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64 Beermann Friedrich | In vivo screening of candidate genes in melanoma (OCS 01500022004) Melanoma is a malignant tumour arising from melanocytes, which are pigment cells derived from the neural crest. In the mouse, melanoma does not occur spontaneously, and, thus transgenic mouse models are used to address genetic changes leading to melanomagenesis or to study melanocyte development. In this project we wanted to address the role of candidate genes, first in melanocyte biology and homeostasis and later in melanoma development. We used transgenic mouse models to analyze the Notch signalling pathway in normal melanocyte biology, and to address the lack of the oncogene cMyc during melanocyte development. Moreover, we addressed the relevance of bcatenin directly in a mouse model of melanoma. Notch signalling: Notch has been shown to be expressed in mouse melanocytes and human melanoma. Using transgenic mouse models, we showed that deletion of Notch signalling in the melanocyte lineage induces precocious hair greying, the intensity of which depends on the number of deleted alleles of Notch1 and Notch2. Further histological analysis showed that this is due to a loss of melanocyte precursors as well as melanocyte stem cells after birth. This confirms that Notch signalling affects hair pigmentation and melanoblast population in a gene dosagedependent manner. When we overexpressed Notch in melanocytes, we could not prevent normal hair greying or induce melanoma tumours, indicating that Notch signalling by itself is not sufficient for melanoma formation. The c-Myc oncogene: cMyc is expressed in many tumours, including melanoma. To understand its role in melanocytes, we removed it specifically in a transgenic mouse model. Removal of cMyc leads to a hair greying phenotype that is not due to an effect in stem cells. In contrast to Notch, the phenotype is caused by a problem in proliferation during midgestation. These results indicated that cMyc is an important player in melanocyte biology, and we plan to address its role in a mouse model of melanoma. b-catenin: This protein is part of the Wnt signalling pathway and has been reported to be mislocalized in human melanoma. In collaboration with Lionel Larue’s group (Orsay, France), we used mice that express a stable form of bcatenin that leads to repression of the tumour suppressor p16 by binding to its promoter. Double transgenic animals expressing both an activated NRas oncogene and an activated bcatenin had a high incidence of melanoma with a short latency period. Histopathological analysis suggested that most melanomas arose from melanocytes located in the hair follicles. The results thus reveal that synergy between the Wnt and mitogenactivated protein (MAP) kinase pathways (due to activated NRas) may represent an important mechanism underpinning the genesis of melanoma. Project coordinator Dr Friedrich Beermann Institut suisse de recherche expérimentale sur le cancer (ISREC) Faculté Sciences de la vie EPF de Lausanne (EPFL) Station 19, Bâtiment SV CH1015 Lausanne Phone +41 (0)21 693 07 27 friedrich.beermann@epfl.ch BentiresAlj Mohamed | Role of GAB2/SHP2 and 11q13 amplification in breast cancer (OCS 01922082006) Each year 1.1 million new cases of breast cancer will occur among women worldwide, and 400,000 women will die of this disease. Although progress has been made in understanding breast tumour biology, most of the relevant molecules and pathways remain undefined. Their delineation is critical to a rational approach to breast cancer therapy. This project focuses on the roles of the signalling proteins GAB2/SHP2 (part 1) and on amplification of the chromosomal region 11q13 (part 2) in breast cancer. To address these questions, we used a combination of 3D cultures and xenograft models. In the first part, we found that inhibition of SHP2 dramatically reduces proliferation and reverses the invasiveness of transformed breast cells grown in 3D cultures. Moreover, SHP2 knockdown after tumour formation blocks tumour progression. In the second part, we found two highly defined genomic regions of 11q13 amplification in breast tumours and identified 8 genes that are coamplified and cooverexpressed in these tumours. Taken together, our studies revealed potential therapeutic targets for the treatment of breast cancer. Project coordinator Dr. Mohamed BentiresAlj Friedrich Miescher Institut für biomedizinische Forschung (FMI) Maulbeerstrasse 66 CH4058 Basel Phone +41 (0)61 697 40 48 Fax +41 (0)61 697 39 76 bentires@fmi.ch Brunner Thomas | Characterization and role of extra-adrenal glucocorticoid synthesis in colorectal cancer (OCS 02025022007) Glucocorticoids are important immunoregulatory steroids, produced mainly in the adrenal glands. However, our past research demonstrated that the epithelial cells of the intestinal crypts are capable of producing glucocorticoids in response to immune cell activation and that intestinal glucocorticoids contribute to the control of local immune responses. The aim of this study was to investigate whether colon carcinoma can produce glucocorticoids, how tumour glucocorticoid synthesis is regulated and whether tumourderived glucocorticoids actively suppress immune cells. The expression and induction of transcription factors and enzymes involved in the synthesis of cortisol from cholesterol in colon carcinoma cell lines as well as primary tumours was investigated using quantitative PCR and luciferase reporter assays. The role of the transcription factor LRH1 (liver receptor homolog1) in the regulation of tumour glucocorticoid synthesis was assessed using overexpression and RNA interference. Cortisol production was measured using radioimmunoassay, thin layer chromatog
