Challenges and opportunities for modeling aging and cancer.

Age is among the main risk factors for cancer, and any cancer study in adults is faced with an aging tissue and organism. Yet, pre-clinical studies are carried out using young mice and are not able to address the impact of aging and associated comorbidities on disease biology and treatment outcomes. Here, we discuss the limitations of current mouse cancer models and suggest strategies for developing novel models to address these major gaps in knowledge and experimental approaches.

Effects of different handling methods on the behavior of adult zebrafish.

The zebrafish is an important biomedical research organism. In most research, zebrafish are removed from their home tank and subsequently their phenotype is measured. The method of handling the fish, however, may significantly affect a variety of phenotypes. This is particularly problematic for studies of brain function that measure behavioral or neuronal responses. Nevertheless, the potential effects of handling have not been analyzed, and in fact are usually ignored. Here, we explore the effects of two usual and two rarely or never-before employed handling methods on the behavior of adult zebrafish. We exposed each fish to one of four handling methods, a between subject experimental design: (1) net chasing followed by air-suspension, (2) gentle net catching (without chasing) followed by air-suspension, (3) gentle net catching followed by being placed in a beaker (no chasing and very short air-suspension), (4) transportation in home tank and pouring the fish directly into the test tank (no chasing, netting or air-suspension). With these handling methods, the fish were placed in a test tank and their swim path was videorecorded and analyzed. Handling significantly affected swim path parameters, duration and frequency of immobility, absolute turn angle and its temporal variance and velocity, but not the distance to bottom. The behavioral effects confirmed that chasing and netting induce robust behavioral changes, and that pouring the fish from its home to its test tank is least aversive for zebrafish. We recommend using this latter method to reduce experimental error variation and increase reproducibility of results.

Tumor-stroma interactions differentially alter drug sensitivity based on the origin of stromal cells.

Due to tumor heterogeneity, most believe that effective treatments should be tailored to the features of an individual tumor or tumor subclass. It is still unclear, however, what information should be considered for optimal disease stratification, and most prior work focuses on tumor genomics. Here, we focus on the tumor microenvironment. Using a large-scale coculture assay optimized to measure drug-induced cell death, we identify tumor-stroma interactions that modulate drug sensitivity. Our data show that the chemo-insensitivity typically associated with aggressive subtypes of breast cancer is not observed if these cells are grown in 2D or 3D monoculture, but is manifested when these cells are cocultured with stromal cells, such as fibroblasts. Furthermore, we find that fibroblasts influence drug responses in two distinct and divergent manners, associated with the tissue from which the fibroblasts were harvested. These divergent phenotypes occur regardless of the drug tested and result from modulation of apoptotic priming within tumor cells. Our study highlights unexpected diversity in tumor-stroma interactions, and we reveal new principles that dictate how fibroblasts alter tumor drug responses.