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P63 regulated epithelial-to-mesenchymal transition state heterogeneity drives collective invasion.

ABSTRACT: Analysis of P63-regulated genes at gene expression level. The hypothesis tested in the present study was that P63 regulates specific epithelial-to-mesenchymal transition states in breast cancer cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE128190 | GEO | 2019/03/13

REPOSITORIES: GEO

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p63 regulated epithelial-to-mesenchymal transition state heterogeneity drives collective invasion.

Project description:p63 regulated epithelial-to-mesenchymal transition state heterogeneity drives collective invasion.

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ΔNp63-Regulated Epithelial-to-Mesenchymal Transition State Heterogeneity Confers a Leader-Follower Relationship That Drives Collective Invasion.

Project description:Defining how interactions between tumor subpopulations contribute to invasion is essential for understanding how tumors metastasize. Here, we find that the heterogeneous expression of the transcription factor ΔNp63 confers distinct proliferative and invasive epithelial-to-mesenchymal transition (EMT) states in subpopulations that establish a leader-follower relationship to collectively invade. A ΔNp63-high EMT program coupled the ability to proliferate with an IL1α- and miR-205-dependent suppression of cellular protrusions that are required to initiate collective invasion. An alternative ΔNp63-low EMT program conferred cells with the ability to initiate and lead collective invasion. However, this ΔNp63-low EMT state triggered a collateral loss of fitness. Importantly, rare growth-suppressed ΔNp63-low EMT cells influenced tumor progression by leading the invasion of proliferative ΔNp63-high EMT cells in heterogeneous primary tumors. Thus, heterogeneous activation of distinct EMT programs promotes a mode of collective invasion that overcomes cell intrinsic phenotypic deficiencies to induce the dissemination of proliferative tumor cells. SIGNIFICANCE: These findings reveal how an interaction between cells in different EMT states confers properties that are not induced by either EMT program alone.

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Genetic heterogeneity within collective invasion packs drives leader and follower cell phenotypes.

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Transcription profiling of skin from p63 null and wild type mice to identify genes that are directly or indirectly regulated by p63.

Project description:In the absence of p63 expression, the epidermis fails to commit to stratification, resulting in aborted skin development. In this study, gene expression profiles of E18.5 p63 null and wt skin, were compared in an effort to identify genes that are directly or indirectly regulated by p63. Experiment Overall Design: E18.5 embryos were obtained from matings between p63 heterozygous mice. RNA was isolated from the skin of two p63 null and two wild type embryos.

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siRNA profiling of human keratinocyte and squamous cell carcinoma cell lines knocked down with p63 reveals loss of p63 leads to increased cell migration and up-regulation of genes involved in invasion and metastasis

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