A multi-omics view of Pancreatic Cancer

The most prevalent type of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). Morphologically, PDAC presents as a solid poorly-defined mass, typically between 2–4 cm at diagnosis, which infiltrates surrounding structures (peripancreatic adipose tissue, duodenum, stomach, portal vein, and regional lymph nodes). Moreover, PDAC epithelial cancer cells are embedded in a prominent desmoplastic reaction, known as the “stroma” which is mainly constituted by cancer-associated fibroblasts (CAFs), immune cells (T & B cells, Natural Killer cells, tumor associated macrophages), blood vessels, extracellular matrix and a liquid milieu of cytokines, growth factors and exosomes. An orchestrated crosstalk between epithelial and stromal cells can stimulates proliferation and metastatic growth alongside drug resistance and tumor relapse. At present, diagnosis and treatment at early and late stage, is challenging. Patients rarely exhibit early symptoms and most of these are non-specific (jaundice, sudden weight loss, fatigue). Moreover, this type of tumor do not have sensitive and specific markers to aid detection. Thus, more sensitive and specific diagnostic markers for PDAC are urgently needed, especially non-invasive biomarkers that can be detectable in accessible biofluids such as blood, urine and saliva. Early diagnosis of PDAC is a crucial step to improve the efficacy of treatment and patient outcomes. Current guidelines mention to adopt systemic chemotherapy with multi-drugs regimens: 5-fluorouracil/leucovorin combined with irinotecan and oxaliplatin (FOLFIRINOX) and the combination of gemcitabine and nab-paclitaxel. However, these protocols are associated with high toxicity and modest response rates. Thus, major efforts should be taken to identify both new treatments and new biomarkers to select subgroups of patients who may benefit from specific therapies. To this end, the analysis of multiple molecular profiles has emerged as an unbiased strategy for the identification of novel drug targets and predictive biomarkers. This thesis aimed to describe the underlying mechanisms of PDAC analyzing different types of molecules at single or multiple -omics layers. The overall goal was to provide improved insights into PDAC biology and novel candidate markers for diagnosis, prognosis, and treatments.