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Chapple, Richard H.; Liu, Xueying; Natarajan, Sivaraman; Alexander, Margaret I. M.; Kim, Yuna; Patel, Anand G.; LaFlamme, Christy W.; Pan, Min; Wright, William C.; Lee, Hyeong-Min; Zhang, Yinwen; Lu, Meifen; Koo, Selene C.; Long, Courtney; Harper, John; Savage, Chandra; Johnson, Melissa D.; Confer, Thomas; Akers, Walter J.; Dyer, Michael A.; Sheppard, Heather; Easton, John; Geeleher, Paul
Genome Biology, 06/2024, Letnik: 25, Številka: 1Journal Article
Abstract Background Neuroblastoma is a common pediatric cancer, where preclinical studies suggest that a mesenchymal-like gene expression program contributes to chemotherapy resistance. However, clinical outcomes remain poor, implying we need a better understanding of the relationship between patient tumor heterogeneity and preclinical models. Results Here, we generate single-cell RNA-seq maps of neuroblastoma cell lines, patient-derived xenograft models (PDX), and a genetically engineered mouse model (GEMM). We develop an unsupervised machine learning approach (“automatic consensus nonnegative matrix factorization” (acNMF)) to compare the gene expression programs found in preclinical models to a large cohort of patient tumors. We confirm a weakly expressed, mesenchymal-like program in otherwise adrenergic cancer cells in some pre-treated high-risk patient tumors, but this appears distinct from the presumptive drug-resistance mesenchymal programs evident in cell lines. Surprisingly, however, this weak-mesenchymal-like program is maintained in PDX and could be chemotherapy-induced in our GEMM after only 24 h, suggesting an uncharacterized therapy-escape mechanism. Conclusions Collectively, our findings improve the understanding of how neuroblastoma patient tumor heterogeneity is reflected in preclinical models, provides a comprehensive integrated resource, and a generalizable set of computational methodologies for the joint analysis of clinical and pre-clinical single-cell RNA-seq datasets.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Vir: Osebne bibliografije
in: SICRIS
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