Oncology

Team MSC: Metabolism and Signaling in Cancer

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.

Mentors

  • Dr. Ralph Lindemann
    Director & Head of Operations Translational Innovation Platform Oncology, Merck, Darmstadt (Industry mentor)
  • Prof. Bernd Bukau
    Center for Molecular Biology (ZMBH), Heidelberg (Academic mentor)

Publications

    1. Ignashkova TI, Gendarme M, Peschk K, Eggenweiler HM, Lindemann RK, Reiling JH.
      Cell survival and protein secretion associated with Golgi integrity in response to Golgi stress-inducing agents. Traffic. 2017
    2. Ramírez-Peinado S, Ignashkova TI, van Raam BJ, Baumann J, Sennott EL, Gendarme M, Lindemann RK, Starnbach MN, Reiling JH.
      TRAPPC13 modulates autophagy and the response to Golgi stress. J Cell Sci. 2017
    3. van Raam BJ, Lacina T, Lindemann RK, Reiling JH.
      Secretory stressors induce intracellular death receptor accumulation to control apoptosis. Cell Death Dis. 2017
    4. Gendarme M, Baumann J, Ignashkova TI, Lindemann RK, Reiling JH.
      Image-based drug screen identifies HDAC inhibitors as novel Golgi disruptors synergizing with JQ1. Mol Biol Cell. 2017
    5. Baumann J, Ignashkova TI, Chirasani SR, Ramírez-Peinado S, Alborzinia H, Gendarme M, Kuhnigk K, Kramer V, Lindemann RK, Reiling JH.
      Golgi stress-induced transcriptional changes mediated by MAPK signaling and three ETS transcription factors regulate MCL1 splicing. Mol Biol Cell. 2017
The research of this team is kindly sponsored by Merck.
The research of this team is kindly sponsored by Merck.

Our Team Members

Dr. Jan H. Reiling

Group Leader

Golgi stress signaling; interest in how stress cues impinge on cellular growth

Previous work
  • 2005–2013: Postdoc with Prof. David Sabatini, Whitehead Institute/MIT, USA
  • 2001–2005: PhD with Prof. Ernst Hafen, University of Zurich, Switzerland
  • Human Frontier Science Program Organization (HFSPO) Long-Term Fellowship
  • European Molecular Biology Organization (EMBO) Long-Term Fellowship
  • Swiss National Science Foundation (SNF) Fellowship

Mathieu Gendarme

Research Associate

DNA damage; image-based screens associated with secretory stress

Previous work
  • 2010–2013: Master of Science in Biotechnology, European School of Biotechnology Strasbourg, France
  • 2008–2010: Bachelor degree in biology, mathematics, chemistry, University of Strasbourg, France