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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

30033936

29883428

29549331

MYCN

MYCN29374092

28860499

28637693

28358317

27707976

27452220

27396325

26474287

26080408

25569455

25535357

25038584

24801363

24599748

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

Marie Arsenian-HenrikssonProfessor

Marie.Arsenian.Henriksson@ki.se

08-524 862 05

Nicola BalboniAnknuten

nicola.balboni@ki.se

+39-(0)3403226125

Maria BejaranoProfessor, adjungerad

Maria.Bejarano@ki.se

Bertha BrodinAnknuten

Bertha.Brodin@ki.se

Basile DalarunAnknuten

basile.dalarun@ki.se

Christer EricssonAnknuten, Senior forskare

Christer.Ericsson@ki.se

08-524 800 00

Elena Eyre SánchezAnknuten

elena.eyre.sanchez@ki.se

Kerstin FalkAnknuten

Kerstin.Falk@ki.se

Vivian HoAnknuten

vivian.ho@ki.se

Yurika KatsuPostdoc

yurika.katsu@ki.se

Tong LiuAnknuten

tong.liu@ki.se

Muhammad MushtaqAnknuten

muhammad.mushtaq@ki.se

Anders MutveiAnknuten

Anders.Mutvei@ki.se

Aida Rodriguez GarciaPostdoc

aida.rodriguez.garcia@ki.se

070-008 76 94

María Ruiz PérezForskarassistent

maria.ruiz.perez@ki.se

Lourdes Sainero AlcoladoDoktorand, Forskarstuderande

lourdes.sainero.alcolado@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