scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapy

Autores: Ocasio, Jennifer Karin; Babcock, Benjamin; Malawsky, Daniel; Weir, Seth J.; Loo, Lipin; Simon, Jeremy M.; Zylka, Mark J.; Hwang, Duhyeong; Dismuke, Taylor; Sokolsky, Marina; Rosen, Elias P.; Vibhakar, Rajeev; Zhang, Jiao; Saulnier, Olivier; Vladoiu, Maria; El-Hamamy, Ibrahim; Stein, Lincoln D.; Taylor, Michael; Smith, Kyle S.; Northcott, Paul A.; Colaneri, Alejandro Cesar; Wilhelmsen, Kirk; Gershon, Timothy R.
Año de publicación: 2019
Idioma: inglés
Tipo de recurso: artículo
Estado: versión publicada
Descripción: 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.
Fil: Ocasio, Jennifer Karin. University of North Carolina; Estados Unidos
Fil: Babcock, Benjamin. University of North Carolina; Estados Unidos
Fil: Malawsky, Daniel. University of North Carolina; Estados Unidos
Fil: Weir, Seth J.. University of North Carolina; Estados Unidos
Fil: Loo, Lipin. University of North Carolina; Estados Unidos
Fil: Simon, Jeremy M.. University of North Carolina; Estados Unidos
Fil: Zylka, Mark J.. University of North Carolina; Estados Unidos
Fil: Hwang, Duhyeong. University of North Carolina; Estados Unidos
Fil: Dismuke, Taylor. University of North Carolina; Estados Unidos
Fil: Sokolsky, Marina. University of North Carolina; Estados Unidos
Fil: Rosen, Elias P.. University of North Carolina; Estados Unidos
Fil: Vibhakar, Rajeev. University of Colorado; Estados Unidos
Fil: Zhang, Jiao. University Of Toronto. Hospital For Sick Children; Canadá
Fil: Saulnier, Olivier. University Of Toronto. Hospital For Sick Children; Canadá
Fil: Vladoiu, Maria. University Of Toronto. Hospital For Sick Children; Canadá
Fil: El-Hamamy, Ibrahim. University of Toronto; Canadá
Fil: Stein, Lincoln D.. University of Toronto; Canadá
Fil: Taylor, Michael. University Of Toronto. Hospital For Sick Children; Canadá
Fil: Smith, Kyle S.. St. Jude Children’s Research Hospital; Estados Unidos
Fil: Northcott, Paul A.. St. Jude Children’s Research Hospital; Estados Unidos
Fil: Colaneri, Alejandro Cesar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. University of North Carolina; Estados Unidos
Fil: Wilhelmsen, Kirk. University of North Carolina; Estados Unidos
Fil: Gershon, Timothy R.. University of North Carolina; Estados Unidos
Materia: scRNA-seq
MEDULLOBLASTOMA
BRAIN TUMOR
TARGETED THERAPY
Nivel de accesibilidad: acceso abierto
Condiciones de uso: https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
Institución: Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador: oai:ri.conicet.gov.ar:11336/271405

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repository_id_str	3498
network_name_str	CONICET Digital (CONICET)
spelling	scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapyOcasio, Jennifer KarinBabcock, BenjaminMalawsky, DanielWeir, Seth J.Loo, LipinSimon, Jeremy M.Zylka, Mark J.Hwang, DuhyeongDismuke, TaylorSokolsky, MarinaRosen, Elias P.Vibhakar, RajeevZhang, JiaoSaulnier, OlivierVladoiu, MariaEl-Hamamy, IbrahimStein, Lincoln D.Taylor, MichaelSmith, Kyle S.Northcott, Paul A.Colaneri, Alejandro CesarWilhelmsen, KirkGershon, Timothy R.scRNA-seqMEDULLOBLASTOMABRAIN TUMORTARGETED THERAPYhttps://purl.org/becyt/ford/3.4https://purl.org/becyt/ford/3Targeting 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.Fil: Ocasio, Jennifer Karin. University of North Carolina; Estados UnidosFil: Babcock, Benjamin. University of North Carolina; Estados UnidosFil: Malawsky, Daniel. University of North Carolina; Estados UnidosFil: Weir, Seth