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MYCN-induced calcium and magnesium signaling regulates Neuroblastoma progression

Award Number: K01CA154758
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/12/2012
PERIOD OF PERFORMANCE END DATE: 08/31/2017

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MYCN-induced calcium and magnesium signaling regulates Neuroblastoma progression - DESCRIPTION (provided by applicant): Neuroblastoma (NB) is an extra-cranial pediatric cancer. Amplification of the proto-oncogene MYCN is associated with advanced stage, high risk NB and poor prognosis. Novel drugs and alternative treatments are being investigated for patients with advanced NB with MYCN amplification. However, finding an effective treatment strategy for advanced stage NB remains elusive. In order to address this limitation, the proposed project examines the effects of calcium and magnesium signaling on cell migration and invasion in NB cells with different MYCN status. The preliminary data indicate that MYCN initiates a change in calcium signaling, accompanied by a change in the transcriptional regulation of calcium channels, namely Orai1, Orai3 and TRPM7. In addition, MYCN induces calcium-dependent NB cell migration. These observations support the hypothesis that MYCN alters calcium and magnesium homeostasis during cell migration and invasion through a mechanism that involves calcium-mediated regulation of integrin signaling and focal adhesion turnover, and calcium- and magnesium-permeable ion channels. The research plan has the following specific aims: (1) Examine the effect of MYCN on [Ca2+] and [Mg2+] homeostasis in NB cells. NB cells with different MYCN status will be cultured in external media with different extracellular [Ca2+]/[Mg2+] ratios. The intracellular calcium and magnesium will be measured, and migration and invasion rates will be determined in these cells. (2) Elucidate the mechanism by which MYCN regulation of calcium and magnesium promotes NB migration and invasion. The effect of calcium and magnesium on the expression and phosphorylation of focal adhesion kinase and integrin, focal adhesion turnover rate (assembly, disassembly and recycling of focal adhesion proteins), and actin cytoskeletal re-organization will be examined in NB cells that are actively migrating. (3) Identify the molecular components regulating NB migration and invasion. The calcium- permeable ORAI channels and the calcium- and magnesium-permeable TRPM7 channel protein will be modulated pharmacologically or using molecular methods (RNAi or transient over-expression), and the effect of these changes on cell migration and invasion, focal adhesion turnover (assembly, disassembly, and recycling of focal adhesion proteins), and intracellular [Ca2+] will be determined in NB cells. This study may identify new biomarkers for advanced stage NB, and reveal novel targets for the development of more effective chemotherapeutic drugs. In addition, this study may lead to a new model of the regulation of NB progression, which includes monitoring the status of the prognostic marker MYCN as well as the dietary intake, metabolism and cellular regulation of calcium and magnesium. This new model may apply to other cancers with MYC amplification (e.g. breast and prostate cancers, and lymphoma, etc).


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2018 ( Subtotal = -$699 )
2018	2016	UNIVERSITY OF HAWAII SYSTEMS	200 W KAWILI ST	HILO	HI	96720	HAWAII	USA	Cancer Research Manpower	000	5	1/17/2018	EXTENSION WITH OR WITHOUT FUNDS	-$699
														Subtotal = -$699

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2016	UNIVERSITY OF HAWAII SYSTEMS	200 W KAWILI ST	HILO	HI	96720	HAWAII	USA	Cancer Research Manpower	001	5	1/28/2017	EXTENSION WITH OR WITHOUT FUNDS	$44
2017	2015	UNIVERSITY OF HAWAII SYSTEMS	200 W KAWILI ST	HILO	HI	96720	HAWAII	USA	Cancer Research Manpower	000	4	1/28/2017	NON-COMPETING CONTINUATION	-$44
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $134,922 )
2016	2016	UNIVERSITY OF HAWAII	2530 Dole St., Sakamaki D200	HONOLULU	HI	96822	HONOLULU	USA	Cancer Research Manpower	000	5	8/5/2016	EXTENSION WITH OR WITHOUT FUNDS	$134,922
														Subtotal = $134,922

Issue Date FY: 2015 ( Subtotal = $134,922 )
2015	2015	UNIVERSITY OF HAWAII	2530 Dole St., Sakamaki D200	HONOLULU	HI	96822	HONOLULU	USA	Cancer Research Manpower	000	4	8/10/2015	NON-COMPETING CONTINUATION	$134,922
														Subtotal = $134,922

Issue Date FY: 2014 ( Subtotal = $134,922 )
2014	2014	UNIVERSITY OF HAWAII	2530 Dole St., Sakamaki D200	HONOLULU	HI	96822	HONOLULU	USA	Cancer Research Manpower	000	3	8/13/2014	NON-COMPETING CONTINUATION	$134,922
														Subtotal = $134,922

Issue Date FY: 2013 ( Subtotal = $134,922 )
2013	2013	UNIVERSITY OF HAWAII	2530 Dole St., Sakamaki D200	HONOLULU	HI	96822	HONOLULU	USA	Cancer Research Manpower	000	2	8/28/2013	NON-COMPETING CONTINUATION	$134,922
														Subtotal = $134,922

Issue Date FY: 2012 ( Subtotal = $134,922 )
2012	2012	UNIVERSITY OF HAWAII	2530 Dole St., Sakamaki D200	HONOLULU	HI	96822	HONOLULU	USA	Cancer Research Manpower	000	1	9/12/2012	NEW	$134,922
														Subtotal = $134,922

Grand Total All Awards = $673,911

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MYCN-induced calcium and magnesium signaling regulates Neuroblastoma progression

Award Number: K01CA154758

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/12/2012

PERIOD OF PERFORMANCE END DATE: 08/31/2017

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