Team MSC

Owing to stressful microenvironments and the accumulation of mutations favoring adaption, cancer cells frequently show alterations in metabolic and other signaling circuits compared with normal cells. As a consequence, cancer cells show increased dependence on certain proteins or stress-support pathways, which themselves might not be deregulated through mutational in-/activation (non-oncogene dependence). On the one hand, stress-stimulated cellular adaptations support cancer development and can contribute to drug-resistance mechanisms; on the other, they might create targetable vulnerabilities of malignant cells.

Our team is interested in learning more about stress-induced pathways, especially secretory/endoplasmic reticulum (ER)/Golgi stress-signaling networks, which support cancer cell survival and thus might be amenable to novel anticancer treatment strategies. For instance, the proteasomal inhibitor bortezomib is an FDA-approved drug to treat multiple myeloma and mantle cell lymphoma and acts partly via ER stress induction. Approximately one third of all cellular proteins traverse the secretory pathway. In some cell types the trafficking rate through the ER/Golgi membrane system replaces the surface of the entire plasma membrane every 10–20 minutes. An example of this high secretory load, which might be further exacerbated in some cancer contexts, is plasma cells that secrete up to 3000 antibodies per second, suggesting that these cells critically depend on a functional trafficking transport machinery along the ER/Golgi axis. Thus interference with secretory stress signaling offers the potential to inhibit adaptive survival strategies and/or to activate cell-death pathways. We are using small molecule screens, genome-wide and candidate-based approaches to identify secretory-stress-regulated factors with the aim of therapeutically exploiting these findings for biomarker and drug target discovery.

Publications

1. Ignashkova TI, Gendarme M, Peschk K, Eggenweiler HM, Lindemann RK, Reiling JH (2017):
   Cell survival and protein secretion associated with Golgi integrity in response to Golgi stress-inducing agents
   Traffic 18(8)
2. Ramírez-Peinado S, Ignashkova TI, van Raam BJ, Baumann J, Sennott EL, Gendarme M, Lindemann RK, Starnbach MN, Reiling JH (2017):
   TRAPPC13 modulates autophagy and the response to Golgi stress
   Journal of Cell Science 130
3. van Raam BJ, Lacina T, Lindemann RK, Reiling JH (2017):
   Secretory stressors induce intracellular death receptor accumulation to control apoptosis
   Cell Death and Disease 8(10)
4. Gendarme M, Baumann J, Ignashkova TI, Lindemann RK, Reiling JH (2017):
   Image-based drug screen identifies HDAC inhibitors as novel Golgi disruptors synergizing with JQ1
   Molecular Biology of the Cell 28(26)
5. Baumann J, Ignashkova TI, Chirasani SR, Ramírez-Peinado S, Alborzinia H, Gendarme M, Kuhnigk K, Kramer V, Lindemann RK, Reiling JH (2017):
   Golgi stress-induced transcriptional changes mediated by MAPK signaling and three ETS transcription factors regulate MCL1 splicing
   Molecular Biology of the Cell 29(1)
6. Alborzinia H, Ignashkova TI, Dejure FR, Gendarme M, Theobald J, Wölfl S, Lindemann RK, Reiling JH (2018):
   Golgi stress mediates redox imbalance and ferroptosis in human cells
   Communications Biology 1