J.. University of North Carolina; Estados UnidosFil: Loo, Lipin. University of North Carolina; Estados UnidosFil: Simon, Jeremy M.. University of North Carolina; Estados UnidosFil: Zylka, Mark J.. University of North Carolina; Estados UnidosFil: Hwang, Duhyeong. University of North Carolina; Estados UnidosFil: Dismuke, Taylor. University of North Carolina; Estados UnidosFil: Sokolsky, Marina. University of North Carolina; Estados UnidosFil: Rosen, Elias P.. University of North Carolina; Estados UnidosFil: Vibhakar, Rajeev. University of Colorado; Estados UnidosFil: Zhang, Jiao. University Of Toronto. Hospital For Sick Children; CanadáFil: Saulnier, Olivier. University Of Toronto. Hospital For Sick Children; CanadáFil: Vladoiu, Maria. University Of Toronto. Hospital For Sick Children; CanadáFil: El-Hamamy, Ibrahim. University of Toronto; CanadáFil: Stein, Lincoln D.. University of Toronto; CanadáFil: Taylor, Michael. University Of Toronto. Hospital For Sick Children; CanadáFil: Smith, Kyle S.. St. Jude Children’s Research Hospital; Estados UnidosFil: Northcott, Paul A.. St. Jude Children’s Research Hospital; Estados UnidosFil: Colaneri, Alejandro Cesar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. University of North Carolina; Estados UnidosFil: Wilhelmsen, Kirk. University of North Carolina; Estados UnidosFil: Gershon, Timothy R.. University of North Carolina; Estados UnidosNature2019-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/271405Ocasio, Jennifer Karin; Babcock, Benjamin; Malawsky, Daniel; Weir, Seth J.; Loo, Lipin; et al.; scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapy; Nature; Nature Communications; 10; 1; 12-2019; 1-172041-1723CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41467-019-13657-6info:eu-repo/semantics/altIdentifier/doi/10.1038/s41467-019-13657-6info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:43:05Zoai:ri.conicet.gov.ar:11336/271405instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:43:05.917CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv	scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapy
title	scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapy
spellingShingle	scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapy Ocasio, Jennifer Karin scRNA-seq MEDULLOBLASTOMA BRAIN TUMOR TARGETED THERAPY
title_short	scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapy
title_full	scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapy
title_fullStr	scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapy
title_full_unstemmed	scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapy
title_sort	scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapy
dc.creator.none.fl_str_mv	Ocasio, Jennifer Karin Babcock, Benjamin Malawsky, Daniel Weir, Seth J. Loo, Lipin Simon, Jeremy M. Zylka, Mark J. Hwang, Duhyeong Dismuke, Taylor Sokolsky, Marina Rosen, Elias P. Vibhakar, Rajeev Zhang, Jiao Saulnier, Olivier Vladoiu, Maria El-Hamamy, Ibrahim Stein, Lincoln D. Taylor, Michael Smith, Kyle S. Northcott, Paul A. Colaneri, Alejandro Cesar Wilhelmsen, Kirk Gershon, Timothy R.
author	Ocasio, Jennifer Karin
author_facet	Ocasio, Jennifer Karin Babcock, Benjamin Malawsky, Daniel Weir, Seth J. Loo, Lipin Simon, Jeremy M. Zylka, Mark J. Hwang, Duhyeong Dismuke, Taylor Sokolsky, Marina Rosen, Elias P. Vibhakar, Rajeev Zhang, Jiao Saulnier, Olivier Vladoiu, Maria El-Hamamy, Ibrahim Stein, Lincoln D. Taylor, Michael Smith, Kyle S. Northcott, Paul A. Colaneri, Alejandro Cesar Wilhelmsen, Kirk Gershon, Timothy R.
