Marie Arsenian Henriksson Group

Neural differentiation as a strategy for neuroblastoma treatment

Neuroblastoma is the most common extra cranial solid tumor of childhood that results in the highest number of cancer-related deaths in infants. In the high-risk group ~ 40% of the patients are incurable despite intense multimodal treatment regiments. Amplification of the MYCN oncogene is strongly associated to poor survival and to an undifferentiated phenotype. Considerable research efforts have been made to explore agents that could induce differentiation as therapeutic options for the high-risk patient group. So far, only retinoic acid treatment has shown promising results and today 13-cis retinoic acid is used as maintenance therapy.

MYCN belongs to the MYC network of transcription factors that plays a key role in the regulation of cell growth, apoptosis and differentiation. Other family members include c-MYC and L-MYC. All three genes are activated in a wide variety of human tumors. While the c-MYC gene is expressed in most tissues, MYCN expression is restricted to early stages of embryonic development, making it a strong candidate as a potential therapeutic target. Importantly, inhibition of MYCN in neuroblastoma cells leads to differentiation, suggesting an important role for MYCN in maintaining an undifferentiated phenotype. We have recently demonstrated that the MYCN-regulated miR-17~92 cluster targets several other nuclear hormone receptors (NHRs) in addition to ERalpha (Ribeiro et al, 2016). The glucocorticoid receptor (GR) emerged as particularly  interesting. We found that it is a direct target of the miR-17~92 cluster, that it is the most significantly downregulated NHR in MYCN amplified neuroblastoma patients and is highly prognostic for patient outcome. Glucocorticoids, the hormones that bind to GR and promote its activation, have been successfully used to treat many diseases due to their anti-inflammatory, anti-proliferative, pro-apoptotic and anti-angiogenic properties. We found that low GR expression in  was associated with an undifferentiated phenotype and decreased patient survival. Importantly, we showed that MYCN inhibition and subsequent reactivation of GR signaling promotes neural differentiation and reduces tumor burden. Our findings reveal a key role for the miR-17~92-regulated NHRs in neuroblastoma biology, thereby providing a potential differentiation approach for treating neuroblastoma patients (Ribeiro et al, 2016).

Together, our research will generate new insights into the pathology and the regulation of neural differentiation of MYCN-amplified neuroblastoma cells. This knowledge may offer novel prediction and diagnostic markers and serve as basis for development of new cancer therapies for children with neuroblastoma  and other tumors since MYC is activated in many different cancer types.

Project Groups within the Marie Arsenian Henriksson Group

Christer Ericsson Project

Publications 2014-2018

Fibroblasts in the Tumor Microenvironment: Shield or Spear?
Alkasalias T, Moyano-Galceran L, Arsenian-Henriksson M, Lehti K
Int J Mol Sci 2018 May;19(5):

A DHODH inhibitor increases p53 synthesis and enhances tumor cell killing by p53 degradation blockage.
Ladds M, van Leeuwen I, Drummond C, Chu S, Healy A, Popova G, et al
Nat Commun 2018 03;9(1):1107

MYCN-amplified neuroblastoma maintains an aggressive and undifferentiated phenotype by deregulation of estrogen and NGF signaling.
Dzieran J, Rodriguez Garcia A, Westermark U, Henley A, Eyre Sánchez E, Träger C, et al
Proc. Natl. Acad. Sci. U.S.A. 2018 02;115(6):E1229-E1238

Neuroblastoma patient-derived xenograft cells cultured in stem-cell promoting medium retain tumorigenic and metastatic capacities but differentiate in serum.
Persson C, von Stedingk K, Bexell D, Merselius M, Braekeveldt N, Gisselsson D, et al
Sci Rep 2017 Aug;7(1):10274

Neuroblast differentiation during development and in neuroblastoma requires KIF1Bβ-mediated transport of TRKA.
Fell S, Li S, Wallis K, Kock A, Surova O, Rraklli V, et al
Genes Dev. 2017 05;31(10):1036-1053

The MYCN Protein in Health and Disease.
Ruiz-Pérez M, Henley A, Arsenian-Henriksson M
Genes (Basel) 2017 Mar;8(4):

Proliferation and Survival of Embryonic Sympathetic Neuroblasts by MYCN and Activated ALK Signaling.
Kramer M, Ribeiro D, Arsenian-Henriksson M, Deller T, Rohrer H
J. Neurosci. 2016 10;36(40):10425-10439

