Metastasis of pancreatic cancer: An uninflamed liver micromilieu controls cell growth and cancer stem cell properties by oxidative phosphorylation in pancreatic ductal epithelial cells.

Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed when liver metastases already emerged. We recently demonstrated that hepatic stromal cells determine the dormancy status along with cancer stem cell (CSC) properties of pancreatic ductal epithelial cells (PDECs) during metastasis. This study investigated the influence of the hepatic microenvironment - and its inflammatory status - on metabolic alterations and how these impact cell growth and CSC-characteristics of PDECs. Coculture with hepatic stellate cells (HSCs), simulating a physiological liver stroma, but not with hepatic myofibroblasts (HMFs) representing liver inflammation promoted expression of Succinate Dehydrogenase subunit B (SDHB) and an oxidative metabolism along with a quiescent phenotype in PDECs. SiRNA-mediated SDHB knockdown increased cell growth and CSC-properties. Moreover, liver micrometastases of tumor bearing KPC mice strongly expressed SDHB while expression of the CSC-marker Nestin was exclusively found in macrometastases. Consistently, RNA-sequencing and in silico modeling revealed significantly altered metabolic fluxes and enhanced SDH activity predominantly in premalignant PDECs in the presence of HSC compared to HMF. Overall, these data emphasize that the hepatic microenvironment determines the metabolism of disseminated PDECs thereby controlling cell growth and CSC-properties during liver metastasis.

Predicted Bacterial Interactions Affect in Vivo Microbial Colonization Dynamics in Nematostella.

The maintenance and resilience of host-associated microbiota during development is a fundamental process influencing the fitness of many organisms. Several host properties were identified as influencing factors on bacterial colonization, including the innate immune system, mucus composition, and diet. In contrast, the importance of bacteria-bacteria interactions on host colonization is less understood. Here, we use bacterial abundance data of the marine model organism Nematostella vectensis to reconstruct potential bacteria-bacteria interactions through co-occurrence networks. The analysis indicates that bacteria-bacteria interactions are dynamic during host colonization and change according to the host's developmental stage. To assess the predictive power of inferred interactions, we tested bacterial isolates with predicted cooperative or competitive behavior for their ability to influence bacterial recolonization dynamics. Within 3 days of recolonization, all tested bacterial isolates affected bacterial community structure, while only competitive bacteria increased bacterial diversity. Only 1 week after recolonization, almost no differences in bacterial community structure could be observed between control and treatments. These results show that predicted competitive bacteria can influence community structure for a short period of time, verifying the in silico predictions. However, within 1 week, the effects of the bacterial isolates are neutralized, indicating a high degree of resilience of the bacterial community.

Analysis of the Microprocessor in Dictyostelium: The Role of RbdB, a dsRNA Binding Protein.

We identified the dsRNA binding protein RbdB as an essential component in miRNA processing in Dictyostelium discoideum. RbdB is a nuclear protein that accumulates, together with Dicer B, in nucleolar foci reminiscent of plant dicing bodies. Disruption of rbdB results in loss of miRNAs and accumulation of primary miRNAs. The phenotype can be rescued by ectopic expression of RbdB thus allowing for a detailed analysis of domain function. The lack of cytoplasmic dsRBD proteins involved in miRNA processing, suggests that both processing steps take place in the nucleus thus resembling the plant pathway. However, we also find features e.g. in the domain structure of Dicer which suggest similarities to animals. Reduction of miRNAs in the rbdB- strain and their increase in the Argonaute A knock out allowed the definition of new miRNAs one of which appears to belong to a new non-canonical class.