dc.contributor.author | Yogev, O | |
dc.contributor.author | Almeida, GS | |
dc.contributor.author | Barker, KT | |
dc.contributor.author | George, SL | |
dc.contributor.author | Kwok, C | |
dc.contributor.author | Campbell, J | |
dc.contributor.author | Zarowiecki, M | |
dc.contributor.author | Kleftogiannis, D | |
dc.contributor.author | Smith, LM | |
dc.contributor.author | Hallsworth, A | |
dc.contributor.author | Berry, P | |
dc.contributor.author | Möcklinghoff, T | |
dc.contributor.author | Webber, HT | |
dc.contributor.author | Danielson, LS | |
dc.contributor.author | Buttery, B | |
dc.contributor.author | Calton, EA | |
dc.contributor.author | da Costa, BM | |
dc.contributor.author | Poon, E | |
dc.contributor.author | Jamin, Y | |
dc.contributor.author | Lise, S | |
dc.contributor.author | Veal, GJ | |
dc.contributor.author | Sebire, N | |
dc.contributor.author | Robinson, SP | |
dc.contributor.author | Anderson, J | |
dc.contributor.author | Chesler, L | |
dc.date.accessioned | 2019-09-20T10:48:14Z | |
dc.date.issued | 2019-10-15 | |
dc.identifier.citation | Cancer research, 2019, 79 (20), pp. 5382 - 5393 | |
dc.identifier.issn | 0008-5472 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3360 | |
dc.identifier.eissn | 1538-7445 | |
dc.identifier.doi | 10.1158/0008-5472.can-18-2759 | |
dc.description.abstract | Neuroblastoma is a pediatric cancer that is frequently metastatic and resistant to conventional treatment. In part, a lack of natively metastatic, chemoresistant in vivo models has limited our insight into the development of aggressive disease. The Th-MYCN genetically engineered mouse model develops rapidly progressive chemosensitive neuroblastoma and lacks clinically relevant metastases. To study tumor progression in a context more reflective of clinical therapy, we delivered multicycle treatment with cyclophosphamide to Th-MYCN mice, individualizing therapy using MRI, to generate the Th-MYCN CPM32 model. These mice developed chemoresistance and spontaneous bone marrow metastases. Tumors exhibited an altered immune microenvironment with increased stroma and tumor-associated fibroblasts. Analysis of copy number aberrations revealed genomic changes characteristic of human MYCN-amplified neuroblastoma, specifically copy number gains at mouse chromosome 11, syntenic with gains on human chromosome 17q. RNA sequencing revealed enriched expression of genes associated with 17q gain and upregulation of genes associated with high-risk neuroblastoma, such as the cell-cycle regulator cyclin B1-interacting protein 1 (Ccnb1ip1) and thymidine kinase (TK1). The antiapoptotic, prometastatic JAK-STAT3 pathway was activated in chemoresistant tumors, and treatment with the JAK1/JAK2 inhibitor CYT387 reduced progression of chemoresistant tumors and increased survival. Our results highlight that under treatment conditions that mimic chemotherapy in human patients, Th-MYCN mice develop genomic, microenvironmental, and clinical features reminiscent of human chemorefractory disease. The Th-MYCN CPM32 model therefore is a useful tool to dissect in detail mechanisms that drive metastasis and chemoresistance, and highlights dysregulation of signaling pathways such as JAK-STAT3 that could be targeted to improve treatment of aggressive disease. SIGNIFICANCE: An in vivo mouse model of high-risk treatment-resistant neuroblastoma exhibits changes in the tumor microenvironment, widespread metastases, and sensitivity to JAK1/2 inhibition. | |
dc.format | Print-Electronic | |
dc.format.extent | 5382 - 5393 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
dc.subject | Animals | |
dc.subject | Mice, Transgenic | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Neuroblastoma | |
dc.subject | Neoplasm Metastasis | |
dc.subject | Disease Models, Animal | |
dc.subject | Disease Progression | |
dc.subject | Benzamides | |
dc.subject | Cyclophosphamide | |
dc.subject | Pyrimidines | |
dc.subject | Neoplasm Proteins | |
dc.subject | Antineoplastic Agents | |
dc.subject | Magnetic Resonance Imaging | |
dc.subject | Tumor Burden | |
dc.subject | Signal Transduction | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | Synteny | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Gene Dosage | |
dc.subject | Genes, myc | |
dc.subject | Child | |
dc.subject | Janus Kinases | |
dc.subject | Tumor Microenvironment | |
dc.subject | N-Myc Proto-Oncogene Protein | |
dc.title | In Vivo Modeling of Chemoresistant Neuroblastoma Provides New Insights into Chemorefractory Disease and Metastasis. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2019-08-06 | |
rioxxterms.versionofrecord | 10.1158/0008-5472.can-18-2759 | |
rioxxterms.licenseref.uri | https://www.rioxx.net/licenses/under-embargo-all-rights-reserved | |
rioxxterms.licenseref.startdate | 2019-10 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Cancer research | |
pubs.issue | 20 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Pre-Clinical MRI | |
pubs.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/16/17 Starting Cohort | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Paediatric Solid Tumour Biology and Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Pre-Clinical MRI | |
pubs.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/16/17 Starting Cohort | |
pubs.publication-status | Published | |
pubs.volume | 79 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Paediatric Solid Tumour Biology and Therapeutics | |
icr.researchteam | Pre-Clinical MRI | |
dc.contributor.icrauthor | George, Sally | |
dc.contributor.icrauthor | Kwok, Colin | |
dc.contributor.icrauthor | Campbell, James | |
dc.contributor.icrauthor | Calton, Elizabeth Anne | |
dc.contributor.icrauthor | Poon, Evon | |
dc.contributor.icrauthor | Jamin, Yann | |
dc.contributor.icrauthor | Lise, Stefano | |
dc.contributor.icrauthor | Robinson, Simon | |
dc.contributor.icrauthor | Chesler, Louis | |