author_role	author
author2	Babcock, Benjamin Malawsky, Daniel Weir, Seth J. Loo, Lipin Simon, Jeremy M. Zylka, Mark J. Hwang, Duhyeong Dismuke, Taylor Sokolsky, Marina Rosen, Elias P. Vibhakar, Rajeev Zhang, Jiao Saulnier, Olivier Vladoiu, Maria El-Hamamy, Ibrahim Stein, Lincoln D. Taylor, Michael Smith, Kyle S. Northcott, Paul A. Colaneri, Alejandro Cesar Wilhelmsen, Kirk Gershon, Timothy R.
author2_role	author author author author author author author author author author author author author author author author author author author author author author
dc.subject.none.fl_str_mv	scRNA-seq MEDULLOBLASTOMA BRAIN TUMOR TARGETED THERAPY
topic	scRNA-seq MEDULLOBLASTOMA BRAIN TUMOR TARGETED THERAPY
purl_subject.fl_str_mv	https://purl.org/becyt/ford/3.4 https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv	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. Fil: Ocasio, Jennifer Karin. University of North Carolina; Estados Unidos Fil: Babcock, Benjamin. University of North Carolina; Estados Unidos Fil: Malawsky, Daniel. University of North Carolina; Estados Unidos Fil: Weir, Seth J.. University of North Carolina; Estados Unidos Fil: Loo, Lipin. University of North Carolina; Estados Unidos Fil: Simon, Jeremy M.. University of North Carolina; Estados Unidos Fil: Zylka, Mark J.. University of North Carolina; Estados Unidos Fil: Hwang, Duhyeong. University of North Carolina; Estados Unidos Fil: Dismuke, Taylor. University of North Carolina; Estados Unidos Fil: Sokolsky, Marina. University of North Carolina; Estados Unidos Fil: Rosen, Elias P.. University of North Carolina; Estados Unidos Fil: Vibhakar, Rajeev. University of Colorado; Estados Unidos Fil: Zhang, Jiao. University Of Toronto. Hospital For Sick Children; Canadá Fil: Saulnier, Olivier. University Of Toronto. Hospital For Sick Children; Canadá Fil: Vladoiu, Maria. University Of Toronto. Hospital For Sick Children; Canadá Fil: El-Hamamy, Ibrahim. University of Toronto; Canadá Fil: Stein, Lincoln D.. University of Toronto; Canadá Fil: Taylor, Michael. University Of Toronto. Hospital For Sick Children; Canadá Fil: Smith, Kyle S.. St. Jude Children’s Research Hospital; Estados Unidos Fil: Northcott, Paul A.. St. Jude Children’s Research Hospital; Estados Unidos Fil: Colaneri, Alejandro Cesar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina. University of North Carolina; Estados Unidos Fil: Wilhelmsen, Kirk. University of North Carolina; Estados Unidos Fil: Gershon, Timothy R.. University of North Carolina; Estados Unidos
description	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.
publishDate	2019
dc.date.none.fl_str_mv	2019-12
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	http://hdl.handle.net/11336/271405 Ocasio, Jennifer Karin; Babcock, Benjamin; Malawsky, Daniel; Weir, Seth J.; Loo, Lipin; et al.; scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapy; Nature; Nature Communications; 10; 1; 12-2019; 1-17 2041-1723 CONICET Digital CONICET
url	http://hdl.handle.net/11336/271405
identifier_str_mv	Ocasio, Jennifer Karin; Babcock, Benjamin; Malawsky, Daniel; Weir, Seth J.; Loo, Lipin; et al.; scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapy; Nature; Nature Communications; 10; 1; 12-2019; 1-17 2041-1723 CONICET Digital CONICET
dc.language.none.fl_str_mv	eng
language	eng
dc.relation.none.fl_str_mv	info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/s41467-019-13657-6 info:eu-repo/semantics/altIdentifier/doi/10.1038/s41467-019-13657-6
dc.rights.none.fl_str_mv	info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv	openAccess
rights_invalid_str_mv	https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv	application/pdf application/pdf
dc.publisher.none.fl_str_mv	Nature
publisher.none.fl_str_mv	Nature
dc.source.none.fl_str_mv	reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str	CONICET Digital (CONICET)
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instname_str	Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv	CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv	dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapy

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