MicroRNA-203 Inversely Correlates with Differentiation Grade, Targets c-MYC, and Functions as a Tumor Suppressor in cSCC.
Lohcharoenkal W, Harada M, Lovén J, Meisgen F, Landén N, Zhang L, et al
J. Invest. Dermatol. 2016 12;136(12):2485-2494

Regulation of Nuclear Hormone Receptors by MYCN-Driven miRNAs Impacts Neural Differentiation and Survival in Neuroblastoma Patients.
Ribeiro D, Klarqvist M, Westermark U, Oliynyk G, Dzieran J, Kock A, et al
Cell Rep 2016 07;16(4):979-993

Direct inhibition of c-Myc-Max heterodimers by celastrol and celastrol-inspired triterpenoids.
Wang H, Teriete P, Hu A, Raveendra-Panickar D, Pendelton K, Lazo J, et al
Oncotarget 2015 Oct;6(32):32380-95

COX/mPGES-1/PGE2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset.
Larsson K, Kock A, Idborg H, Arsenian Henriksson M, Martinsson T, Johnsen J, et al
Proc. Natl. Acad. Sci. U.S.A. 2015 Jun;112(26):8070-5

Acetylation of the c-MYC oncoprotein is required for cooperation with the HTLV-1 p30(II) accessory protein and the induction of oncogenic cellular transformation by p30(II)/c-MYC.
Romeo M, Ko B, Kim J, Brady R, Heatley H, He J, et al
Virology 2015 Feb;476():271-288

TAp73 suppresses tumor angiogenesis through repression of proangiogenic cytokines and HIF-1α activity.
Stantic M, Sakil H, Zirath H, Fang T, Sanz G, Fernandez-Woodbridge A, et al
Proc. Natl. Acad. Sci. U.S.A. 2015 Jan;112(1):220-5

Impact of MYC in regulation of tumor cell metabolism.
Wahlström T, Henriksson M
Biochim. Biophys. Acta 2015 May;1849(5):563-9

X-ray phase contrast with injected gas for tumor microangiography.
Lundström U, Westermark U, Larsson D, Burvall A, Arsenian Henriksson M, Hertz H
Phys Med Biol 2014 Jun;59(11):2801-11

MYC proteins promote neuronal differentiation by controlling the mode of progenitor cell division.
Zinin N, Adameyko I, Wilhelm M, Fritz N, Uhlén P, Ernfors P, et al
EMBO Rep. 2014 Apr;15(4):383-91

Book Chapters

Frenzel, A., and Arsenian Henriksson, M
MYC
Encyclopedia of Signalling Molecules, Springer Verlag. 2012
    •    Encyclopedia of Signalling Molecules

Publications 2006-2013

Publications 2010-2013 (pdf file)

publications 2006-2009 (pdf file)

Group Members

Nyosha AlikhaniAssistant professor

nyosha.alikhani@ki.se

Marie Arsenian-HenrikssonProfessor

Marie.Arsenian.Henriksson@ki.se

08-524 862 05

Maria BejaranoAdjunct professor

Maria.Bejarano@ki.se

Bertha BrodinAssociated

Bertha.Brodin@ki.se

Barbro Ehlin-HenrikssonCoordinator

Barbro.Ehlin-Henriksson@ki.se

08-524 867 31

Christer EricssonAssociated

Christer.Ericsson@ki.se

08-524 800 00

Elena Eyre SánchezAssociated

elena.eyre.sanchez@ki.se

Kerstin FalkAssociated

Kerstin.Falk@ki.se

Eva KleinProfessor emerita

Eva.Klein@ki.se

Francisca LameirasAssociated

francisca.lameiras@ki.se

Tong LiuAssociated

tong.liu@ki.se

Ganna OliynykPostdoc

ganna.oliynyk@ki.se

Aida Rodriguez GarciaPostdoc

aida.rodriguez.garcia@ki.se

María Ruiz PérezPostdoc

maria.ruiz.perez@ki.se

Lourdes Sainero AlcoladoPhD student, Graduate Student

lourdes.sainero.alcolado@ki.se

Hamid Reza SharifiAssociated

hamid.sharifi@ki.se

Former Group Members

Former Group Members

Funding

We are indebted to the following organizations for their valuable support for our research! Thank you! 

Funds from the Karolinska Institutet