Sir Peter MacCallum Department of Oncology - Theses
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ItemInvestigating mechanisms of metastasis in melanoma( 2016)Metastasis is a complex process that is responsible for most human cancer deaths. Autopsy findings across multiple cancers suggest that metastatic dissemination from the primary site of disease to distant organs is not a random process; cancers can have different predilections to metastasize to particular organs. These observations raise the general question of whether determinants of metastasis, including organ-specificity, are driven by cancer cell-intrinsic or cell-extrinsic factors, or a combination of both. A fundamental question in cancer biology is whether metastasis capability in human tumours is acquired in a heritable manner. Work pertaining to this thesis tested whether organ-specificity during melanoma metastasis is a biologically heritable trait, using PDX modelling. Collectively, these studies suggest that while metastatic potential per se is a biologically heritable trait, organ-specificity of metastasis is not. To examine a candidate cell-intrinsic regulator of melanoma metastasis, desmoglein 2 (DSG2), expression and correlative studies were also performed on patient melanomas. DSG2, a member of the cadherin class of proteins that mediate cell-cell contacts, has been previously but inconsistently detected in human melanoma, however its role and function remain poorly defined. Herein, DSG2 expression was investigated as a potential prognostic factor in melanoma linked to the development of vasculogenic mimicry and poor patient outcomes. These studies confirm that DSG2 is expressed in primary and metastatic melanomas, but not in normal cutaneous melanocytes, and is associated with poor survival in melanoma. Although DSG2-positive melanomas consistently contained more features of VM than DSG2-negative, the differences were not statistically significant.