PANCREATIC CANCER: In search of new therapeutic targets

Pancreatic cancer (or pancreatic ductal adenocarcinoma, PDAC) is a devastating disease with a 5-year survival rate of less than 5%. Late diagnosis and therapy resistance are determining factors in PDAC treatment failure. Better insight in the processes of tumour progression, metastasis and therapy failure is clearly needed to advance the field. In the present work, we used different experimental approaches to better understand these processes with the eventual aspiration to identify new prognostic markers and therapeutic targets.In the first chapter, we identified shortcomings in current PDAC treatment by studying the pattern of disease recurrence after curative resection. Disease relapse was observed within 2 years after surgery in almost all patients. The first recurrence occurred within the abdominal cavity in more than 90% of the patients, most frequently in the liver. R1 resection did not influence locoregional recurrence rate, but was related to overall survival (OS). Our study indicates that a combination of better local control and more effective adjuvant treatment mainly locoregional - is needed.In the second chapter, we deciphered whole-genome expression profiles of 2 PDAC subgroups of clinicopathologically similar PDAC patients, 1 subgroup with extraordinary good (OS and disease-free survival or DFS &gt; 50 months; referred to as Good ) and 1 subgroup with poor (OS < 19.5 months and DFS < 7 months; referred to as Bad ) outcome after resection with curative intent. The Integrin and Ephrin pathways, both involved in the interplay between tumour and stromal cells, are overexpressed in the PDAC samples of both subgroups when compared to the surrounding pancreatic tissue, supportive of the reported role of these pathways in PDAC growth, migration and therapy resistance. Furthermore, the non-canonical Wnt/b-catenin pathway is upregulated in the Bad versus Good PDAC samples, with DKK1 ad Wnt5A as potential prognostic markers. In addition, many components of epithelial-mesenchymal transition (EMT) are upregulated in Bad versus Good PDAC samples, thereby also endowing EMT with a prognostic character. Finally, comparison of PDAC metastasis with the primary tumour showed a potential role for b-catenin in the metastatic process. In the third chapter, we searched for the therapy-resistant cells within PDAC using the side population (SP) approach. The SP is identified by high efflux capacity and may accordingly enrich for chemoresistant cells. In addition, it is known that the SP simultaneously may also enrich for potential cancer stem cells (CSC). We detected a SP in clinical human PDAC samples as well as in samples expanded in immunodeficient mice as xenografts. The SP was further purified from co-segregating CD45+ immune and CD31+ endothelial cells. Whole-genome expression profiling revealed in the SP upregulated expression (versus the main population or MP) of genes related to therapy resistance, such as ABC multidrug transporters and apoptosis-relatedgenes. The SP was indeed found to be more resistant to gemcitabine using an in vivo xenograft model. Moreover, proposed pancreatic CSC markers and other stemness genes are overexpressed in the (clinical) PDAC SP, suggesting a CSC-related character. Along the same line, tumourigenic activity of the SP was higher than that of the MP as far as assessed in the in vitro sphere-forming assay. Again, the Ephrin pathway (EPHA2 and EPHA4) are upregulated in the SP, as well as ErbB3, both reported as central players in PDAC pathogenesis. Finally, we determined a discriminative SP signature from clinical PDAC, based on 32 genes of which ABCB1 and CXCR4 are negatively related to survival. In conclusion, this thesis study yields new promising elements to advance the clinical management of PDAC, including potential therapeutic and prognostic tools. Further research is needed, in particular to definitely demonstrate the CSC phenotype of the PDAC SP.status: publishe