Elucidation of Key Signaling Components in Development and Cancer: Wnt/Planar Cell Polarity Contribution to Glioblastoma Multiforme Aggressiveness and the Role of Mucin-4 in Mammary Gland Development and Breast Cancer Metastasis

Field: Biochemistry, Genetics and Molecular Biology (Life Sciences)

Tumorigenesis is a multistep process wherein normal cells lose their original cellular properties and gain malignant characteristics to initiate the formation of tumors. The means by which cells are transformed and acquire tumorigenic properties is complex, and largely context- and tissue-dependent. However, a reoccurring theme in cancer is that tumor cells can both hijack and reactivate developmental pathways or repurpose and exploit constitutively expressed proteins critical to tissue homeostasis, to drive their aggressive properties. Critically, understanding the function of these key signaling components during development and in normal tissues, and how they are aberrantly engaged by tumors, could provide insight into promising therapeutic approaches to benefit patients. This dissertation features the current research of two distinct signal transduction components critical to development and cancer progression: (1) the contribution of Wnt/Planar cell polarity (PCP) signaling to glioblastoma multiforme (GBM) aggressiveness, and (2) the role of Mucin-4 (Muc4) in mammary branching morphogenesis. Discussion of each finding is preceded by a review of the literature highlighting our current knowledge of Wnt/PCP signaling or Muc4 in development and disease. Wnt/PCP signaling is a branch of noncanonical Wnt signaling critical to the establishment of tissue polarity during embryonic development. Recent studies have implicated Wnt/PCP signaling components in driving the progression of several solid tumor types. However, many of the mechanistic details underlying how these components are engaged in tumor cells remain elusive. Here, we identify a critical role for Wnt/PCP components Vangl1 and Fzd7 in mediating GBM progression. Vangl1 and Fzd7 regulate GBM cell proliferation, migration, and invasion, and engage downstream Rho GTPases to mediate actin dynamics. Vangl1 and Fzd7 colocalize and interact within cellular protrusions in migrating GBM cells, where they may engage downstream effectors to yield biological outcomes. Further, loss of FZD7 significantly affects GBM tumor growth and survival in vivo, suggesting that targeting of this pathway could provide clinical benefit to patients diagnosed with GBM. Muc4 is a large cell surface glycoprotein that functions to lubricate and protect epithelial and vascular surfaces. Muc4 has been widely studied in a variety of tumor types, but it is most well-characterized in breast cancer, where it drives breast cancer progression and metastasis. However, little is known about the function of Muc4 in the normal mammary gland and its role during mammary gland development. Here, using a genetically engineered Muc4 knockout mouse, we identify a role for Muc4 in regulating mammary branching morphogenesis. Muc4 is expressed throughout the mammary epithelium and is critical to proper mammary branching during adolescent development. Our understanding of the mechanisms by which Muc4 is involved in these processes could provide insight to additional roles for Muc4 in mediating breast cancer metastasis.