Biomarkers in Liquid Biopsies for Prediction of Early Liver Metastases in Pancreatic Cancer

Individualized diagnostics approaches in modern cancer therapy require predictive and prognostic biomarkers that are easily accessible and stratify patients for optimal and individualized treatment. Pancreatic ductal adenocarcinoma (PDAC) is still a life-threatening disease mainly because of its late diagnosis in advanced stages or rapid progress even in patients with curative resection of the primary tumor. Moreover, patients with liver metastases exhibit an even worse prognosis. Hence, this retrospective multi-center study aims to identify biomarkers in perioperative serum of PDAC patients predicting early liver metastasis. A highly sensitive biomarker analysis was performed using two different methodological approaches. Olink® analysis, which was also used to validate LEGENDplexTM results, identified significant differences in proteins involved in chemotaxis and migration of immune cells as well as cell growth in serum of patients with early versus late onset of liver metastasis. Further studies with larger cohorts are required to validate these findings for clinical translation

Cellular Heterogeneity of Pancreatic Stellate Cells, Mesenchymal Stem Cells, and Cancer-Associated Fibroblasts in Pancreatic Cancer

Pancreatic cancer is projected to become the second deadliest cancer by 2030 in the United States, and the overall five-year survival rate stands still at around 9%. The stroma compartment can make up more than 90% of the pancreatic tumor mass, contributing to the hypoxic tumor microenvironment. The dense stroma with extracellular matrix proteins can be a physical and metabolic barrier reducing therapeutic efficacy. Cancer-associated fibroblasts are a source of extracellular matrix proteins. Therefore, targeting these cells, or extracellular matrix proteins, have been considered as therapeutic strategies. However, several studies show that deletion of cancer-associated fibroblasts may have tumor-promoting effects. Cancer-associated fibroblasts are derived from a variety of different cell types, such as pancreatic stellate cells and mesenchymal stem cells, and constitute a diverse cell population consisting of several functionally heterogeneous subtypes. Several subtypes of cancer-associated fibroblasts exhibit a tumor-restraining function. This review article summarizes recent findings regarding origin and functional heterogeneity of tumor-promoting as well as tumor-restraining cancer-associated fibroblasts. A better understanding of cancer-associated fibroblast heterogeneity could provide more specific and personalized therapies for pancreatic cancer patients in the future

Targeting and Reprograming Cancer-Associated Fibroblasts and the Tumor Microenvironment in Pancreatic Cancer

Pancreatic cancer is the fourth leading cause of cancer deaths in the United States both in female and male, and is projected to become the second deadliest cancer by 2030. The overall five-year survival rate remains at around 10%. Pancreatic cancer exhibits a remarkable resistance to established therapeutic options such as chemotherapy and radiotherapy, due to dense stromal tumor microenvironment. Cancer-associated fibroblasts are the major stromal cell type and source of extracellular matrix proteins shaping a physical and metabolic barrier thereby reducing therapeutic efficacy. Targeting cancer-associated fibroblasts has been considered a promising therapeutic strategy. However, depleting cancer-associated fibroblasts may also have tumor-promoting effects due to their functional heterogeneity. Several subtypes of cancer-associated fibroblasts have been suggested to exhibit tumor-restraining function. This review article summarizes recent preclinical and clinical investigations addressing pancreatic cancer therapy through targeting specific subtypes of cancer-associated fibroblasts, deprogramming activated fibroblasts, administration of mesenchymal stem cells, as well as reprogramming tumor-promoting cancer-associated fibroblasts to tumor-restraining cancer-associated fibroblasts. Further, inter-cellular mediators between cancer-associated fibroblasts and the surrounding tissue microenvironment are discussed. It is important to increase our understanding of cancer-associated fibroblast heterogeneity and the tumor microenvironment for more specific and personalized therapies for pancreatic cancer patients in the future

Lipid Droplet-Associated Factors, PNPLA3, TM6SF2, and HSD17B Proteins in Hepatopancreatobiliary Cancer

