Yogev, O;
Almeida, GS;
Barker, KT;
George, SL;
Kwok, C;
Campbell, J;
Zarowiecki, M;
... Chesler, L; + view all
(2019)
In vivo modelling of chemo-resistant neuroblastoma provides new insights into chemo-refractory disease and metastasis.
Cancer Research
, 79
(20)
pp. 5382-5393.
10.1158/0008-5472.CAN-18-2759.
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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 multi-cycle treatment with cyclophosphamide to Th-MYCN mice, individualizing therapy using MRI, to generate the Th-MYCNCPM32 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 (CNAs) 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 anti-apoptotic, pro-metastatic 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 which mimic chemotherapy in human patients, Th-MYCN mice develop genomic, microenvironmental and clinical features reminiscent of human chemorefractory disease. The Th-MYCNCPM32 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.
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