Ruprecht-Karls-Universität Heidelberg
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Augustin0118 - Scientist (f/m) / PhD position
Project no:
Augustin0118

Project leader:

Project supervisor:
Augustin, Hellmut G.
Application deadline:
31. Oct 2018
Start of PhD project:
1. Nov 2018

Project description:

Title:
Molecular and functional analysis of novel anti-metastatic therapy
Summary:
The incidence of cancer has globally been steadily rising in the last decades. While the primary tumor can be cured in most cases, the formation of metastasis represents the leading cause of cancer-associated death. Despite intense efforts to understand the molecular mechanisms of metastasis, our current knowledge in this research field is insufficient to achieve curative long-term results.
We developed novel surgical mouse models of metastasis which allow the spatiotemporal deciphering of the communication between the primary tumor and distant metastases. Using such models, we identified novel tumor cell secreted proteins acting long distance to suppress metastatic growth. These findings support “the concept of selfishness of the primary tumor” as proposed 30 years ago by Judah Folkman according to which the primary tumor is capable of controlling metastatic growth. We have recombinantly produced one of the newly identified candidate molecules formally demonstrating that it can potently suppress metastatic growth (patent filing ongoing; therefore no details in this public announcement). Based on these preliminary data, a PhD position is now to be filled within the DFG Graduate School “Hallmarks of Skin Cancer” (www.rtg2099.de) (joint appointment at Heidelberg University and DKFZ with physical work in DKFZ laboratory). The goals of this project will be (i) to validate the anti-metastatic effect of the protein in other state-of-the-art mouse preclinical tumor models, (ii) to unravel the molecular mechanisms involved in metastasis inhibition mediated by the protein, and (iii) to determine the specificity of the protein-induced anti-metastatic effect by comparing it with proteins of the same gene family.
References:
Bauer C, Abdul Pari AA, Umansky V, Utikal J, Boukamp P, Augustin HG, Goerdt S, Géraud C, Felcht M: T-lymphocyte profiles differ between keratoacanthomas and invasive squamous cell carcinomas of the human skin. Cancer Immunol Immunother 67: 1147-57, 2018.

La Porta S, Roth L, Singhal M, Mogler C, Spegg C, Schieb B, Qu X, Adams RH, Baldwin HS, Savant S, Augustin HG: Endothelial Tie1-mediated angiogenesis and vascular abnormalization promote tumor progression and metastasis. J Clin Invest, 128: 834-845, 2018

Felcht M, Luck R, Schering A, Seidel P, Srivastava K, Hu J, Bartol A, Kienast Y, Vettel C, Loos EK, Kutschera S, Bartels S, Appak S, Besemfelder E, Terhardt D, Chavakis E, Wieland T, Klein C, Thomas M, Uemura A, Goerdt S, Augustin HG: Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling. J Clin Invest, 122: 1991-2005, 2012
Methods that will be used:
Different metastatic mouse models including our newly developed surgical models will be employed. Besides standard methods (qPCR, immunofluorescence, Western blotting, immunoprecipitation, FACS), a broad portfolio of angiogenesis- and metastasis-specific models in vitro, ex vivo and in vivo will be applied (adhesion assays, detection of circulating tumor cells in vivo, invasion assays, transmigration assays, anoikis assays, colony formation assays, sprouting assays, tube formation assays, aortic ring assays, cornea pocket assay).
Cooperation partners:
Prof. Dr. Gergana Dobreva, Prof. Dr. Thomas Wieland, Prof. Dr. Sergij Goerdt
Personal qualifications:
The successful PhD student should be highly motivated and ambitious, be a good team player and be endowed with curiosity and creativity to embark on a challenging high-risk, high-gain project. The candidate will work embedded in a group with 5 postdoctoral fellows and 10 graduate students. Yet, PhD training is not kindergarden. As such, the successful candidate will be tightly supervised by the PI and the Co-PI, but should be capable of independent work and initiative taking. Excellent hands-on laboratory skills are a must. Experience with mouse work would be a plus, but is not mandatory requirement.
Keywords:
cancer, mechanisms of metastasis, therapy, preclinical research