Investigating the Mechanisms Underlying the First Steps of Cancer Metastasis

Metastasis underlies 90% of cancer deaths, nonetheless its mechanisms remain poorly understood. The Epithelial-to-Mesenchymal Transition (EMT) is critical in onsetting metastasis and is therefore a sought-after therapeutic target. Unfortunately, targeting EMT has been difficult, as it is driven by undruggable transcription factors (EMT-TFs). Identifying metastatic effectors downstream of EMT may therefore represent a more efficacious means of targeting metastasis. However, by virtue of genetic redundancy, most metastatic models have failed to identify such drivers. Given, its low redundancy and remarkable similarities to the mammalian gut, the Drosophila Melanogaster midgut has emerged a powerful system in dissecting the genetic progression of Colorectal Cancer (CRC). Our lab previously established that activation of the EMT-TF Snail, triggers metastasis when added to a benign model of CRC involving mutations to APC and Ras. Nonetheless, its underlying mechanisms were left undetermined. This thesis sought to identify the mechanisms of Snail mediated metastasis, with the rationale of identifying downstream targets with potential therapeutic relevance. Following histological characterisation of metastatic tumours, three central behaviours could be identified, all occurring concurrently at the tumour invasive edge: destruction of the basement membrane, loss of E-Cadherin, and dysregulation of ADAMTS-A: a protease with strong potential as a drug target. Following experimental knockdown of ADAMTS-A, a loss of metastasis was observed. Although, ADAMTS-A has previously been correlated with metastatic outgrowth, a causal role has rarely been supported in-vivo. Put together, the results presented herein demonstrate that the Drosophila midgut is a powerful system for identifying metastatic mechanisms with strong therapeutic implications.