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JRG IX: Dr. Jay Gopalakrishnan

·       Mechanisms and regulation of centrosome biogenesis

With a group of young scientists, we are fascinated in studying the basic principles of centrosome biogenesis and functions. A macromolecular eukaryotic structure that is fundamentally important for many cellular functions.

To understand the basic principles of centrosome biogenesis, we focus on the following topics using an ideal model organism, fruit fly. We develop a robust system using fruit fly where genetic and biochemical strategies are applied together to study centrosome biogenesis both in vivo and in vitro.

1.       Identification and analysis of factors that trigger the centriole initiation and organization.

2.       Studies on the mechanisms by which PCM is assembled and recruited to developing centrosomes.

3.       Analysis of the molecular switches and regulatory mechanisms that sense the formation and diffusion of centrosomal protein complexes in the cytoplasm.

4.       Studies on the differential role of centrosomes as Microtubule Organizing Centers (MTOC) and signaling hub in cellular processes.

5.       Identification of the centrosome activation and inactivation mechanisms.

6.       Translating and analyzing the results obtained from flies to higher model organisms. 

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A1: Prof. Dr. Reinhard Büttner / PD Dr. Margarete Odenthal

· The multifaceted function of histone methylases and demethylases in lung cancer SFB 832

Histone modifiying corepressor and activator complexes are central players of tumor related gene regulation, leading to cancer specific cell signaling that may affect future therapeutic approaches. In particular, overexpression and high activity of the histone lysine-specific demethylase LSD1 is a central feature in lung cancer progression validated as an oncogenic driver in a transgenic mouse model.
Therefore, we aim to study LSD1-driven oncogenic signal pathways by chromatin immunoprecipitation (CHIP) linked to next generation sequencing of LSD1 targeted gene promoters in cell systems and transgenic mouse models that harbor lung cancer specific mutations.

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A2: Prof. Dr. Matthias Hammerschmidt

Identification of small molecules blocking matriptase-dependent morphogenesis and carcinogenesis in zebrafish and mouse, and characterization of the relevant target proteins

· Identification of small molecules blocking matriptase-dependent morphogenesis and carcinogenesis in zebrafish and mouse, and characterization of the relevant target proteins

The cell surface-associated type II transmembrane protease matriptase 1 (MT-SP1, ST14) is implicated in the growth and invasion of multiple epithelial tumors, including ovarian, prostate, colorectal and skin cancer (Uhland, 2006; List, 2009). Several substrates of matriptase have been described, ranging from growth factors and their receptors to structural ECM proteins. However, no systematic searchers for matriptase substrates have been carried out as yet.

 

A3: Dr. Sandra Iden:

· Intrinsic and extrinsic functions of polarity proteins in melanoma formation and progression SFB 829, 832

Cell polarization is crucial for a variety of biological processes such as oriented cell division, adhesion or migration, and is regulated by conserved polarity proteins of the Scribble, Crumbs, and Par complexes. How cell morphology is coordinated in the context of tumor formation and progression is an intriguing question in cancer cell biology. In the proposed project we will now ask how loss of polarity protein (Par3) function affects the formation and progression of metastatic melanoma, a frequent non-epithelial skin cancer characterized by high lethality and poor treatment options and thus of high medical and economic impact for society.

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A4: Dr. Roman-Ulrich Müller / Dr. Francesca Fabretti

· Characterizing the molecular functions of the tumor suppressor protein Folliculin using the model organism Caenorhabditis elegans

Birt-Hogg-Dubé syndrome is an autosomal dominant multitumor syndrome that is characterized by the triad of benign skin tumors, recurrent pneumothoraces and renal cyst and tumor formation. Germline mutations in Folliculin are the underlying cause of this syndrome.

In a recent study we have been able to introduce the nematode C. elegans as a novel model organism for studying the biology of BHD syndrome by characterizing a knockout strain of flcn-1, the worm homologue of Folliculin[2]. Doing so we could confirm a previous report on a possible role of Folliculin in hypoxia-inducible factor signaling[3].
We will now continue this project using both cell culture and particularly the nematode model to examine the signaling pathways Folliculin is involved in more closely and to address a possible ciliary function of this tumor suppressor protein.

