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Cell type-specific chromatin states differentially prime squamous cell carcinoma tumor-initiating cells for epithelial to mesenchymal transition [expression 2]

ABSTRACT: Epithelial to mesenchymal transition (EMT) in cancer cells has been associated with metastasis, stemness and resistance to therapy. The reason why some tumors undergo EMT and other not might reflect intrinsic properties of their cell of origin, although this possibility is largely unexplored. By targeting the same oncogenic mutations to discrete skin compartments, we show cell type-specific chromatin and transcriptional states differentially prime tumors to EMT. Squamous cell carcinomas (SCCs) derived from intrafollicular epidermis (IFE) are generally well-differentiated, while hair follicle (HF) stem cell-derived SCCs frequently exhibit EMT, efficiently form secondary tumors, and possess increased metastatic potential. Transcriptional and epigenomic profiling revealed IFE and HF tumor-initiating cells possess distinct chromatin landscapes and gene regulatory networks associated with tumorigenesis and EMT that correlate with accessibility of key epithelial and EMT transcription factor binding sites. These findings highlight the importance of chromatin states and transcriptional priming in dictating tumor phenotypes and EMT.

ORGANISM(S): Mus musculus

PROVIDER: GSE88762 | GEO | 2016/10/15

SECONDARY ACCESSION(S): PRJNA348520

REPOSITORIES: GEO

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Cell type-specific chromatin states differentially prime squamous cell carcinoma tumor-initiating cells for epithelial to mesenchymal transition [ATAC-seq]

Project description:Epithelial to mesenchymal transition (EMT) in cancer cells has been associated with metastasis, stemness and resistance to therapy. The reason why some tumors undergo EMT and other not might reflect intrinsic properties of their cell of origin, although this possibility is largely unexplored. By targeting the same oncogenic mutations to discrete skin compartments, we show cell type-specific chromatin and transcriptional states differentially prime tumors to EMT. Squamous cell carcinomas (SCCs) derived from intrafollicular epidermis (IFE) are generally well-differentiated, while hair follicle (HF) stem cell-derived SCCs frequently exhibit EMT, efficiently form secondary tumors, and possess increased metastatic potential. Transcriptional and epigenomic profiling revealed IFE and HF tumor-initiating cells possess distinct chromatin landscapes and gene regulatory networks associated with tumorigenesis and EMT that correlate with accessibility of key epithelial and EMT transcription factor binding sites. These findings highlight the importance of chromatin states and transcriptional priming in dictating tumor phenotypes and EMT. Accessible chromatin regions were profiled using ATAC-seq, enriched peak regions were used to infer transcription factor binding sites.

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Pharmacological targeting Netrin-1 inhibits EMT in cancer [BulkRNA-seq]

Project description:Epithelial-to-Mesenchymal transition (EMT) regulates tumour initiation, progression, metastasis and resistance to anti-cancer therapy. Whereas great progress had recently been made in understanding the role and mechanisms that regulate EMT in cancer, no therapeutic strategy to pharmacologically target EMT had been identified so far. Here, we found that Netrin-1 is upregulated in a primary mouse model of skin squamous cell carcinoma (SCCs) presenting spontaneous EMT. Pharmacological inhibition of Netrin-1 by administrating NP137, an anti-Netrin-1 blocking monoclonal antibody currently used in clinical trials in human cancer, decreased the proportion EMT tumour cells in skin SCCs, as well as decreased the number of metastasis and increased the sensitivity of tumour cells to chemotherapy. Single-cell RNA-seq revealed the presence of different EMT states including epithelial, early and late hybrid EMT as well as fully EMT states in control SCCs. In contrast, administration of NP137 prevents the progression of cancer cells towards a late EMT state and sustains tumour epithelial states. ShRNA knockdown (KD) of Netrin-1 and its receptor Unc5b in EPCAM+ tumour cells inhibited EMT in vitro in the absence of stromal cells and regulated a common gene signature promoting tumour epithelial state and restricting EMT. To assess the relevance of these findings to human cancers, we treated mice transplanted with A549 human cancer cell line that undergoes EMT following TGF-b1 administration with NP137. Netrin-1 inhibition decreased EMT in A549 cells in vivo. Altogether, our results identify a new pharmacological strategy to target EMT in cancer opening novel therapeutic interventions for anti-cancer therapy.

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