Ruprecht-Karls-Universität Heidelberg
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Sleeman0117 - Scientist (f/m) / PhD position
Project no:
Sleeman0117

Project leader:

Project supervisor:
Sleeman, Jonathan
Application deadline:
31. Jul 2018
Start of PhD project:
1. Sep 2018

Project description:

Title:
Cell-intrinsic and microenvironmental control of melanoma metastasis and therapy resistance
Summary:
Cancer is the second leading cause of death worldwide and in the vast majority of cases mortality is not due to the primary tumour, but to its metastatic dissemination to distant sites, coupled with the development of therapy resistance. Despite the enormous medical importance of metastasis, its molecular underpinnings remain insufficiently understood and there is an urgent need for novel or improved therapies for metastatic cancer. Tumour metastasis is a highly complex, multistep process that comprises local invasion of cells from the primary tumour, dissemination through the vasculature, colonization of distant sites and growth as secondary tumours. At all steps, cancer cells engage in intricate interactions with diverse cellular and molecular components in their microenvironment, including immune cells, fibroblasts, endothelial cells and the extracellular matrix. Furthermore, accumulating evidence indicates that different types of anti-cancer therapies, while holding the primary tumour in check, can simultaneously induce changes in tumour cells or their microenvironment that promote metastatic spread.
The Department of Microvascular Biology and Pathobiology at the European Center for Angioscience (ECAS), Medical Faculty Mannheim, University of Heidelberg (https://www.umm.uni-heidelberg.de/mikrovaskulaere-biologie-und-pathobiologie/) is inviting applications for a PhD student position (E13/65%) to work on the cell-intrinsic and microenvironmental control of melanoma metastasis and therapy resistance. Our lab has long-standing expertise in the study of the metastatic process, with a particular focus on changes in genes and signalling pathways that regulate tumour metastasis, as well as the role of the crosstalk between cancer cells and their microenvironment in this process. The proposed project, which will be funded within the Research Training Group “Hallmarks of Skin Cancer” (http://www.rtg2099.de/), will be focused on metastatic melanoma, a highly aggressive cancer with poor prognosis. While significant progress in the management of melanoma has been achieved through molecularly targeted drugs and immunotherapy, these treatments only benefit a small fraction of the patients or are thwarted by the acquisition of resistance. A better understanding of the molecular mechanisms mediating metastasis and therapy resistance in melanoma is therefore needed to improve existing treatments. Our previous work has identified genes, including osteopontin, CD44, Ier2 and ID1/3 that play crucial roles in controlling the metastatic potential of tumour cells, as well as their interplay with the tumour microenvironment. The project will aim to dissect the cellular and molecular mechanisms through which these genes interplay to control the capacity of melanoma cells to metastasise and acquire therapy resistance. We will investigate both intrinsic alterations in melanoma cells themselves, as well as changes in their communication with other cell types that are involved in supporting metastatic propensity or drug resistance. Furthermore, we will assess whether these changes lead to the establishment of a prometastatic niche that can support spontaneous or treatment-induced metastasis.
References:
• Thaler, S, Schmidt, M, Robetawag, S, Thiede, G, Schad, A, and Sleeman, JP. Proteasome inhibitors prevent bi-directional HER2/estrogen-receptor cross-talk leading to cell death in endocrine and lapatinib-resistant HER2+/ER+ breast cancer cells. Oncotarget 2017; 8(42):72281-72301.

• Alishekevitz, D, Gingis-Velitski, S, Kaidar-Person, O, Gutter-Kapon, L, Scherer, SD, Raviv, Z, Merquiol, E, Ben-Nun, Y, Miller, V, Rachman-Tzemah, C, Timaner, M, Mumblat, Y, Ilan, N, Loven, D, Hershkovitz, D, Satchi-Fainaro, R, Blum, G, Sleeman, JP, Vlodavsky, I, and Shaked, Y. Macrophage-Induced Lymphangiogenesis and Metastasis following Paclitaxel Chemotherapy Is Regulated by VEGFR3. Cell Rep 2016; 17(5):1344-1356.

• Thaler, S, Thiede, G, Hengstler, JG, Schad, A, Schmidt, M, and Sleeman, JP. The proteasome inhibitor Bortezomib (Velcade) as potential inhibitor of estrogen receptor-positive breast cancer. Int J Cancer 2015; 137(3):686-97.

• Hansen, MT, Forst, B, Cremers, N, Quagliata, L, Ambartsumian, N, Grum-Schwensen, B, Klingelhofer, J, Abdul-Al, A, Herrmann, P, Osterland, M, Stein, U, Nielsen, GH, Scherer, PE, Lukanidin, E, Sleeman, JP*, and Grigorian, M*. A link between inflammation and metastasis: serum amyloid A1 and A3 induce metastasis, and are targets of metastasis-inducing S100A4. Oncogene 2015; 34(4):424-35.

