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.
Selected publications 2014-2020
p53 controls genomic stability and temporal differentiation of human neural stem cells and affects neural organization in human brain organoids.
Marin Navarro A, Pronk RJ, van der Geest AT, Oliynyk G, Nordgren A, Arsenian-Henriksson M, et al
Cell Death Dis 2020 Jan;11(1):52
Integrative discovery of treatments for high-risk neuroblastoma.
Almstedt E, Elgendy R, Hekmati N, Rosén E, Wärn C, Olsen TK, et al
Nat Commun 2020 01;11(1):71
MYCN-enhanced Oxidative and Glycolytic Metabolism Reveals Vulnerabilities for Targeting Neuroblastoma.
Oliynyk G, Ruiz-Pérez MV, Sainero-Alcolado L, Dzieran J, Zirath H, Gallart-Ayala H, et al
iScience 2019 Nov;21():188-204
Serine-Glycine-One-Carbon Metabolism: The Hidden Achilles Heel of MYCN-Amplified Neuroblastoma?
Garcia AR, Arsenian-Henriksson M
Cancer Res. 2019 Aug;79(15):3818-3819
Single-Cell RNA Sequencing of the T Helper Cell Response to House Dust Mites Defines a Distinct Gene Expression Signature in Airway Th2 Cells.
Tibbitt CA, Stark JM, Martens L, Ma J, Mold JE, Deswarte K, et al
Immunity 2019 07;51(1):169-184.e5
High-spatial-resolution x-ray fluorescence tomography with spectrally matched nanoparticles.
Larsson JC, Vogt C, Vågberg W, Toprak MS, Dzieran J, Arsenian-Henriksson M, et al
Phys Med Biol 2018 08;63(16):164001
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 MJGW, van Leeuwen IMM, Drummond CJ, Chu S, Healy AR, 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 UK, Henley AB, 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 CU, von Stedingk K, Bexell D, Merselius M, Braekeveldt N, Gisselsson D, et al
Sci Rep 2017 08;7(1):10274
Neuroblast differentiation during development and in neuroblastoma requires KIF1Bβ-mediated transport of TRKA.
Fell SM, 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 MV, Henley AB, 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 NX, 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 MDR, Westermark UK, Oliynyk G, Dzieran J, Kock A, et al
Cell Rep 2016 07;16(4):979-993
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 JI, 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 MM, Ko B, Kim J, Brady R, Heatley HC, 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 HA, 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 MA
Biochim. Biophys. Acta 2015 May;1849(5):563-9
X-ray phase contrast with injected gas for tumor microangiography.
Lundström U, Westermark UK, Larsson DH, Burvall A, Arsenian Henriksson M, Hertz HM
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
Frenzel, A., and Arsenian Henriksson, M
Encyclopedia of Signalling Molecules, Springer Verlag. 2012
• Encyclopedia of Signalling Molecules
Former Group Members
We are indebted to the following organizations for their valuable support for our research! Thank you!
- KI Cancer Network
- Swedish Cancer Society
- Swedish Research Council
- King Gustaf V Jubilee Foundation
- Royal Academy of Sciences
- Åke Wiberg Memorial Foundation
- Swedish Childhood Cancer Foundation
- Hedlunds Foundation
- Åke Olsson Foundation
- The National Board of Health and Welfare Funds
- KID Funding
- Golje Memorial Fund
- Lars Hierta's Memorial Fund
- Robert Lundberg Foundation
- Ida och Henning Persson Foundation