Medema J.P.: Cell death induction and resistance in tumor cells

Jan Paul Medema is scientific co-director of the Cancer Center of Amsterdam and professor in Experimental Oncology and Radiobiology. He is heading the Laboratory of EXperimental Oncology and Radiobiology (LEXOR) in the Academic Medical Center of the University of Amsterdam, The Netherlands. His laboratory consists of multiple independent research teams that focus on gastrointestinal cancer, including colorectal, pancreatic and esophageal cancer. The research lines headed by Jan Paul Medema all zoom in on a central theme, which is the mechanisms of cell death resistance of tumor cells against therapeutic interventions. The research lines roughly fall into three categories.

1. Colorectal Cancer stem cells. This specific subset of cancer cells has been shown by the LEXOR laboratory to be the driving force of cancers and to reconstitute a complete tumor upon xenotransplantation even when a single cell is used. Moreover, these cells possess a selective resistant to apoptosis induced by chemotherapy and are thus considered to initiate re-growth of the tumor upon therapy cessation. This research program is therefore directed at understanding the signals that maintain the Cancer Stem Cell properties of these cells and at defining their plasticity. Moreover, the aim is to define the mechanisms that underly the cell death resistance and identify therapies that can directly kill or sensitize cancer stem cells.

2. Colorectal cancer prognosis and response to therapy. LEXOR has, together with several international teams, shown that colon cancer patients can be divided into four subgroups, which have clearly distinct biological properties and follow a different clinical course. Of these the mesenchymal subgroup is shown to be associated with dismal prognosis and poor response to therapy. The research in the laboratory is therefore aimed at understanding the origin of the subtypes, the signals that are responsible for the maintenance of the specific biological programs and at identification of the vulnerabilities of the distinct subgroups. Combined with the development of diagnostic tools to identify these subtypes, this program therefore is directed at increasing the insight into the subtype and optimizing therapy for the individual patient.

3. Survival signaling by the TNF family member APRIL. APRIL is a factor that is expressed in a wide range of tumor cells and appears to enhance their tumorigenicity by stimulating growth and pro-survival signaling. The LEXOR lab has invested strongly in the development of antagonistic tools to inhibit APRIL-induced pro-survival signaling and shown that these affect colorectal cancer growth. This program is currently aimed at understanding the mechanism behind this APRIL-induced survival and growth potentiation in colon cancer, with a final aim to develop the antagonistic tools for clinical use.