High-Throughput Molecular and Histopathologic Profiling of Tumor Tissue in a Novel Transplantable Model of Murine Neuroblastoma: New Tools for Pediatric Drug Discovery

Stauffer, Jimmy K.; Orentas, Rimas J.; Lincoln, Erin; Khan, Tahira; Salcedo, Rosalba; Hixon, Julie A.; Back, Timothy C.; Wei, Jun S.; Patidar, Rajesh; Song, Young Woo; Hurd, Laura; Tsokos, Maria; Lai, Edwin W.; Eisenhofer, Graeme; Weiss, William A.; Khan, Javed Masood; Wigginton, Jon M.

doi:10.3109/07357907.2012.664670

Cited by 10 publications

(12 citation statements)

References 103 publications

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“…Cell lines derived from spontaneous tumors retain many molecular and biological characteristics of NBL . Moreover, newly formed tumors from transplantable cell lines show close correspondence with spontaneous NBL tumors in many ways . For these reasons, the TH‐MYCN model has been used to study the pathophysiology of NBL and to test novel targeted therapeutics .…”

Section: Discussionmentioning

confidence: 99%

“…31 Moreover, newly formed tumors from transplantable cell lines show close correspondence with spontaneous NBL tumors in many ways. 32 For these reasons, the TH-MYCN model has been used to study the pathophysiology of NBL and to test novel targeted therapeutics. 19,[33][34][35] We now extend the use of the TH-MYCN model to immunotherapeutic studies by showing the striking similarities with the reported immunobiology of human NBL.…”

Section: Discussionmentioning

confidence: 99%

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A transplantable TH‐MYCN transgenic tumor model in C57Bl/6 mice for preclinical immunological studies in neuroblastoma

Kroesen

Nierkens

Ansems

et al. 2013

Intl Journal of Cancer

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Current multimodal treatments for patients with neuroblastoma (NBL), including anti-disialoganglioside (GD2) monoclonal antibody (mAb) based immunotherapy, result in a favorable outcome in around only half of the patients with advanced disease. To improve this, novel immunocombinational strategies need to be developed and tested in autologous preclinical NBL models. A genetically well-explored autologous mouse model for NBL is the TH-MYCN model. However, the immunobiology of the TH-MYCN model remains largely unexplored. We developed a mouse model using a transplantable TH-MYCN cell line in syngeneic C57Bl/6 mice and characterized the immunobiology of this model. In this report, we show the relevance and opportunities of this model to study immunotherapy for human NBL. Neuroblastoma (NBL) is an extracranial solid tumor of childhood that accounts for 12% of all deaths associated with cancer in children under 15 years of age.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A transplantable TH‐MYCN transgenic tumor model in C57Bl/6 mice for preclinical immunological studies in neuroblastoma

Kroesen

Nierkens

Ansems

et al. 2013

Intl Journal of Cancer

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“…Quantitative RT-PCR was performed using Taqman assays (Life Technologies, Carlsbad, CA) on a Fluidigm system as previously described [46]. Briefly, cDNA was generated from 200 ng of RNA using reverse transcription.…”

Section: Methodsmentioning

confidence: 99%

MYCN controls an alternative RNA splicing program in high-risk metastatic neuroblastoma

Zhang

Wei

et al. 2016

Cancer Letters

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The molecular mechanisms underlying the aggressive behavior of MYCN driven neuroblastoma (NBL) is under intense investigation; however, little is known about the impact of this family of transcription factors on the splicing program. Here we used high-throughput RNA sequencing to systematically study the expression of RNA isoforms in stage 4 MYCN-amplified NBL, an aggressive subtype of metastatic NBL. We show that MYCN-amplified NBL tumors display a distinct gene splicing pattern affecting multiple cancer hallmark functions. Six splicing factors displayed unique differential expression patterns in MYCN-amplified tumors and cell lines, and the binding motifs for some of these splicing factors are significantly enriched in differentially-spliced genes. Direct binding of MYCN to promoter regions of the splicing factors PTBP1 and HNRNPA1 detected by ChIP-seq demonstrates MYCN controls the splicing pattern by direct regulation of the expression of these key splicing factors. Furthermore, high expression of PTBP1 and HNRNPA1 was significantly associated with poor overall survival of stage4 NBL patients (p≤0.05). Knocking down PTBP1, HNRNPA1 and their downstream target PKM2, an isoform of pro-tumor-growth, result in repressed growth of NBL cells. Therefore, our study reveals a novel role of MYCN in controlling global splicing program through regulation of splicing factors in addition to its well-known role in the transcription program. These findings suggest a therapeutically potential to target the key splicing factors or gene isoforms in high-risk NBL with MYCN-amplification.

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“…RNA integrity number (RIN) was calculated using the RNA 6000 Nano Kit (Agilent) and all were greater than 9.0. Quantitative RT-PCR using Taqman assays (FGFR4: Hs00242558_m1 and GAPDH: Hs99999905_m1) on a Fluidigm system was previously described [21]. Briefly, cDNA was generated from 200 ng of RNA using reverse transcription.…”

Section: Methodsmentioning

confidence: 99%

Targeting Wild-Type and Mutationally Activated FGFR4 in Rhabdomyosarcoma with the Inhibitor Ponatinib (AP24534)

Cheuk

Shern

et al. 2013

PLoS ONE

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Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. Despite advances in modern therapy, patients with relapsed or metastatic disease have a very poor clinical prognosis. Fibroblast Growth Factor Receptor 4 (FGFR4) is a cell surface tyrosine kinase receptor that is involved in normal myogenesis and muscle regeneration, but not commonly expressed in differentiated muscle tissues. Amplification and mutational activation of FGFR4 has been reported in RMS and promotes tumor progression. Therefore, FGFR4 is a tractable therapeutic target for patients with RMS. In this study, we used a chimeric Ba/F3 TEL-FGFR4 construct to test five tyrosine kinase inhibitors reported to specifically inhibit FGFRs in the nanomolar range. We found ponatinib (AP24534) to be the most potent FGFR4 inhibitor with an IC50 in the nanomolar range. Ponatinib inhibited the growth of RMS cells expressing wild-type or mutated FGFR4 through increased apoptosis. Phosphorylation of wild-type and mutated FGFR4 as well as its downstream target STAT3 was also suppressed by ponatinib. Finally, ponatinib treatment inhibited tumor growth in a RMS mouse model expressing mutated FGFR4. Therefore, our data suggests that ponatinib is a potentially effective therapeutic agent for RMS tumors that are driven by a dysregulated FGFR4 signaling pathway.

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High-Throughput Molecular and Histopathologic Profiling of Tumor Tissue in a Novel Transplantable Model of Murine Neuroblastoma: New Tools for Pediatric Drug Discovery

Cited by 10 publications

References 103 publications

A transplantable TH‐MYCN transgenic tumor model in C57Bl/6 mice for preclinical immunological studies in neuroblastoma

A transplantable TH‐MYCN transgenic tumor model in C57Bl/6 mice for preclinical immunological studies in neuroblastoma

MYCN controls an alternative RNA splicing program in high-risk metastatic neuroblastoma

Targeting Wild-Type and Mutationally Activated FGFR4 in Rhabdomyosarcoma with the Inhibitor Ponatinib (AP24534)

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