Project 466663

Pancreatic cancer (PC) is an extremely aggressive disease that requires a better understanding to improve treatment options. The 4 Tissue Inhibitors of Matrix Metalloproteinases (TIMPs) are key players in PC biology through their unique ability to influence the activity of hundreds of other proteins in a tissue, and thereby affecting both tumour and surrounding stromal cell behaviour and function. Intriguingly, these powerful functions rest on a network of unique and shared targets among the 4 TIMPs. Yet, so far only individual TIMPs have been studied. Here, we will analyse all 4 TIMPs in conjunction, taking into consideration their co-expression patterns within tissues so that the cumulative biological and clinical effects of TIMPs in PC can be determined. In various PC datasets, we will identify main TIMP co-expression clusters and compare their relationship with patient outcome to assess clinical relevance. Next, we will identify the biology associated with each cluster using computational means and a wide range of tissue stains. This will detangle how all TIMPs in conjunction influence tumour and stromal cells in human tissues. Finally, we will use 3D tumour models that have been created using patient-derived cells to model and manipulate TIMP expression in vitro to definitively pinpoint the impact of these molecules in human PC malignant behaviour (i.e., tumour cell survival, ability of the cancer to invade, and resistance to chemotherapy). This will enable us to manipulate TIMP cluster expression and assess potential therapeutic benefit. Our integrative approach to TIMP net effects will provide key insights into this influential protein family and determine their therapeutic potential by defining and blocking their key effects on a human pre-clinical platform.