A handful of hybrid EMT cells are characterized as the origin from lung adenocarcinoma
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ABSTRACT:
PROVIDER: PRJNA987618 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25030500_1.fastq.gz | Fastqsanger.gz | |||
| SRR25030500_2.fastq.gz | Fastqsanger.gz | |||
| SRR25030497_1.fastq.gz | Fastqsanger.gz | |||
| SRR25030497_2.fastq.gz | Fastqsanger.gz | |||
| SRR25030498_1.fastq.gz | Fastqsanger.gz |
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Project description: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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