In many solid tumors, metastatic progression and poor outcome associate with deregulated nuclear envelope composition, including up- or downregulation of A- and B-type lamins. We have previously identified the cell nucleus as rate-limiting cell organelle that determines the efficacy of tumor cell invasion in vitro, and have mapped lamin A/C and lamin B2 as key regulators of nuclear deformability during altered 3D tissue invasion. Strong nuclear deformation in vitro increases the risk of nuclear envelope (NE) rupture, followed by DNA damage and even fragmentation of the nucleus, and lamin deregulation contributes thus to nuclear damage.
The aim of this project is to test whether and how lamin deregulation contributes to metastatic disease progression in the living organism. Lamin downregulation in particular could enhance cell deformability but also vulnerability of nuclei and DNA damage, thereby directing invasion modes and metastatic efficacy. Using defined solid tumor models of melanoma, sarcoma and breast cancer in vitro and in living mice, the project aims to address the following questions: (1) How are increased or decreased lamin expression levels associated with successful tissue invasion, systemic dissemination and formation of distant metastases? (2) What is the relevance of increased or decreased lamin levels on NE rupture, survival and DNA damage during metastatic progression?
The techniques used in this project comprise the generation and characterization of tumor cell lines of specific lamin expression levels in vitro, intravital tumor imaging in mice by high resolution multiphoton microscopy, and histological analysis of tumor patient samples.
The candidate should have a master's degree (or equivalent) in the field of molecular life sciences and a strong interest in studying processes involved in cancer progression.
Scale 10A: max € 40814 gross per year at full employment (incl. vacation bonus and end of year payments).
Expected start date is July to November 2018.
This 4-year-project is funded by the Dutch Cancer Foundation (KWF Kankerbestrijding).