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A5: Dr. Catherin Niemann

· Molecular function of Lef1 mutations (E45K/S61P and DNLef1) in epithelial tissues and cancer, SFB 572, 829

The overall goal is to understand cellular and molecular mechanisms that control adult epithelial stem cells, both under homeostatic and pathological conditions. Our research is focussing on epithelial stem cells of the skin that generate a diverse set of differentiated cell lineages, including keratinocytes of the interfollicular epidermis, hair follicles and sebaceous glands. We are investigating regulatory pathways of stem cell activation and lineage selection to explore their therapeutic value and we aim to identify the underlying molecular mechanisms of stem and progenitor cell activation in the process of epidermal tumour formation.

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A6: Prof. Dr. Manolis Pasparakis

· Stem cell-specific role of NF-kB signalling in cancer

NF-κB has a critical role in cancer development by acting in initiated and/or transformed cells to promote tumour cell survival and growth. In addition, NF-kB activation in immune and stromal cells also contributes to tumour development by orchestrating the formation of a tumour-promoting microenvironment.
In this project, we aim to address the stem cell specific role of NF-kB in cancer by generating and applying novel genetic models allowing the stem cell specific manipulation of NF-kB signalling.

 

A7: Dr. Martin Peifer

· Systematic identification of significantly mutated gene groups in cancer genomes by co-expression patterns

Whole-genome sequencing provides a portrait of all relevant genomic alterations in cancer genomes, whereas transcriptome sequencing yields a complete characterization of gene expression. Genomic alterations can be distinguished between random passenger mutations and drivers, where only driver mutations are contributing to pathogenesis. Their identification is therefore necessary to translate results from cancer genome analysis into new therapeutic strategies. However, single gene approaches are often limited by a lack of statistical power to detect rare events. To overcome this limitation, a systematic integration of transcriptome and genome-sequencing data may reveal groupings of rare driver events along paths of dysregulated genes. We propose a data-driven approach to, first, reduce complexity of the gene expression data and in a subsequent step, to map genomic alterations to resulting transcriptome profiles with the aim to identify connected groups of mutated and co-expressed genes

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A8: Prof. Dr. Hans-Christian Reinhardt / Prof. Dr. Björn Schumacher

· Differential modulation of the p53 network in cancer therapy

· Genome instability contributes to cancer development, while radiation and chemotherapy routinely rely on inflicting genotoxic stress to trigger apoptotic demise of cancer cells. DNA damage response (DDR) pathways that are mediated through the tumor suppressor p53 play an important role in the cell intrinsic responses to genome instability, including a transient cell cycle arrest, senescence and apoptosis.
Also non-cell autonomous interactions of the p53 network with the innate immune system and the systemic adjustments during the aging process comprise important aspects of p53-mediated tumor suppression. The network of p53 target genes thus functions as an important regulator of cancer prevention, tumor therapy responses and also the physiological adjustments during aging.
To gain a better understanding of the mechanisms of the differential outcomes of p53 activity, we aim to investigate by in vitro and in vivo live imaging of key effectors of the p53-mediated DDR.

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A9: Prof. Dr. Rita Schmutzler / PD Dr. Eric Hahnen

· Identification of new disease-causing and -modifying genes for familial breast and ovarian cancer

Due to the multifaceted architecture of breast and ovarian cancer, our vision is to identify and validate novel genetic and non-genetic risk factors and their interactions, followed by the implementation of both into personalised risk prediction and cancer prevention programmes. To reach these goals we are closely cooperating with international study groups and coordinate the German Consortium for Hereditary Breast- and Ovarian Cancer, which raised international attention due to the identification of new disease and disease-modifying genes.
The aim of our CMMC project is to identify novel causative genes by employing a family-based next-generation exome sequencing (NGES) approach, followed by national and international gene validation studies, functional analyses and implementation of the new findings into individual risk assessment.

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