Marie Arsenian Henriksson Group
Approaches to target the MYC oncoprotein to combat cancer
Neuroblastoma (NB), a tumor that arises from neural crest cells in the developing sympathetic nervous system, is the most common and deadly solid childhood tumor outside the CNS. NB cells show complex patterns of genetic defects, including specific chromosomal aberrations and MYCN amplification. This occurs in 40-50% of high-risk cases and is associated with advanced-stage disease, rapid tumor progression and a survival rate of less than 15%. An alternative treatment option for these children is therefore urgently needed.
Our research is focused on the MYCN oncogene in order to identify targets for development of novel anti-cancer therapies. To this end we will: 1) analyze the functional significance of MYCN-regulated microRNAs for NB pathogenesis; 2) characterize the role of MYCN in invasion and migration; 3) identify small compounds that selectively kill cells with high MYCN expression; 4) explore the normal function of MYCN during development of the nervous system.
It was recently shown that MYCN regulates expression of micro-RNAs in NB cells. We have demonstrated that miR-18a and miR- 19a from the oncogenic miR-17~92 cluster target and subsequently repress the expression of estrogen receptor ± (ESR1). Downregulation of mir-18a as well as ectopic ESR1 expression resulted in growth arrest and neuronal differentiation of NB cells. Importantly, we demonstrated expression of ESR1 in human fetal sympathetic ganglia suggesting a role during neuronal development. We propose that MYCN amplification may disrupt estrogen-signaling sensitivity in primitive sympathetic cells through downregulation of ESR1, thereby preventing normal neuroblast differentiation.
Collectively, our studies will give insights to the normal function of MYCN and its contribution to NB pathogenesis. This knowledge could serve as basis for development of novel cancer therapies for children with neuroblastoma as well as other diseases, since MYC is activated in many different malignancies.
Project Groups within the Marie Arsenian Henriksson Group
-amplified neuroblastoma maintains an aggressive and undifferentiated phenotype by deregulation of estrogen and NGF signaling.
Proc. Natl. Acad. Sci. U.S.A. 2018 Feb;115(6):E1229-E1238
Neuroblast differentiation during development and in neuroblastoma requires KIF1Bβ-mediated transport of TRKA.
Genes Dev. 2017 05;31(10):1036-1053
The MYCN Protein in Health and Disease.
Genes (Basel) 2017 Mar;8(4):
Proliferation and Survival of Embryonic Sympathetic Neuroblasts by MYCN and Activated ALK Signaling.
J. Neurosci. 2016 Oct;36(40):10425-10439
MicroRNA-203 Inversely Correlates with Differentiation Grade, Targets c-MYC, and Functions as a Tumor Suppressor in cSCC.
J. Invest. Dermatol. 2016 Dec;136(12):2485-2494
Direct inhibition of c-Myc-Max heterodimers by celastrol and celastrol-inspired triterpenoids.
Oncotarget 2015 Oct;6(32):32380-95
COX/mPGES-1/PGE2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset.
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.
Virology 2015 Feb;476():271-88
TAp73 suppresses tumor angiogenesis through repression of proangiogenic cytokines and HIF-1α activity.
Proc. Natl. Acad. Sci. U.S.A. 2015 Jan;112(1):220-5
Impact of MYC in regulation of tumor cell metabolism.
Biochim. Biophys. Acta 2015 May;1849(5):563-9
X-ray phase contrast with injected gas for tumor microangiography.
Phys Med Biol 2014 Jun;59(11):2801-11
MYC proteins promote neuronal differentiation by controlling the mode of progenitor cell division.
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