###### Abstract  
Clinical follow-up aided by changes in the expression of circulating microRNAs (miRNAs) may improve prognostication of pancreatic ductal adenocarcinoma (PDAC) patients. Changes in 179 circulating miR8 due to cancer progression in the transgenic _Kras_G12D/+; _Trp53_R172H/+; _P48-Cre_ (KPC) animal model of PDAC were analyzed for serum miR8 that are altered in metastatic disease. In addition, expression levels of 250 miR8 were profiled before and after pancreaticoduodenectomy in the serum of two patients with resectable PDAC with different progression free survival (PFS) and analyzed for changes indicative of PDAC recurrence after resection. Three miR8 that were upregulated \(\geq\)3-fold in progressive PDAC in both mice and patients were selected for validation in 26 additional PDAC patients before and after resection. We found that high serum miR-125b-5p and miR-99a-5p levels after resection are significantly associated with shorter PFS (HR 1.34 and HR 1.73 respectively). In situ hybridization for miR detection in the paired resected human PDAC tissues showed that miR-125b-5p and miR-99a-5p are highly expressed in inflammatory cells in the tumor stroma, located in clusters of CD79A expressing cells of the B-lymphocyte lineage. In conclusion, we found that circulating miR-125b-5p and miR-99a-5p are potential immune-cell related prognostic biomarkers in PDAC patients after surgery.  
pancreatic cancer; resection; circulating microRNAs; biomarkers; progression free survival; immune cells +
Footnote †: journal: Medical Cancer  
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Footnote 1: email: _Applied_[[https://doi.org/10.1145/1.4211.4211](https://doi.org/10.1145/1.4211.4211)]([https://doi.org/10.1145/1.4211.4211](https://doi.org/10.1145/1.4211.4211)).  
whereas molecular markers of PDAC progression during follow-up remain underexplored. Since collection of tissue biopsies from the pancreas is difficult and expensive, minimally invasive biomarkers attainable as 'liquid biopsies' from blood draws are sorely needed to aid in prognostic stratification of patients and possible adjustment of the treatment regimen. Here, we describe circulating cell free non-coding nucleic acids as potential prognostic biomarkers.  
Mature microRNAs (miRNAs) are highly conserved short strands of non-coding RNAs that regulate gene expression. To date, more than 2600 human mature miRs have been identified and annotated [7] and more than half of human protein-coding genes are likely regulated by at least one miR [8]. MiRs are dysregulated in cancer and play crucial roles in immune function, cell proliferation, apoptosis, metastasis, angiogenesis, and tumor-stroma interactions [9; 10; 11]. It is noteworthy that miRs released from cells can induce miR-mediated gene expression alterations in neighboring as well as in distant cells when entering the circulation [12; 13]. In the circulation, miRs are relatively stable and easy to measure, which has inspired a vast amount of biomarker research. The majority of research on circulating miR signatures in oncology is focused on diagnostics [14; 15; 16; 17; 18], however miRs can provide crucial insights into cancer progression and the effects of therapeutic interventions [19; 20; 21; 22]. In the present study, we profiled serum miRs in a transgenic mouse model of PDAC progression and in PDAC patients with early and late disease progression, using blood samples before and after tumor resection, to identify novel circulating biomarkers of PDAC progression.