Pancreatic adenocarcinoma is one of the deadliest malignancies worldwide, mainly due to frequent diagnosis at an advanced stage and its strong chemoresistance. Tumor heterogeneity is evident at the histological level, both between tumors and even within a tumor. Recent high-throughput analyses have confirmed that intertumor heterogeneity is greater than intratumor heterogeneity that is mostly driven by successive catastrophic genetic events in the early stage and by epigenetic modifications in the metastatic stage. While this heterogeneity may complicate the search for a universal cure, these analyses have distinguished several subtypes at the genomic, transcriptomic, and metabolomic levels that offer, for some, new therapeutic opportunities.

Data from the Cancer Genome Atlas (TCGA) are now easily accessible through web-based platforms with tools to assess the prognostic value of molecular alterations. Pancreatic tumors have heterogeneous biology and aggressiveness ranging from the deadly adenocarcinoma (PDAC) to the better prognosis, neuroendocrine tumors. We assessed the availability of the pancreatic cancer TCGA data (TCGA_PAAD) from several repositories and investigated the nature of each sample and how non-PDAC samples impact prognostic biomarker studies. While the clinical and genomic data (n = 185) were fairly consistent across all repositories, RNAseq profiles varied from 176 to 185. As a result, 35 RNAseq profiles (18.9%) corresponded to a normal, inflamed pancreas or non-PDAC neoplasms. This information was difficult to obtain. By considering gene expression data as continuous values, the expression of the 5312 and 4221 genes were significantly associated with the progression-free and overall survival respectively. Considering the cohort was not curated, only 4 and 14, respectively, had prognostic value in the PDAC-only cohort. Similarly, mutations in key genes or well-described miRNA lost their prognostic significance in the PDAC-only cohort. Therefore, we propose a web-based application to assess biomarkers in the curated TCGA_PAAD dataset. In conclusion, TCGA_PAAD curation is critical to avoid important biological and clinical biases from non-PDAC samples.

Cancer associated fibroblasts (CAFs) from pancreatic adenocarcinoma (PDA) present high protein synthesis rates. CAFs express the G protein-coupled somatostatin receptor sst1. The sst1 agonist SOM230 blocks CAF pro-tumoral features in vitro and in immunocompromised mice. We have explored here the therapeutic potential of SOM230, and underlying mechanisms, in immunocompetent models of murine PDA mimicking the heavy fibrotic and immunosuppressive stroma observed in patient tumors. Large scale mass spectrometry analyses were performed on the media conditioned from nine patient PDA-derived CAF primary cultures. Spontaneous transgenic and experimental (orthotopic co-graft of tumor cells plus CAFs) PDA-bearing mice were longitudinally ultrasound-monitored for tumor and metastatic progression. Histopathology and flow cytometry analyses were performed on primary tumors and metastases. Stromal signatures were functionally validated through bioinformatics using several published, and one original, PDA database. Proteomics on the CAF secretome revealed that SOM230 controls stromal activities including inflammatory responses. Amongst the identified secreted proteins, we validated that CSF-1 (macrophage colony-stimulating factor) was reduced by SOM230 in the tumor and plasma of PDA-harboring mice, alongside intra-tumor stromal normalization (reduced CAF and macrophage activities), and dramatic metastasis reduction. In transgenic mice, these SOM230 benefits alleviate the chemotherapy (gemcitabine) -induced immunosuppressive stroma reshaping. Mechanistically, SOM230 acts in vivo on CAFs through sst1 to disrupt pro-metastatic CAF production of CSF-1 and cross-talk with macrophages. We found that in patients, stromal CSF-1 was associated with aggressive PDA forms. We propose SOM230 as an anti-metastatic therapy in PDA for its capacity to remodel the fibrotic and immunosuppressive myeloid stroma. This pharmacotherapy should benefit PDA patients treated with chemotherapies.

Oenococcus oeni is the lactic acid bacterium that most commonly drives malolactic fermentation (MLF) in wine. Though the importance of MLF in terms of wine microbial stability and sensory improvement is well established, it remains a winemaking step not so easy to control. O. oeni displays many adaptation tools to resist the harsh wine conditions which explain its natural dominance at this stage of winemaking. Previous findings showed that capsular polysaccharides and endogenous produced dextran increased the survival rate and the conservation time of malolactic starters. In this paper, we showed that exopolysaccharides specific production rates were increased in the presence of single stressors relevant to wine (pH, ethanol). The transcription of the associated genes was investigated in distinct O. oeni strains. The conditions in which eps genes and EPS synthesis were most stimulated were then evaluated for the production of freeze dried malolactic starters, for acclimation procedures and for MLF efficiency. Sensory analysis tests on the resulting wines were finally performed.

Gemcitabine is still one of the standard chemotherapy regimens for pancreatic ductal adenocarcinoma (PDAC). Gemcitabine uptake into tumor cells is mainly through the human equilibrative nucleoside transport 1 (hENT1). It was therefore proposed as a potential predictive biomarker of gemcitabine efficacy but reports are conflicting, with an important heterogeneity in methods to assess hENT1 expression. A multicenter cohort of 471 patients with a resected PDAC was used to assess simultaneously the predictive value of the 2 best described hENT1 antibodies (10D7G2 and SP120). Three additional antibodies and the predictive value of hENT1 mRNA were also tested on 251 and 302 patients, respectively. hENT1 expression was assessed in 54 patients with matched primary tumors and metastases samples. The 10D7G2 clone was the only hENT1 antibody whose high expression was associated with a prolonged progression free survival and overall survival in patients who received adjuvant gemcitabine. hENT1 mRNA level was also predictive of gemcitabine benefit. hENT1 status was concordant in 83% of the cases with the best concordance in synchronous metastases. The 10D7G2 clone has the best predictive value of gemcitabine benefit in PDAC patients. Since it is not commercially available, hENT1 mRNA level could represent an alternative to assess hENT1 status.