Clinically relevant treatment of PDX models reveals patterns of neuroblastoma chemoresistance

Abstract

Chemotherapy resistance and relapses are common in high-risk neuroblastoma (NB). Here, we developed a clinically relevant in vivo treatment protocol mimicking the first-line five-chemotherapy treatment regimen of high-risk NB and applied this protocol to mice with MYCN -amplified NB patient-derived xenografts (PDXs). Genomic and transcriptomic analyses were used to reveal NB chemoresistance mechanisms. Intrinsic resistance was associated with high genetic diversity and an embryonic phenotype. Relapsed NB with acquired resistance showed a decreased adrenergic phenotype and an enhanced immature mesenchymal–like phenotype, resembling multipotent Schwann cell precursors. NBs with a favorable treatment response presented a lineage-committed adrenergic phenotype similar to normal neuroblasts. Novel integrated phenotypic gene signatures reflected treatment response and patient prognosis. NB organoids established from relapsed PDX tumors retained drug resistance, tumorigenicity, and transcriptional cell states. This work sheds light on the mechanisms of NB chemotherapy response and emphasizes the importance of transcriptional cell states in chemoresistance.

Patient-derived models: Advanced tools for precision medicine in neuroblastoma

“…However, serial in vivo passaging of orthotopic NB PDXs for up to two years has shown that PDXs retain key genetic aberrations (e.g., 1p loss, MYCN amplification, and 17q gain) and acquire only minor genetic changes over time, as would be expected from their natural evolution ( 39 ). Clonal dynamics studies during tumor progression in PDXs have shown the presence of branched evolution, clonal sweeps, and convergent evolution of specific small deletions in potentially tumor-associated genes ( 46 ), a pattern similar to tumor evolution in NB patients ( 47 ).…”

“…A few studies have used PD models to identify diverse mechanisms implicated in NB invasion, migration, metastasis ( 64 , 65 ), and resistance to specific chemotherapies ( 66 ). Using a clinically relevant treatment protocol (COJEC-induction therapy), NB PDXs show similar chemotherapy responses to their corresponding patients, suggesting that NB PDXs are useful for modelling chemoresistance and relapse ( 46 ). The models showed that chemoresistant NBs have a lower ADR signature and enrichment for an immature MES-like phenotype, suggesting an association between the MES cell state and relapse ( 46 ).…”

“…Using a clinically relevant treatment protocol (COJEC-induction therapy), NB PDXs show similar chemotherapy responses to their corresponding patients, suggesting that NB PDXs are useful for modelling chemoresistance and relapse ( 46 ). The models showed that chemoresistant NBs have a lower ADR signature and enrichment for an immature MES-like phenotype, suggesting an association between the MES cell state and relapse ( 46 ). These results are consistent with recent findings in the clinical setting ( 24 , 67 ).…”

“…In our experience, PD models show high intra-model variability in drug response ( 46 , 75 , 77 ) and are often less responsive to different treatments than conventional cell lines and xenografts [discussed also in ( 29 )]. The lower sensitivity of PD models could indicate an even smaller effect in patients, thus providing important information with respect to optimal clinical implementation.…”

Analysis of Serial Neuroblastoma PDX Passages in Mice Allows the Identification of New Mediators of Neuroblastoma Aggressiveness

“…PDXs avoid cell selection and adaptation typical of in vitro conditions, hence allowing a more comprehensive representation of the diversity of high-risk neuroblastomas. Moreover, this model provides opportunities to refine personalized therapy recommendations for neuroblastoma patients [ 12 , 13 ].…”