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Status |
Public on Sep 30, 2021 |
Title |
RNA-sequencing of mouse mammary tumor organoids that were modified to generate knockout lines for SOX4 |
Organism |
Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
The transcription factor SOX4 is widely expressed during development and is essential to maintain progenitor pools in a variety of organs. In breast cancer SOX4 has been shown to be associated with poor survival and increased tumor size and metastasis formation. This has mostly been attributed to the ability of SOX4 to regulate Epithelial-to-Mesenchymal-Transition (EMT). However, SOX4 regulates target gene transcription in a plastic manner that is dependent on the cellular and epigenetic context. In this study we have investigated the loss of SOX4 in mammary tumor development utilizing organoids derived from a PyMT genetic mouse model. CRISPR-mediated loss of SOX4 led to a strong impairment in growth of primary mammary tumors and subsequent metastases through an EMT-independent mechanism. Instead, SOX4 is required for inhibiting differentiation by controlling genes that are highly activated in foetal mammary stem cells (fMaSC). These SOX4-dependent genes are associated with cell cycle progression, DNA biosynthesis, RNA processing and ribosome biogenesis suggesting that SOX4 controls active cycling of tumor cells. Analysis of genes co-expressed with SOX4 in the TCGA and METABRIC studies revealed that these cell cycle-related genes correlate with SOX4 expression in human tumors. Our study identifies a novel role for SOX4 in maintaining mammary tumors in an undifferentiated proliferative state.
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Overall design |
Organoids were derived from tumors from a MMTV-PyMT; MMTV-Cre; Ecadherin-mCFP genetically engineered mouse model. Control and SOX4KO organoids were generated using CRISPR/Cas9. We performed both bulk RNA-seq and single-cell RNA-seq to understand the consequences of loss of SOX4 in this breast cancer model.
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Contributor(s) |
Roukens G, Coffer P |
Citation(s) |
- Roukens MG, Frederiks CL, Seinstra D, Braccioli L et al. Regulation of a progenitor gene program by SOX4 is essential for mammary tumor proliferation. Oncogene 2021 Nov;40(45):6343-6353. PMID: 34584219
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Submission date |
Jun 24, 2020 |
Last update date |
Jan 03, 2022 |
Contact name |
Guy Roukens |
E-mail(s) |
m.g.roukens-2@umcutrecht.nl
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Organization name |
UMCU
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Lab |
Coffer
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Street address |
Uppsalalaan 8
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City |
Utrecht |
ZIP/Postal code |
3584 CT |
Country |
Netherlands |
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Platforms (1) |
GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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Samples (8)
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Relations |
BioProject |
PRJNA641700 |
SRA |
SRP268706 |