMed 18337650

Cabezón TCelis JESkibshøj IKlingelhöfer JGrigorian MGromov PRank FMyklebust JHMaelandsmo GMLukanidin EAmbartsumian N (2007)
Expression of S100A4 by a variety of cell types present in the tumor microenvironment of human breast cancer
Int J Cancer121 (7)1433-44
PubMed 17565747

Lillehammer TEngesaeter BOPrasmickaite LMaelandsmo GMFodstad OEngebraaten O (2007)
Combined treatment with Ad-hTRAIL and DTIC or SAHA is associated with increased mitochondrial-mediated apoptosis in human melanoma cell lines
J Gene Med9 (6)440-51
PubMed 17410615

Tveito SMaelandsmo GMHoifodt HKRasmussen HFodstad O (2007)
Specific isolation of disseminated cancer cells: a new method permitting sensitive detection of target molecules of diagnostic and therapeutic value
Clin Exp Metastasis24 (5)317-27
PubMed 17530423

Rafferty MFaller WJMoss CMcCormack JMãlandsmo GMEasty DJGallagher WM (2007)
Real-time quantitative reverse transcriptase-polymerase chain reaction analysis of melanoma progression-associated genes
Anticancer Res27 (3A)1301-7
PubMed 17593623

Boye KAndersen KTveito SØyjord TMaelandsmo GM (2007)
Interferon-gamma-induced suppression of S100A4 transcription is mediated by the class II transactivator
Tumour Biol28 (1)27-35
PubMed 17143014

 

 

Gunhild Mælandsmo laboratory