The Integrin family of cell adhesion receptors has been implicated in tumour progression as they contribute to the interplay between tumour and micro-environment by binding directly to components of the extracellular matrix (ECM) [24]. Due to the abundance of ECM, the integrin-mediated cell adhesion signalling may play an important role in PDAC tumour growth, migration and even in therapy resistance [25, 26]. Various integrins, such as ITGA6, ITGB4 and ITGB5, are upregulated in ‘Good’ and/or ‘Bad’ PDAC samples. In cell culture studies, ITGB1 has been shown to play a critical role in pancreatic cancer progression and in metastasis in particular [27, 28]. Upregulation of ITGB1

VEGFR inhibitor in ‘Bad’ PDAC, might highlight its potential therapeutical impact. Ephrin receptors are similarly promising therapeutical targets as they mediate cell-cell interactions both in tumour cells and in the tumour micro-environment, and thereby may affect tumour growth, invasiveness, angiogenesis, and metastasis [29]. EPHA2, related to poor

clinical outcome in PDAC, has already been successfully investigated as target in PDAC cell lines [30, 31]. Indeed, in our study, EPHA2 was highly upregulated as PDAC with poor outcome, supporting its potential clinical relevance. Embryonic signalling pathways are known to play a role in both the tumoural and the stromal compartment and in different stages of PDAC [32]. Hedgehog signalling (Shh) e.g. has been implicated in the initiation PR-171 supplier of PDAC, and was overexpressed in PDAC samples with good overall survival in our series [33, 34]. The Wnt/β-catenin TGF-beta inhibitor pathway seems to be involved in a later stage of PDAC tumorigenesis [9, 34, 35]. In our study, elements from the canonical Wnt/β-catenin pathway were upregulated in all PDAC samples. However, in patients with poor survival, genes

from both the canonical and non-canonical pathway, including Wnt5A and DVL1, were upregulated [35, 36]. The expression of Wnt5A has already been shown to be induced in PSC [35]. Upregulation of DKK1, a Wnt/β-catenin pathway antagonist, may promote tumour invasiveness though the exact mechanism is yet unknown [37]. Overexpression of Notch signalling in PDAC correlates with tumour proliferation and migration [38]. Notch has been shown to Cediranib (AZD2171) regulate pancreatic cancer stem cells and would have a role in the acquisition of epithelial-mesenchymal transition (EMT) by inducing SNAI2 expression due to JAG1 overexpression [39, 40]. Although JAG1 was upregulated in all our PDAC samples irrespective of survival, SNAI2 was upregulated in the ‘Bad’ versus ‘Good’ PDAC samples. The upregulation of many EMT-related genes, such as TGFβR1, FGFBP1 TGFβ1 LOXL2, TWIST1 and Wnt5A, and the downregulation of FOXA1 in the ‘Bad’ PDAC samples might support the role of EMT in the aggressiveness of PDAC [41].