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1.
bioRxiv ; 2024 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-38585889

RESUMEN

The cellular plasticity of neuroblastoma is defined by a mixture of two major cell states, adrenergic (ADRN) and mesenchymal (MES), which may contribute to therapy resistance. However, how neuroblastoma cells switch cellular states during therapy remains largely unknown and how to eradicate neuroblastoma regardless of their cell states is a clinical challenge. To better understand the lineage switch of neuroblastoma in chemoresistance, we comprehensively defined the transcriptomic and epigenetic map of ADRN and MES types of neuroblastomas using human and murine models treated with indisulam, a selective RBM39 degrader. We showed that cancer cells not only undergo a bidirectional switch between ADRN and MES states, but also acquire additional cellular states, reminiscent of the developmental pliancy of neural crest cells. The lineage alterations are coupled with epigenetic reprogramming and dependency switch of lineage-specific transcription factors, epigenetic modifiers and targetable kinases. Through targeting RNA splicing, indisulam induces an inflammatory tumor microenvironment and enhances anticancer activity of natural killer cells. The combination of indisulam with anti-GD2 immunotherapy results in a durable, complete response in high-risk transgenic neuroblastoma models, providing an innovative, rational therapeutic approach to eradicate tumor cells regardless of their potential to switch cell states.

2.
Nat Commun ; 10(1): 5806, 2019 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-31862972

RESUMEN

The lack of model systems has limited the preclinical discovery and testing of therapies for Wilms tumor (WT) patients who have poor outcomes. Herein, we establish 45 heterotopic WT patient-derived xenografts (WTPDX) in CB17 scid-/- mice that capture the biological heterogeneity of Wilms tumor (WT). Among these 45 total WTPDX, 6 from patients with diffuse anaplastic tumors, 9 from patients who experienced disease relapse, and 13 from patients with bilateral disease are included. Early passage WTPDX show evidence of clonal selection, clonal evolution and enrichment of blastemal gene expression. Favorable histology WTPDX are sensitive, whereas unfavorable histology WTPDX are resistant to conventional chemotherapy with vincristine, actinomycin-D, and doxorubicin given singly or in combination. This WTPDX library is a unique scientific resource that retains the spectrum of biological heterogeneity present in WT and provides an essential tool to test targeted therapies for WT patient groups with poor outcomes.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Evolución Clonal , Resistencia a Antineoplásicos/genética , Neoplasias Renales/genética , Tumor de Wilms/genética , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Masculino , Ratones , Ratones SCID , Secuenciación del Exoma , Tumor de Wilms/tratamiento farmacológico , Tumor de Wilms/patología , Ensayos Antitumor por Modelo de Xenoinjerto
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