Practical Course HP-F8: Components and Mechanisms of Signal Transduction

Type: Practical Course with Student Seminars

Date: 12.-30. April 2021

 

Hosts: Violaine Goidts (v.goidts@dkfz.de); Ursula Klingmüller (u.klingmueller@dkfz.de); Tobias Dick (responsible organizer contact: t.dick@dkfz.de)

 

Topics:

Cancer cells fail to obey the social constraints that normally maintain tissue organization: they proliferate when they should not, survive where they should not, and invade regions that they should keep out of. Often this is because they have a reduced dependence on signals from other cells for growth, survival, and division. The aim of this course is to gain an insight into problems arising in the field of signal transduction and how they can be addressed.

Content:

Week 1: Brain Tumor Translational Targets (Violaine Goidts and her team)

In this practical course, we will have a closer look at SRC, one of the first oncogenes to be described and a key regulator of several signal transduction pathways that control growth and cellular architecture. Although there is a wealth of pre-clinical data pointing to the importance of SRC in tumor progression and infiltration in solid tumors, including glioblastoma, clinical trials with SRC inhibitors in brain tumours did not yield a significant effect on progression-free or overall patient survival. We will use glioblastoma stem-like cells as a model to understand how tumor heterogeneity might explain the failure of the inhibition of this non-receptor tyrosine kinase. Using Western blotting, RNA expression profiling, pathway analysis and cell viability assays, we will examine the response to SRC inhibition in different glioblastoma subtypes and find out how to improve the therapeutic response to SRC inhibition.

 

Week 2: Systems Biology and Signaling (Ursula Klingmüller, Piotr Zadora, Marcel Schilling, Lorenza D'Alessandro)

Complex intracellular signaling networks mediate signal transmission from cell surface receptors to the nucleus and regulate the activation of transcriptional programs and subsequent cellular responses. Many components of signaling networks have been identified but it remains to be elucidated how information is processed and how cellular decisions are regulated. The aim of systems biology of signal transduction is to identify key regulatory mechanisms that determine biological responses and to predict novel targets for intervention that will facilitate the targeted development of novel anti-cancer therapies. Dynamic activation of signaling components by growth factor stimulation at the cell population level will be performed by mass spectrometry. In parallel, the impact of growth factors stimulation and inhibitor treatment on cell proliferation will be monitored by measuring proliferation rate. The generation of a dynamic pathway model and data-based parameter estimation will be demonstrated in a computer practical. Additionally, the registration of patient data through OpenBIS software, study protocol, and standard operating procedure (SOP) will be introduced in this practical course.

 

Week 3: Oxidative Signaling (Tobias Dick, Brandan Perez)

Reactive oxygen species (ROS) and oxidative stress have long been recognized to be associated with tissue damage and age-related disorders, including malignant, neurodegenerative and cardiovascular disease. More recently, it has also become clear that moderate levels of ROS play essential roles as cellular messengers, causing reversible modifications (thiol oxidation) in specific target proteins. For example, transient oxidative modification of transcription factors contributes to the regulation of inflammatory and stress responses. The fleeting and labile nature of oxidants and intracellular redox states has been a major limitation for research. We will learn about new techniques which allow to identify proteins and pathways regulated by oxidation-reduction processes.

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