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 (in print)
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

Dr. Hamed Alborzinia

Postdoctoral Researcher

Cell metabolism and cell-death mechanisms, reactive oxygen species (ROS) signaling

Previous work
  • 20142016: Research collaboration, BioQuant and German Cancer Research Center (DKFZ) Heidelberg, Prof. Dr. Thomas Höfer
  • 2011–2015: Postdoc Heidelberg University, Prof. Dr. Stefan Wölfl
  • 2011: PhD Heidelberg University, Prof. Dr. Stefan Wölfl
  • 2005: Shiraz University (Iran), graduation in Veterinary Medicine
  • 2016: DKFZ-Bayer Alliance Award Novel Ideas in Drug Discovery

Dr. Bram van Raam

Postdoctoral Researcher

Proteomics; cell death regulation in response to secretory stress

Previous work
  • 2012–2014: Postdoc at the Sanford-Burnham Institute for Medical Research (SBMRI, currently the Sanford-Burnhum-Prebys Medical Discovery Institute; SBPMDI) under supervision of Prof. Dr. G.S. Salvesen
  • 2004–2009: PhD at the University of Amsterdam (http://dare.uva.nl/document/2/60324) under supervision of Prof. Dr. D. Roos and Prof. Dr. T.W. Kuijpers
  • 1999–2004: Biomedical Sciences at Utrecht University
  • Member of the group of Prof. Dr. R. Beyaert at the Inflammation Research Center, VIB in Gent

Mathieu Gendarme

Research Associate

DNA damage; image-based screens associated with secretory stress

Tatiana Ignashkova

Research Associate

Genetic screening approaches; ARF GTPases

Previous work
  • 2012: Fraunhofer USA, Center for Molecular Biotechnology, Newark, USA – development of recombinant proteins and protein purification
  • 2006–2012: Research Institute of General Pathology and Pathophysiology, Moscow, Russia

Cornelia Wirth

Research Associate

Lab manager; experimental support to all group members

Previous work
  • 2008–2014: German Cancer Research Center – Molecular Genome Analysis, Heidelberg