Polarity-Mediated Suppression of Tumorigenesis

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (provided by applicant): The vast majority of human malignancies originate from cells of epithelial origin (carcinomas). Epithelial cells exhibit apical-basal polarity, and lss of apical-basal polarity is considered both a defining characteristic and prerequisite for human cancer. Disruption of epithelial polarity in the setting of infection by oncogenic viruses (e.g. HP) or during breast cancer formation contributes to both cancer development and metastasis. The loss of polarity regulation is also associated with increased proliferation, through mechanisms that are poorly understood. Epithelia are dynamic structures with a high capacity for renewal and repair. In response to injury (genetic mutation, irradiation, physical), JNK-dependent apoptosis is induced and these dying cells secrete various mitogens that induce compensatory proliferation of the surrounding unaffected cells, so as to maintain the integrity of the epitheliu. The precise proximal signals regulating this process are not clear. The Longmore lab recently demonstrated that the Cdc42-containing Cdc42/Par6/aPKC polarity complex regulates proliferation in Drosophila epithelia (imaginal discs), and does so, in part, by limiting Rho activity. Disrupting the formation of the Cdc42/Par6/aPKC complex, but not other polarity complexes, by genetically depleting individual components or inhibiting complex assembly induces JNK-dependent apoptosis and compensatory proliferation following radiation injury. Surprisingly, disruption of the Cdc42/Par6/aPKC complex leads to activation of JNK through the increased ability of Rho and Rok to specifically activate myosin. When apoptosis execution is blocked, Cdc42/Par6/aPKC-depleted tissues exhibit tissue overgrowth (a tumorous phenotype), suggesting that in cancer where apoptotic regulation is compromised, disruption of this polarity complex may contribute to tumor hyperproliferation. The specific signaling changes resulting from Cdc42 depletion remain unknown and will be studied in the aims presented in this research project. The molecular signals proximal and distal to myosin in this pathway will be delineated, and the role myosin plays in the activation of JNK in this context will be determined. Furthermore, this project will aim to study whether these signaling events are unique to Cdc42 depletion or shared following depletion of any of the other known polarity-regulating proteins. These advances will further illustrate how the loss of cell polarity contributes to tumor development and progression.