scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapy.
Nat Commun
; 10(1): 5829, 2019 12 20.
Article
en En
| MEDLINE
| ID: mdl-31863004
ABSTRACT
Targeting oncogenic pathways holds promise for brain tumor treatment, but inhibition of Sonic Hedgehog (SHH) signaling has failed in SHH-driven medulloblastoma. Cellular diversity within tumors and reduced lineage commitment can undermine targeted therapy by increasing the probability of treatment-resistant populations. Using single-cell RNA-seq and lineage tracing, we analyzed cellular diversity in medulloblastomas in transgenic, medulloblastoma-prone mice, and responses to the SHH-pathway inhibitor vismodegib. In untreated tumors, we find expected stromal cells and tumor-derived cells showing either a spectrum of neural progenitor-differentiation states or glial and stem cell markers. Vismodegib reduces the proliferative population and increases differentiation. However, specific cell types in vismodegib-treated tumors remain proliferative, showing either persistent SHH-pathway activation or stem cell characteristics. Our data show that even in tumors with a single pathway-activating mutation, diverse mechanisms drive tumor growth. This diversity confers early resistance to targeted inhibitor therapy, demonstrating the need to target multiple pathways simultaneously.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Transducción de Señal
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Neoplasias Cerebelosas
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Resistencia a Antineoplásicos
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Proteínas Hedgehog
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Meduloblastoma
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Año:
2019
Tipo del documento:
Article