Ruprecht-Karls-Universität Heidelberg
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WielandT0118 - Scientist (f/m) / PhD position
Project no:
WielandT0118

Project leader:

Project supervisor:
Wieland, Thomas
Application deadline:
31. Dec 2018
Start of PhD project:
1. Feb 2019

Project description:

Title:
Regulation of the tumor microenvironment by chronic ß-adrenergic activation in the tumor vasculature
Summary:
Catecholamines bind to and activate the α- and β-adrenergic receptors (AR) thereby regulating a variety of cellular behaviors. Antagonists of β-ARs, β-blockers, have been one of the most widely used drugs for the last half century. Increasing evidence from the concomitant use β-blockers in cancer patients and of mechanistic studies in animal models implicates a role of the β2-adrenergic receptor (β2-AR) in tumor progression. As tumors grow, oxygen and nutrient demands surpasses supply. This triggers a process known as the angiogenic switch in which the tumor instructs the tumor microenvironment to promote the formation of new vasculature, thereby increasing supply. An emerging paradigm in angiogenic research considers the newly formed tumor-associated vasculature not merely a passive bystander in the further progression of the tumor, but a crucial metabolic and signaling hub that actively instructs the tumor microenvironment by secretion of angiocrine factors. Considering the importance of β2-AR signaling in cardiovascular (patho-)physiology , its role in the tumor vasculature is currently understudied. Recent findings in our group showed that β2-AR signaling, via the cyclic AMP (cAMP) effector exchange protein directly activated by cAMP-1 (Epac1), plays an important role in angiogenic and pro-tumorigenic processes by means of transcriptional regulation of secreted factors. This project aims to elaborate on the role of vascular β2-AR signaling in the tumor microenvironment.
References:
Cole SW, Nagaraja AS, Lutgendorf SK, et al. Nature Reviews, 2015.
Zahalka HA, Arnal-Estape A, Maryanovich M, et al. Science, 2017.
Garg J, Feng YX, Jansen SR, et al. 2017.

Jansen SR, Poppinga WJP, De Jager WA, et al. Oncotarget, 2016.
Korn C, Augustin HG. Developmental Cell, 2015.
Methods that will be used:
The project uses in vitro pharmacological and cell biological techniques in human primary endothelial cells. Mechanistically, the project focuses on protein-protein interactions and gene transcription regulated by adrenergic signaling and how this affects functional angiogenic cell behaviour and secretion of angiocrine factors that act on the tumor microenvironment. In addition to the in vitro studies, the project involves in vivo angiogenic and tumorigenic studies using endothelial specific Epac1 KO mice.
Cooperation partners:
Prof. Dr. M. Schmidt (Molecular Pharmacology, University of Groningen, The Netherlands), Prof. Dr. F. Lezoualc’h (Institut des Maladies Métaboliques et Cardiovasculaires, Université Toulouse III, France).
Personal qualifications:
Applicants should hold a MSc degree in biology/life sciences or related field with a background in cell biology or biochemistry, and have strong laboratory, analytical and communication skills.
Keywords:
Tumor angiogenesis, chronic stress, cAMP