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

Jennifer Karin Ocasio, Benjamin Babcock, Daniel Malawsky, Seth J. Weir, Lipin Loo, Jeremy M. Simon, Mark J. Zylka, Duhyeong Hwang, Taylor Dismuke, Marina Sokolsky, Elias P. Rosen, Rajeev Vibhakar, Jiao Zhang, Olivier Saulnier, Maria Vladoiu, Ibrahim El-Hamamy, Lincoln D. Stein, Michael D. Taylor, Kyle S. Smith, Paul A. Northcott, Alejandro Colaneri, Kirk Wilhelmsen () and Timothy R. Gershon ()
Additional contact information
Jennifer Karin Ocasio: University of North Carolina School of Medicine
Benjamin Babcock: University of North Carolina School of Medicine
Daniel Malawsky: University of North Carolina School of Medicine
Seth J. Weir: University of North Carolina School of Medicine
Lipin Loo: University of North Carolina School of Medicine
Jeremy M. Simon: University of North Carolina School of Medicine
Mark J. Zylka: University of North Carolina School of Medicine
Duhyeong Hwang: University of North Carolina School of Medicine
Taylor Dismuke: University of North Carolina School of Medicine
Marina Sokolsky: University of North Carolina School of Medicine
Elias P. Rosen: University of North Carolina School of Medicine
Rajeev Vibhakar: University of Colorado Anschutz Medical Campus
Jiao Zhang: The Hospital for Sick Children
Olivier Saulnier: The Hospital for Sick Children
Maria Vladoiu: The Hospital for Sick Children
Ibrahim El-Hamamy: University of Toronto
Lincoln D. Stein: University of Toronto
Michael D. Taylor: The Hospital for Sick Children
Kyle S. Smith: St. Jude Children’s Research Hospital
Paul A. Northcott: St. Jude Children’s Research Hospital
Alejandro Colaneri: University of North Carolina School of Medicine
Kirk Wilhelmsen: University of North Carolina School of Medicine
Timothy R. Gershon: University of North Carolina School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13657-6

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