Functional precision medicine using zebrafish PDX models
Researchers in the lab are developing and using advanced models and methodologies to translate zebrafish patient-derived xenograft (PDX) models to clinical applications. Examples include 1) efforts to accurately recapitulate signaling events in the tumor cells that are important for their behaviour and response to therapies by reconstituting the relevant human molecular microenvironment within the tumor explants. These programs are supported by the EIC-PATHFINDER grant ALADDIN, 2) efforts to understand the immune-regulation within tumors in general but zebrafish tumor xenografts in particular, that is associated with resistance to immune-mediated cytotoxicity. Alternatively mechanisms that may therapeutically re-establish immune-mediated cytotoxicity. These programs are supported by a grant from the Swedish Cancer Research Foundation and the EU project EVEREST. 3) Robust characterization of the accuracy by which zebrafish PDX models predict patient treatment outcomes and early dissemination/progression, coupled to an understanding of the underlying molecular mechanisms. These programs are supported by numerous mural, inter-mural and external grants and collaborations.
Disease models of human diseases coupled to vascular leakage and dysfunction
The Jensen lab have previously, in collaboration with Prof. Yihai Cao at the Karolinska Institute and John Fleng Steffensen at Copenhaguen University, developed and characterized disease models wherein exposure to prolonged hypoxia is converting pre-neovascular retinopathies to neovascular retinopathies. Based on these experiences, the Jensen lab continues its efforts to understand the molecular regulation of hypoxia-induced vascular leakage and growth in the retina and in the central nervous system in various ways. 1) VEGFR2 does not seem to be important for hypoxia-induced retinal hypoxia in adult zebrafish, but VEGFR1 is critical. VEGFR1 does not, however, have angiogenic properties by itself. In an effort to understand potential signaling partners involved in VEGF-VEGFR1-induced retinal angiogenesis we have by RNA-sequencing found a number of potentially (co-) angiogenic factors that are currently poorly understood. We are currently investigating the mechanisms by which these interesting candidates may contribute to vascular leakage and growth in the retina. 2) As neurological symptoms are common in patients suffering from hypoxemia (e.g. patients with respiratory diseases or altitude sickness), we are investigating if and how acute or chronic hypoxemia may affect vascular leakage across the blood-brain barrier. We are using adult zebrafish as a model system where mechanistic readouts are coupled to clinical findings in patients.
