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Lack of evidence for the transitional cerebellar progenitor

Nature volume 643, pages E1–E8 (2025)Cite this article

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The Original Article was published on 30 November 2022

arising from: Z. Luo et al. Nature https://doi.org/10.1038/s41586-022-05487-2 (2022).

Single-cell ‘atlasing’ of developing and mature human tissues has profoundly advanced knowledge of cancer origins1. In their recent article2, Luo et al.2 generated a single-cell RNA-sequencing atlas of fetal human cerebellum and reported the identification of a previously uncharacterized cell type, designated transitional cerebellar progenitor (TCPs)2. By mapping transcriptional similarity between identified cell types and medulloblastoma, a malignant childhood cerebellar tumour3, TCP-like populations were implicated in developmental origin. Here we present extensive computational and experimental evidence that refutes the existence of the TCP, and challenge the proposed biological, mechanistic and therapeutic relevance associated with this population and its marker genes in the context of both cerebellar development and medulloblastoma.

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Fig. 1: TCP cells are consistent with low-quality cells.
Fig. 2: Invariant expression of proposed TCP marker genes.

Data availability

All datasets used were previously published and are publicly available. The re-analysed human fetal cerebellum dataset (Gene Expression Omnibus (GEO) accession GSM5952337) is available under GEO accession GSE295804.

Code availability

All analyses were conducted using standard R and Python packages to write and visualize the data.

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Acknowledgements

This work was principally supported by the American Lebanese Syrian Associated Charities and St. Jude (P.A.N.), St. Baldrick’s Foundation (Robert J. Arceci Innovation Award; P.A.N.), the Mark Foundation for Cancer Research (Emerging Leader Award, P.A.N.), and the National Cancer Institute (P.A.N.: P01CA096832-16A1 and 1R01CA270785-01A1; and K.J.M.: R37NS095733). P.A.N. is a Pew-Stewart Scholar for Cancer Research (Margaret and Alexander Stewart Trust) and Sontag Foundation Distinguished Scientist Awardee. Normal human material was provided by the Birth Defects Research Laboratory at the University of Washington (supported by NICHD R24 HD000836 to I. A. Glass) and the Joint Medical Research Council/Wellcome (MR/R006237/1) Human Developmental Biology Resource, UK. Human tissue used in this study was covered by a material transfer agreement between SCRI and HDBR.

Author information

Author notes

  1. These authors contributed equally: Kyle S. Smith, Yiran Li

Authors and Affiliations

  1. Center of Excellence in Neuro-Oncology Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Kyle S. Smith, Yiran Li, Brian L. Gudenas & Paul A. Northcott

  2. Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Kyle S. Smith, Yiran Li, Brian L. Gudenas & Paul A. Northcott

  3. Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA, USA

    Parthiv Haldipur & Kathleen J. Millen

  4. Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA, USA

    Volker Hovestadt

Authors
  1. Kyle S. Smith
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  2. Yiran Li
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  7. Paul A. Northcott
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Contributions

K.S.S., Y.L., B.L.G. and P.A.N. designed the study. K.S.S., Y.L. and B.L.G. performed computational analyses. P.H. performed in situ hybridizations of human fetal cerebellum. K.J.M. and V.H. supported the project. K.S.S., Y.L., B.L.G., V.H. and P.A.N. wrote the paper with contributions from all authors. P.A.N. supervised and funded the study.

Corresponding author

Correspondence to Paul A. Northcott.

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The authors declare no competing interests.

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Extended data figures and tables

Extended Data Fig. 1 Transcriptomic quality control of TCP cells.

(a,b) UMAP plots of the reanalyzed Luo study2 human cerebellar dataset, including all cells (a) and isolated neuronal cell types (b). (c,d) UMAP plots of PCW13 and PCW14 samples indicating cell type composition, predicted background fraction, and droplet efficiency with TCP cells outlined in red. (e) Predicted nuclear fraction and log10 UMI counts per sample (PCW8-17) with TCP cells indicated in black. Empty droplets are highlighted in orange and the damaged cell prediction threshold is shown as determined by DropletQC. (f,g) UMAP plots of the reanalyzed cerebellar dataset after removing TCP cells from the PCW12 sample with remaining TCP cells outlined in red (f) and colored by unsupervised clustering analysis (g).

Extended Data Fig. 2 Biases associated with differential expression of proposed TCP marker genes.

(a) Scatter plot showing the proportion of NSC cells expressing individual genes compared to non-NSC cells with exemplary marker genes highlighted in red. (b) Volcano plot of differentially expressed genes in NSC versus non-NSC cells from the complete Luo study2 cerebellar atlas (two-sided Wilcoxon rank sum test). (c) Volcano plot of differentially expressed genes in TCP versus non-TCP cells (two-sided Wilcoxon rank sum test). (d) UMAP plots of all annotated TCP cells colored by sample and showing normalized gene expression of proposed TCP marker genes. (e) Volcano plots of differentially expressed genes in TCP versus non-TCP cells using (two-sided Wilcoxon rank sum test) for PCW12, PCW13, and PCW14 samples.

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Smith, K.S., Li, Y., Haldipur, P. et al. Lack of evidence for the transitional cerebellar progenitor. Nature 643, E1–E8 (2025). https://doi.org/10.1038/s41586-025-09247-w

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