Pancreatic and liver cancer are leading causes of cancer deaths, and by 2030, they are projected to become the second and the third deadliest cancer respectively. Cancer metabolism, especially lipid metabolism, plays an important role in progression and metastasis of many types of cancer, including pancreatic and liver cancer. Lipid droplets are intracellular organelles that store neutral lipids, but also act as molecular messengers, and signaling factors. It is becoming increasingly evident that alterations in the regulation of lipid droplets and their associated factors influence the risk of developing not only metabolic disease but also fibrosis and cancer. In the current review article, we summarized recent findings concerning the roles of lipid droplet-associated factors, patatin-like phospholipase domain-containing 3, Transmembrane 6 superfamily member 2, and 17β-hydroxysteroid dehydrogenase 11 and 13 as well as genetic variants in pancreatic and hepatic diseases. A better understanding of cancer type- and cell type-specific roles of lipid droplet-associated factors is important for establishing new therapeutic options in the future

Lipid Metabolism and Lipid Droplets in Pancreatic Cancer and Stellate Cells

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second deadliest cancer by 2030, and the overall 5-year survival rate is currently less than 7%. Cancer cells frequently exhibit reprogramming of their metabolic activity. It is increasingly recognized that aberrant de novo lipid synthesis and reprogrammed lipid metabolism are both associated with the development and progression of various cancers, including pancreatic cancer. In this review, the current knowledge about lipid metabolism and lipid droplets in pancreatic cancer is discussed. In the first part, molecular mechanisms of lipid metabolism and roles of enzymes involved in lipid metabolism which are relevant for pancreatic cancer research are presented. Further, preclinical studies and clinical trials with drugs/inhibitors targeting cancer metabolic systems in cancer are summarized. An increase of our knowledge in lipid metabolism in pancreatic cancer cells and in tumor stroma is important for developing novel strategies of future individualized therapies of pancreatic cancer

Etude moléculaire de la voie non-canonique de NF-kappaB

On a montré ici que les voies canonique/non-canonique de NF- B ne sont pas indépendantes et qu un rôle principal de la voie canonique est l activation des acteurs de la voie non-canonique. La traduction est requise et la stimulation par LPS régule positivement un éventuel intermédiaire dans la signalisation par LPS/CD40 qui supporte l'activation de la voie non-canonique. De plus, la voie non-canonique est constitutivement activée dans les cellules de HL, impliquant la phosphorylation persistante de p100. L'activation transitoire et constitutive de la voie non-canonique implique l'incorporation de p100 et p52 dans un complexe megadalton . TAP a permis d identifier des partenaires interagissant avec p100. EDD (une molécule identifiée) induit le processing de p100 par co-expression. La formation du complexe de TRAF3 (autre facteur identifié) avec p100 est médiée par NIK et requiert son activité kinase. L'expression de NIK favorise le recrutement de TRAF3/p100 au signalosome p100.It is shown here that the canonical/non-canonical NF- B pathways are not independent and a master regulatory role of the canonical pathway is to upregulate activators of the non-canonical pathway. The data further implicate a translation requirement and that LPS stimulation upregulates a potential intermediate in LPS/CD40 signaling which supports activation of the non-canonical pathway. Further, the non-canonical pathway is constitutively activated in HL cells, involving persistent p100 phosphorylation. It was found that transient and constitutive activation of the non-canonical pathway involves incorporation of p100 and p52 into a megadalton complex. TAP was employed to identify novel p100 interacting partners. EDD (an identified molecule) induces processing of p100 upon co-expression. The complex formation of TRAF3 (another p100 interactor) with p100 is mediated by NIK and requires its kinase activity. The expression of NIK promotes recruitment of TRAF3/p100 to the p100 signalosome.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Cancer-Associated Fibroblasts and Tumor Cells in Pancreatic Cancer Microenvironment and Metastasis: Paracrine Regulators, Reciprocation and Exosomes

Pancreatic cancer is currently the fourth leading cause of cancer deaths in the United States, and the overall 5 year survival rate is still only around 10%. Pancreatic cancer exhibits a remarkable resistance to established therapeutic options such as chemotherapy and radiotherapy, in part due to the dense stromal tumor microenvironment, where cancer-associated fibroblasts are the major stromal cell type. Cancer-associated fibroblasts further play a key role in cancer progression, invasion, and metastasis. Cancer-associated fibroblasts communicate with tumor cells, not only through paracrine as well as paracrine-reciprocal signaling regulators but also by way of exosomes. In the current manuscript, we discuss intercellular mediators between cancer-associated fibroblasts and pancreatic cancer cells in a paracrine as well as paracrine-reciprocal manner. Further recent findings on exosomes in pancreatic cancer and metastasis are summarized