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Status |
Public on Dec 04, 2020 |
Title |
Fat1 deletion promotes hybrid EMT state with enhanced tumor progression, stemness, and metastasis (ATAC-Seq) |
Organism |
Mus musculus |
Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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Summary |
FAT1, a protocadherin, is among the most frequently mutated genes in human cancers. However, the role and the molecular mechanisms by which FAT1 mutations control tumor initiation and progression are poorly understood. Here, using different mouse cancer models including skin squamous cell carcinoma (SCC) and lung tumors we found that Fat1 deletion accelerated tumor initiation and malignant progression and promoted hybrid epithelial to mesenchymal transition (EMT) phenotype. This hybrid EMT state was also found in FAT1 mutated human SCCs. Fat1 deleted skin SCCs presented increased tumor stemness and spontaneous metastasis. Transcriptional and chromatin profiling combined with proteomic analyses and mechanistic studies revealed that FAT1 loss of function activates a CAMK2/CD44/SRC axis that promotes YAP/ZEB1 nuclear translocation and stimulates the mesenchymal state, as well as a CAMK2-EZH2 axis that promotes activation of SOX2, which sustains the epithelial state. This comprehensive analysis also identified drug resistance and vulnerabilities in FAT1 deficient tumors with important implications for cancer therapy. Altogether, our studies revealed that Fat1 loss of function promotes tumor initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state.
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Overall design |
FACS isolated Epcam+ and Epcam- tumor cells from DMBA/TPA K14Cre;RYFP and K14Cre;Fat1fl/fl;RYFP skin SCCs.
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Contributor(s) |
Pastushenko I, Mauri F, Song Y, Blanpain C |
Citation(s) |
33328637 |
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Submission date |
Sep 24, 2020 |
Last update date |
Mar 05, 2021 |
Contact name |
Yura Song |
E-mail(s) |
yura.song@ulb.be
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Organization name |
Université Libre de Bruxelles
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Lab |
Laboratory of Stem Cells and Cancer
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Street address |
808, route de Lennik
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City |
Bruxelles |
ZIP/Postal code |
1070 |
Country |
Belgium |
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Platforms (1) |
GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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Samples (3) |
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This SubSeries is part of SuperSeries: |
GSE158506 |
Fat1 deletion promotes hybrid EMT state with enhanced tumor progression, stemness, and metastasis |
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Relations |
BioProject |
PRJNA665480 |
SRA |
SRP285247 |