Pancreatic cancer has a poor prognosis, with a 5-year survival rate of 12% in Australia. This survival rate has seen a less than 10% increase over the past two decades, highlighting the need to improve current treatment options. Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of pancreatic cancers. One of the reasons for this poor prognosis is that PDAC is often diagnosed at a late stage of disease when metastasis has already occurred and surgical resection is not possible. As such, chemotherapy remains the main treatment provided to PDAC patients. Another factor largely contributing to this poor prognosis is the dense, highly fibrotic stroma that surrounds the tumour and is characteristic of PDAC. This stroma presents both a physical and biological barrier, limiting drug penetration into the tumour and reducing the efficacy of standard of care chemotherapy treatments, as well as contributing to cancer disease progression and chemoresistance.
Stromal normalisation aims to improve chemotherapy outcomes by targeting tumour-promoting elements within the PDAC stroma, re-engineering the tumour ECM to be similar to that seen in healthy tissue. To identify components of the PDAC stroma that are contributing to disease progression, and may therefore be useful novel targets for stromal normalisation, we utilised the KPC mouse model of PDAC. Tissue samples were collected from early, mid and late-stage PDAC tumours, as well as age matched healthy wild type mice as controls. These samples were then de-celled to enrich for stromal components before the proteins present in each sample were quantified using mass spectrometry.
Our data identified a total of 287 matrisomal proteins within the PDAC ECM. 85 proteins were significantly differentially expressed between the healthy wild type pancreatic tissue samples and the late-stage KPC tumour samples, with 48 of these upregulated in PDAC tumours compared to healthy tissue. Survival analysis demonstrated that high expression of several of these proteins was associated with poor patient outcomes and increased probability of distant metastasis in the human setting. Further investigations into the biological role that these various proteins play in the progression of PDAC, its metastasis, and the response to chemotherapy in vitro and in vivo will further validate their potential as targetable components of the extracellular matrix for stromal normalisation.