• Schmaus, A, Klusmeier, S, Rothley, M, Dimmler, A, Sipos, B, Faller, G, Thiele, W, Allgayer, H, Hohenberger, P, Post, S, and Sleeman, JP. Accumulation of small hyaluronan oligosaccharides in tumour interstitial fluid correlates with lymphatic invasion and lymph node metastasis. Br J Cancer 2014; 111(3):559-67.

• Thaler, S, Schmidt, M, Schad, A, and Sleeman, JP. RASSF1A inhibits estrogen receptor alpha expression and estrogen-independent signalling: implications for breast cancer development. Oncogene 2012; 31(47):4912-22.

• Sleeman, JP. The metastatic niche and stromal progression. Cancer Metastasis Rev 2012; 31(3-4):429-40.

• Neeb, A, Wallbaum, S, Novac, N, Dukovic-Schulze, S, Scholl, I, Schreiber, C, Schlag, P, Moll, J, Stein, U, and Sleeman, JP. The immediate early gene Ier2 promotes tumor cell motility and metastasis, and predicts poor survival of colorectal cancer patients. Oncogene 2012; 31(33):3796-806.

• Sleeman, JP and Thiery, JP. SnapShot: The epithelial-mesenchymal transition. Cell 2011; 145(1):162 e1.

• Muller, T, Stein, U, Poletti, A, Garzia, L, Rothley, M, Plaumann, D, Thiele, W, Bauer, M, Galasso, A, Schlag, P, Pankratz, M, Zollo, M, and Sleeman, JP. ASAP1 promotes tumor cell motility and invasiveness, stimulates metastasis formation in vivo, and correlates with poor survival in colorectal cancer patients. Oncogene 2010; 29(16):2393-403.

• Dopeso, H, Jiao, HK, Cuesta, AM, Henze, AT, Jurida, L, Kracht, M, Acker-Palmer, A, Garvalov, BK*, and Acker, T*. PHD3 controls lung cancer metastasis and resistance to EGFR inhibitors through TGFα. Cancer Res 2018, in press

• Filatova, A, Seidel, S, Böğürcü, N, Graf, S, Garvalov, BK*, and Acker, T*. Acidosis Acts through HSP90 in a PHD/VHL-Independent Manner to Promote HIF Function and Stem Cell Maintenance in Glioma. Cancer Res 2016; 76(19):5845-5856.

• Garvalov, BK, Foss, F, Henze, AT, Bethani, I, Graf-Hochst, S, Singh, D, Filatova, A, Dopeso, H, Seidel, S, Damm, M, Acker-Palmer, A, and Acker, T. PHD3 regulates EGFR internalization and signalling in tumours. Nature Commun 2014; 5:5577.
* equal contribution
Methods that will be used:
We use a wide spectrum of methods: cloning, cell culture, biochemistry, qRT-PCR, FACS, ELISA, cell-based assays (proliferation, apoptosis, migration, invasion, drug resistance etc.), shRNA/siRNA, transactivation assays, CRISPR/Cas9-mediated silencing, immunohistochemistry, light, epifluorescence and confocal microscopy, image analysis, in vivo animal tumour models
Cooperation partners:
The project will be embedded in the Research Training Group “Hallmarks of Skin Cancer” at the Medical Faculties in Mannheim and Heidelberg, and the German Cancer Research Center (DKFZ, see http://www.rtg2099.de/index.php?page=projects), within which we have several running collaborations, for example with the group of Jochen Utikal. Furthermore, through the Research Training Group we have close cooperation with research teams from the St. John’s Institute of Dermatology, King’s College and Cancer Research UK in London, UK, most notably with the group of Caroline Hill at the Francis Crick Institute. In addition, it is foreseen that the proposed project will involve collaborative work with the lab of Yuval Shaked in Haifa, Israel.
Personal qualifications:
We are looking for enthusiastic and highly motivated applicants, holding, or about to obtain an MSc degree or equivalent. The applicants should possess a strong interest in cancer research, molecular or cell biology, the ability to integrate in an international team and to master new research topics and experimental techniques. Prior experience with cell culture or tumor biology related assays would be an advantage.
Keywords:
cancer, tumor, melanoma, metastasis, invasion, immune cells, cell biology, molecular biology, biochemistry, signalling pathways, microscopy, immunostaining, animal experiments, in vivo experiments, cell-based assays, gene silencing, niche, tumor microenvironment, CRISPR/Cas9, therapy-induced metastasis, Mannheim, Heidelberg, tumour