Oncotarget

Research Papers:

Genomic imbalance of HMMR/RHAMM regulates the sensitivity and response of malignant peripheral nerve sheath tumour cells to aurora kinase inhibition.

Pooja Mohan, Joan Castellsague, Jihong Jiang, Kristi Allen, Helen Chen, Oksana Nemirovsky, Melanie Spyra, Kaiji Hu, Lan Kluwe, Miguel Angel Pujana, Alberto Villanueva, Victor F. Mautner, Jonathan J. Keats, Sandra E. Dunn, Conxi Lazaro, Christopher A. Maxwell _

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Abstract

Pooja Mohan1, Joan Castellsague2, Jihong Jiang1, Kristi Allen3, Helen Chen1, Oksana Nemirovsky1, Melanie Spyra4, Kaiji Hu1, Lan Kluwe4, Miguel Angel Pujana5, Alberto Villanueva5, Victor F. Mautner4, Jonathan J. Keats3, Sandra E. Dunn1, Conxi Lazaro2, Christopher A. Maxwell1

1 Department of Pediatrics, Child & Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.

2 Hereditary Cancer Program, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research, L’Hospitalet de Llobregat, Barcelona, Spain.

3 Integrated Cancer Genomics Division, The Translational Genomics Research Institute, Phoenix, AZ, USA.

4 Department of Neurology, University Hospital Eppendorf, Hamburg, Germany.

5 Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research, L’Hospitalet de Llobregat, Barcelona, Spain.

Correspondence:

Chris Maxwell , email:

Keywords: MPNST, AURKA, RHAMM, TPX2, cancer stem cell

Received: December 26, 2012, Accepted: January 07, 2013, Published: January 09, 2013

Abstract

Malignant peripheral nerve sheath tumours (MPNST) are rare, hereditary cancers associated with neurofibromatosis type I. MPNSTs lack effective treatment options as they often resist chemotherapies and have high rates of disease recurrence. Aurora kinase A (AURKA) is an emerging target in cancer and an aurora kinase inhibitor (AKI), termed MLN8237, shows promise against MPNST cell lines in vitro and in vivo. Here, we test MLN8237 against two primary human MPNST grown in vivo as xenotransplants and find that treatment results in tumour cells exiting the cell cycle and undergoing endoreduplication, which cumulates in stabilized disease. Targeted therapies can often fail in the clinic due to insufficient knowledge about factors that determine tumour susceptibilities, so we turned to three MPNST cell-lines to further study and modulate the cellular responses to AKI. We find that the sensitivity of cell-lines with amplification of AURKA depends upon the activity of the kinase, which correlates with the expression of the regulatory gene products TPX2 and HMMR/RHAMM. Silencing of HMMR/RHAMM, but not TPX2, augments AURKA activity and sensitizes MPNST cells to AKI. Furthermore, we find that AURKA activity is critical to the propagation and self-renewal of sphere-enriched MPNST cancer stem-like cells. AKI treatment significantly reduces the formation of spheroids, attenuates the self-renewal of spheroid forming cells, and promotes their differentiation. Moreover, silencing of HMMR/RHAMM is sufficient to endow MPNST cells with an ability to form and maintain sphere culture. Collectively, our data indicate that AURKA is a rationale therapeutic target for MPNST and tumour cell responses to AKI, which include differentiation, are modulated by the abundance of HMMR/RHAMM.


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