Abstract 4099: IGF1R signaling connects DNp73-mediated EMT with the acquisition of cancer stem cell properties

Metastatic spread is the major cause of cancer-associated mortality and induced in primary tumor cells by the acquisition of mesenchymal features. Emerging evidence suggests that metastasis-initiating cancer cells undergoing epithelial-mesenchymal transition (EMT) possess stem cell-like traits. In this study, we demonstrate that oncogenic DNp73, an inhibitor of p53 tumor suppressor family members, has a fundamental role in driving both, transition into a mesenchymal state and providing cancer cells with stem cell-like properties through constitutive activation of IGF1R signaling. In patient melanoma tissues, DNp73 expression correlates with increased Breslow depth and is enriched in skin cancer metastases. Knockdown of endogenous DNp73 in highly metastatic cell lines abolishes the aggressive phenotype, whereas tumor xenografts overexpressing DNp73 possess significantly greater capacity to invade the surrounding tissue and form metastatic lesions. Transition from an epithelial to a motile mesenchymal phenotype is accompanied by a drastic reorganization of the cytoskeleton and modulation of cell-cell adhesion molecules. Importantly, regulation of EMT by DNp73 is induced through activation of IGF1R-AKT signaling followed by an increase of Slug and loss of E-cadherin. Additionally, we identified a novel interplay between DNp73 and IGF1R in the development of cancer stemness. Tumor spheres derived from metastatic melanoma cells with endogenously high DNp73 display a strong capacity for self-renewal and tumor growth after subcutaneous injection in mice compared to DNp73-depleted cancer stem cells. Our results clearly demonstrate that DNp73-driven stemness involves IGF1R activation. Selective inhibition of IGF1R blocks DNp73-mediated upregulation of Nanog, Oct4 and CD133, which is accompanied by a decrease in spheroid formation and tumor invasiveness. Taken together, our findings show for the first time that DNp73 is crucial to endow cancer cells with mesenchymal properties and the ability to self-renew, which is responsible for malignant progression and tumor dissemination. Moreover, we establish IGF1R as driving force for a DNp73-induced aggressive cancer phenotype, highlighting the DNp73-IGF1R cascade as promising therapeutic target to selectively prevent metastasis initiation. Citation Format: Claudia Meier, Marc Steder, Philip Hardtstock, Vijay Alla, Brigitte M. Putzer. IGF1R signaling connects DNp73-mediated EMT with the acquisition of cancer stem cell properties. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4099. doi:10.1158/1538-7445.AM2015-4099