ΔNp63-Regulated Epithelial-to-Mesenchymal Transition State Heterogeneity Confers a Leader–Follower Relationship That Drives Collective Invasion
| Autor: | Jill M. Westcott, Raneen Rahhal, Anna T. Riegel, Sharon Camacho, Rolf A. Brekken, Gray W. Pearson, Molly E. Huysman, Tuyen T. Dang, Apsra Nasir |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Epithelial-Mesenchymal Transition Cell Cell Culture Techniques Breast Neoplasms Triple Negative Breast Neoplasms Tumor cells Biology Article Mice 03 medical and health sciences 0302 clinical medicine Cell Movement Cell Line Tumor Interleukin-1alpha Spheroids Cellular medicine Animals Humans Neoplasm Invasiveness Epithelial–mesenchymal transition RNA Small Interfering Transcription factor Cell Proliferation Tumor Suppressor Proteins Phenotype Extracellular Matrix Neoplasm Proteins Cell biology MicroRNAs 030104 developmental biology medicine.anatomical_structure Oncology Tumor progression 030220 oncology & carcinogenesis embryonic structures Disease Progression Trans-Activators Interleukin 1α Female Cell Surface Extensions Leader follower Transcription Factors |
| Zdroj: | Cancer Res |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-20-0014 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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