Unraveling the role of autophagy in cancer using zebrafish cancer models
PURPOSE: Cancer is a leading cause of death worldwide and suitable treatment regimens are missing for a large number of patients. Hence, more work is needed to understand the mechanisms underlying different types of cancers and develop future therapy. In this project, we will use three zebrafish cancer models to determine the role of autophagy in tumorigenesis. Autophagy is a cellular process that mediates degradation of damaged or dysfunctional cellular components (the cell’s renovation system). Autophagy is tightly linked to cancer and is a promising therapeutic target, but further mechanistic insight is needed. We will use autophagy reporters and other molecular tools to study how autophagy affects cancer and its microenvironment interactions, as well as the abilities of cancers to invade and metastasize. We will also evaluate if pharmacological compounds or genetic modifications that regulate autophagy can inhibit cancer.
BENEFIT: Currently, there is no clear understanding of the role of autophagy in cancers, but previous studies indicate that autophagy regulation may be a promising treatment strategy. From this project, we will determine how established autophagy regulators affect cancers, but we will also gain further mechanistic insights that will guide future therapy developments.
REPLACEMENT, REDUCTION AND REFINEMENT: Using animal cancer models allows us to apply our knowledge from in vitro cell studies of autophagy and cancer to a more complex and relevant biological setting. It will allow us to evaluate both the cancer progression and its microenvironment interactions. By choosing zebrafish larvae as our animal model, we replace rodents with a lower sentient vertebrate. Larvae with localised tumours will not be kept beyond experimental endpoint and we will refine our protocols based on <120 hpf (hours post fertilisation) outcomes, to reduce the numbers of older animals required for statistical significance.
DISTRESS: Animals are expected to experience moderate discomfort due to the presence of localised tumours. Genetic modifications that promote cancer may lead to exacerbated symptoms. However, all animals will be monitored and euthanized prior to reaching defined humane endpoints or else at defined experimental endpoints. Any pharmacological treatment will be supplied via immersion in a diluted compound/E3 mix, and is estimated to lead to a mild discomfort.
BENEFIT: Currently, there is no clear understanding of the role of autophagy in cancers, but previous studies indicate that autophagy regulation may be a promising treatment strategy. From this project, we will determine how established autophagy regulators affect cancers, but we will also gain further mechanistic insights that will guide future therapy developments.
REPLACEMENT, REDUCTION AND REFINEMENT: Using animal cancer models allows us to apply our knowledge from in vitro cell studies of autophagy and cancer to a more complex and relevant biological setting. It will allow us to evaluate both the cancer progression and its microenvironment interactions. By choosing zebrafish larvae as our animal model, we replace rodents with a lower sentient vertebrate. Larvae with localised tumours will not be kept beyond experimental endpoint and we will refine our protocols based on <120 hpf (hours post fertilisation) outcomes, to reduce the numbers of older animals required for statistical significance.
DISTRESS: Animals are expected to experience moderate discomfort due to the presence of localised tumours. Genetic modifications that promote cancer may lead to exacerbated symptoms. However, all animals will be monitored and euthanized prior to reaching defined humane endpoints or else at defined experimental endpoints. Any pharmacological treatment will be supplied via immersion in a diluted compound/E3 mix, and is estimated to lead to a mild discomfort.