Prof. Dr. med. Alexander Rösch
Group LeaderE-Mail schreiben
Melanoma is an aggressive tumor with dramatically reduced patient survival when disseminated to distant organs. The overall focus of our group is the phenotypic tumor heterogeneity in malignant melanoma and the long-term fate of distinct melanoma cell subpopulations. Despite the historic response rates that are seen for targeted therapies in melanomas, relapses recur within a few months indicating gradually developing therapy resistance, e.g. via adaptive and acquired (re-) activation of key pathways such as MAPK or PI3K signaling. However, some melanoma cells can also survive the very first contact with drugs (primary resistance via intrinsic resistance). Cytotoxic drugs but also modern targeted therapies principally affect rapidly dividing cells. Thus, particularly slow-cycling cell subpopulations may escape therapy a priori irrespective of their genetic origin and contribute to disease progression. We have recently confirmed that slow-cycling and long-term tumor maintaining melanoma cells are resistant to therapeutic attacks irrespective of the pharmacologic agents used. These cells play an important role in tumor repopulation but do not follow a classic cancer stem cell hierarchy. Our quest for the molecular basis of slow-cycling melanoma cells (characterized by the histone 3 K4 demethylase JARID1B/KDM5B) surprisingly indicated a possible role of bioenergetic proteins such as mitochondrial enzymes. Following the basic hypothesis that rapidly growing cancer cells are characterized by high glycolysis, whereas slow-cycling, therapy resistant cells more rely on mitochondrial oxidative phosphorylation (OXPHOS), we further dissect the different bioenergetic states of melanoma cell subpopulations in vitro and in vivo under changing microenvironmental conditions. At the moment, we are working on ways to overcome the intrinsic therapy resistance of melanoma cell subpopulations in vitro and in vivo.
Topic 1: Biology of melanoma
Topic 2: Translational research