Abstract SY23-01: Early endosomes: Platforms for the induction of oncogenic phenotypes

Abstract

Abstract Oncogenic signaling markedly impacts the adhesive and migratory potential of tumor cells. Many of the resulting cellular changes are elicited by coordinated alterations in endosomal membrane trafficking. Although long regarded as a means for cells to internalize nutrients and cell surface molecules, emerging evidence suggests that the endosomal circuitry is also an essential platform for signal transduction and a conduit for the transport of cellular machinery, including adhesion proteins and signaling molecules, appropriate compartmentalization of which appears to be essential for eliciting changes that accompany disease progression. The disruption of epithelial glandular architecture and the acquisition of aggressive invasive phenotypes, two hallmarks of tumor progression, exemplify the above paradigm. Our efforts are directed at elucidating and defining the role of ARF6-coupled endocytic pathways in the acquisition of migratory/invasive phenotypes. Recent work using three-dimensional basement membrane cultures of renal and mammary epithelial cells reveals that the formation of signaling endosomes during glandular cyst morphogenesis, serve as platforms for hyperactive receptor signaling leading to the disruption of epithelial cysts and generation of certain tumorigenic phenotypes. We are also investigating the structural and molecular changes at the invasive front of tumor cells. Our recent studies, and others, have shown that selective sorting of specific cargo such as the membrane-type proteases along early endocytic recycling pathways, is tightly coupled to the biogenesis and function of invasive structures such as invadopodia and microvesicles. Invadopodia are actin-rich protrusions that form at the adherent cell surface and mediate pericellular proteolysis. Microvesicles, generated by the outward budding and fission of the plasma membrane, facilitate the horizontal transfer of bioactive molecules and are now thought to have vital roles in tumor invasion and metastasis, inflammation and stem-cell expansion. Since endosomes confer spatial and temporal dimensions to oncogenic signaling, understanding the interplay between endocytic trafficking and the activation of invasive cell programs could provide new and important insights into the progression toward pathophysiological states. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY23-01. doi:10.1158/1538-7445.AM2011-SY23-01