Childhood Cerebellar Tumors Mirror Conserved Fetal Transcriptional Programs

Vladoiu, Maria C.; El-Hamamy, Ibrahim; Donovan, Laura; Farooq, Hamza; Holgado, Borja L.; Ramaswamy, Vijay; Mack, Stephen C.; Lee, John Jy; Kumar, Sachin; Przelicki, David; Michaelraj, Antony; Juraschka, Kyle; Skowron, Patryk; Luu, Betty; Suzuki, Hiromichi; Morrissy, Sorana; Cavalli, Florence M.G.; Garzia, Livia; Daniels, Craig; Wu, Xiaochong; Qazi, Maleeha; Singh, Sheila K.; Chan, Jennifer A.; Marra, Marco A.; Malkin, David; Dirks, Peter B.; Pugh, Trevor J.; Notta, Faiyaz; Kleinman, Claudia L.; Joyner, Alexandra L.; Jabado, Nada; Stein, Lincoln; Taylor, Michael D.

doi:10.1101/350280

Cited by 9 publications

(9 citation statements)

References 54 publications

(62 reference statements)

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“…Of note, our findings also recapitulate the historical understanding of the distinct COOs for gliomas and CNS-Medullo wherein gliomas were thought to derive from glia cells, while CNS-Medullo was believed to derive from neuronal-type cells 41,42 . Further support for our findings comes from single-cell transcriptomics of the developing mouse brain showing that CNS-Medullo tumors mirror primitive cells in the neuronal lineage that are found in the germinal matrix but are allbut-gone at birth 43 .…”

Section: Chromatin Differences Between Cell Differentiation States Insupporting

confidence: 63%

Tumor mutational landscape is a record of the pre-malignant state

Kübler

Haradhvala

et al. 2019

Preprint

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Chromatin structure has a major influence on the cell-specific density of somatic mutations along the cancer genome. Here, we present a pan-cancer study in which we searched for the putative cancer cell-of-origin of 2,550 whole genomes, representing 32 cancer types by matching their mutational landscape to the regional patterns of chromatin modifications ascertained in 104 normal tissue types. We found that, in almost all cancer types, the cell-of-origin can be predicted solely from their DNA sequences. Our analysis validated the hypothesis that high-grade serous ovarian cancer originates in the fallopian tube and identified distinct origins of breast cancer subtypes. We also demonstrated that the technique is equally capable of identifying the cell-of-origin for a series of 2,044 metastatic samples from 22 of the tumor types available as primaries. Moreover, cancer drivers, whether inherited or acquired, reside in active chromatin regions in the respective cell-of-origin. Taken together, our findings highlight that many somatic mutations accumulate while the chromatin structure of the cell-of-origin is maintained and that this historical record, captured in the DNA, can be used to identify the often elusive cancer cell-of-origin.

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Section: Chromatin Differences Between Cell Differentiation States Insupporting

confidence: 63%

Tumor mutational landscape is a record of the pre-malignant state

Kübler

Haradhvala

et al. 2019

Preprint

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“…We then prepared and sequenced amplified libraries from the pooled cDNA and used cell-specific bar codes to identify the transcriptomes of individual cells in the resulting sequence data. We filtered cells identified by bead-specific bar codes to address unintentional cell-cell multiplexing and premature cell lysis ( 24 , 25 ). 1530 out of 4959 cells from POx-Palbo treated tumors, and 8699 out of 16489 cells from control tumors met criteria and were included in the analysis.…”

Section: Resultsmentioning

confidence: 99%

Enhancing CDK4/6 inhibitor therapy for medulloblastoma using nanoparticle delivery and scRNA-seq-guided combination with sapanisertib

Lim

Dismuke

Malawsky

et al. 2021

Preprint

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While targeting CDK4/6 is highly effective in breast cancer and is a promising approach for brain tumor treatment, palbociclib, FDA-approved CDK4/6 inhibitor, failed to induce durable benefits in preclinical models of brain cancers (intrinsic pontine glioma and medulloblastoma) and in clinical trial against glioblastoma. In our study in transgenic, medulloblastoma-prone mice, orally dosed palbociclib induces no benefits. However, nanoparticle formulation of palbociclib, POx-Palbo enables systemic administration of the drug, improves CNS pharmacokinetics and induces survival benefit. In addition, we analyzed the response to the POx-Palbo treatment using scRNA-seq to identify treatment targets in palbociclib resistant cells. In parallel, we tested the potential of agents targeting SHH signaling or DNA replication to limit resistance, identifying combination regiment of palbociclib and etoposide which slightly improved efficacy. The brains of mice repeatedly treated with POx-Palbo showed a distinct population of proliferating cells cluster with a transcriptomic profile that was different from proliferating cells in control tumors. With Gene Ontology (GO) enrichment analysis of the genes in each cluster, we found that POx-Palbo treatment increased the expression of the glutamate transporter Slc1a2 and decreased diverse ribosomal genes, which both are indicating the inhibition of mTORC1 signaling pathway. Treatment with small molecule mTORC1 inhibitor, sapanisertib, induced survival benefits and the combination of palbociclib and sapanisertib markedly increased anti-tumor efficacy and survival with dramatic suppression of phosphorylation in RB and 4EBP1, indicating a potentially effective new therapy for pediatric medulloblastoma.One Sentence SummaryNanoparticle-delivered palbociclib enable CDK4/6 inhibitor therapy while combination with mTORC1 inhibitor sapanisertib induces long term benefits in SHH medulloblastoma.

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“…Analysis on the normalised data has been restricted to cells with more than 500 detected genes. Furthermore, outlier cells with more than 4 standard deviations above the median number of genes were excluded from the analysis, along with UMIs and mitochondrial content per cell in order to address the common problems of gene drop out, unintentional cell-cell multiplexing and premature cell lysis (Vladoiu et al, 2018). The resulting pre-processed expression matrix X consists of p " 16680 genes measured over n " 17746 different cells;…”

Section: Sil Kbet Lisi Pcregmentioning

confidence: 99%

Projected t-SNE for batch correction

et al. 2020

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Motivation: Low-dimensional representations of high-dimensional data are routinely employed in biomedical research to visualize, interpret and communicate results from different pipelines. In this article, we propose a novel procedure to directly estimate t-SNE embeddings that are not driven by batch effects. Without correction, interesting structure in the data can be obscured by batch effects.The proposed algorithm can therefore significantly aid visualization of high-dimensional data.Results: The proposed methods are based on linear algebra and constrained optimization, leading to efficient algorithms and fast computation in many high-dimensional settings. Results on artificial single-cell transcription profiling data show that the proposed procedure successfully removes multiple batch effects from t-SNE embeddings, while retaining fundamental information on cell types. When applied to single-cell gene expression data to investigate mouse medulloblastoma, the proposed method successfully removes batches related with mice identifiers and the date of the experiment, while preserving clusters of oligodendrocytes, astrocytes, and endothelial cells and microglia, which are expected to lie in the stroma within or adjacent to the tumors.Availability: Source code implementing the proposed approach in R and Julia is available at the link https://github.com/emanuelealiverti/BC tSNE, including a tutorial to reproduce the simulation studies.

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Childhood Cerebellar Tumors Mirror Conserved Fetal Transcriptional Programs

Cited by 9 publications

References 54 publications

Tumor mutational landscape is a record of the pre-malignant state

Tumor mutational landscape is a record of the pre-malignant state

Enhancing CDK4/6 inhibitor therapy for medulloblastoma using nanoparticle delivery and scRNA-seq-guided combination with sapanisertib

Projected t-SNE for batch correction

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