Pfister lab - research
Molecular mechanisms of tumor biology
Mechanisms regulating cell growth, proliferation and survival play a crucial role in development and disease. Ribosomes are essential for regulating growth and survival. Ribosomes are formed in a process termed ribosome biogenesis, which takes place in the sub-nuclear structure, the nucleoli. Wnt signaling regulates various cellular effects, among them ribosome biogenesis (Pfister & Kühl, 2019). Defective ribosome biogenesis leads to nucleolar stress - a situation, which is linked to cell cycle arrest and apoptosis.
Wnt/b-catenin signaling drives the expression of target genes regulating e.g. proliferation, migration and apoptosis. De-regulation of Wnt signaling has severe consequences leading to tumors, for instance colon cancer and leukaemia. In contrast, increasing evidence suggests that Wnt/b-catenin signaling is down-regulated during aging, e.g. in hematopoietic stem cells.
Our research aims to better understand the cellular and molecular mechanisms underlying tumor growth and survival. Thus, we currently focus on Wnt target genes that give rise to hallmarks of tumor development and aging when being mis-expressed or mutated. We focus on interesting candidates acting as pro-survival factors by use of various molecular biology methods, cell biology, biochemistry and in vitro cell-culture assays on primary, cancer and acute myeloic leukemia (AML) cells. Moreover, we investigate their in vivo function in Xenopus laevis as a potent model organism.
Our research on the Wnt target gene Peter Pan (PPAN).
We previously demonstrated that nucleophosmin (NPM), which is commonly mutated in AML, interacts with the nucleolar protein Peter Pan (PPAN) (Pfister et al., 2015). Both factors are Wnt target genes and are crucial for cell growth and survival, as they regulate ribosome biogenesis in the nucleolus. We showed that PPAN also localizes to mitochondria, PPAN knockdown triggers apoptosis and induces nucleolar stress independently of p53 (Pfister et al., 2015). In contrast, PPAN overexpression made cancer cells more resistant to treatment with chemotherapeutic agents.
We could further demonstrate that PPAN knockdown mediates cell cycle defects and apoptosis-related DNA damage (Keil et al., 2019). In a recent project we have shown that PPAN is involved in autophagy and the homeostasis of mitochondrial architecture (Dannheisig et al. 2019).
In our on-going projects we are elucidating the molecular mechanisms underlying PPAN function and nucleolar stress in more detail.
Medical Faculity Ulm University, Bausteinprogramm