aphy and bioassay. The suppressive and apoptosisinducing activity of tumour glucocorticoids was assessed on activated T cells and thymocytes. Our study could show that colon carcinoma cell lines as well as primary tumours express all enzymes required for synthesis of glucocorticoids and secrete bioactive cortisol. Similar to primary intestinal epithelial cells, LRH1 was found to play a critical role in the regulation of tumour glucocorticoid synthesis and to be overexpressed in many primary colon carcinomas. Cortisol produced by colon carcinomas potently suppressed T cell activation and induced apoptosis in glucocorticoidsensitive thymocytes. This is the first demonstration of glucocorticoid synthesis in tumours not derived from steroidogenic organs, and it suggests that tumourderived glucocorticoids could play an important role in the regulation of antitumour immune responses. Whereas the glucocorticoid synthesis in primary epithelial cells contributes to intestinal immune homeostasis and prevents intestinal inflammation, glucocorticoid synthesis in colon carcinoma cells may represent a tumourpromoting factor. Project coordinator Prof. Dr. Thomas Brunner Lehrstuhl für biochemische Pharmakologie Fachbereich Biologie Universität Konstanz D78457 Konstanz Deutschland Phone +49 (0)7531 88 53 70 thomas.brunner@unikonstanz.de
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Cancer Research in Switzerland A pu
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Cancer Research in Switzerland
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Basic biomedical research 55 Cancer
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policy work and was in charge of de
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The main focus of the research fund
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gramme research funding decreased b
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Table 2 Distribution of funds for i
Page 15 and 16: Funding patient-centred research Pa
Page 17 and 18: value was not clearly discernible.
Page 19 and 20: New organization of the Foundation
Page 21 and 22: The board of the Foundation Cancer
Page 23 and 24: The president of the Scientific Com
Page 25 and 26: Prof. Martin Pruschy, PhD Departmen
Page 27 and 28: Swartz wants to find out how tumour
Page 29 and 30: The scientific and medical research
Page 31 and 32: 3. The original order/sequence of t
Page 33 and 34: As a federation, the Cancer League
Page 35 and 36: List of funded research projects, i
Page 37 and 38: Zippelius Alfred | 2009: CHF 100,00
Page 39 and 40: Kridel Robert | 2010: CHF 100,000.-
Page 41 and 42: Thurgau Cancer League Biotechnologi
Page 43 and 44: Weller Michael | 2010: CHF 65,828.-
Page 45 and 46: manageable funding of individual pr
Page 47 and 48: enhances breast cancer cell motilit
Page 49 and 50: Rüegg Curzio et al. | Tumor-mediat
Page 51 and 52: International Clinical Cancer Resea
Page 53 and 54: in PHIV were shown for Hodgkin’s
Page 55: Zucca Emanuele et al. | Internation
Page 58 and 59: 56 “hierarchical structure” of
Page 60 and 61: 58 the attempt should be made to st
Page 62 and 63: 60 Gönczy Pierre | KLS 0202402
Page 64 and 65: 62 Romero Pedro | OCS 020110220
Page 68 and 69: 66 Christofori Gerhard | Podoplanin
Page 70 and 71: 68 Frei Christian | The function of
Page 72 and 73: 70 cell, this novel mechanism serve
Page 74 and 75: 72 Results The induction of viral p
Page 76 and 77: 74 Hübscher Ulrich | Repair of oxi
Page 78 and 79: 76 Methods and experimental approac
Page 80 and 81: 78 of cMyc and/or NMyc and demo
Page 82 and 83: 80 In summary, this work improves o
Page 84 and 85: 82 Pruschy Martin | Microtubule int
Page 86 and 87: 84 Renner Christoph | Selective inh
Page 88 and 89: 86 Goal Here we build on these obse
Page 90 and 91: 88 by TDG prevents efficient downst
Page 92 and 93: 90 To address these questions, we a
Page 94 and 95: 92 Translational relevance The resu
Page 96 and 97: 94 Grünberg Jürgen | KFS 025460
Page 98 and 99: 96 Tschan Mario P. | KFS 0248608
Page 100 and 101: 98 Boyman Onur | Preclinical testin
Page 102 and 103: 100 Constam Daniel | Role of activi
Page 104 and 105: 102 this study we will examine the
Page 106 and 107: 104 Janscak Pavel | Study of the ro
Page 108 and 109: 106 Müller Anne | The molecular pa
Page 110 and 111: 108 Radtke Freddy | The role of Not
Page 112 and 113: 110 Schär Primo | DNA repair, epig
Page 114 and 115: 112 In this project we will investi
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114
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116 and Research). Other financial
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118 be totally unaffordable for aca
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120 Clinical research List of compl
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122 Hunger Robert E. | OCS 02262-08
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124 Clinical research Presentation
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126 Benhattar Jean | Identification
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128 Bertoni Francesco | Genome-wide
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130 Interpretation ESA treatment in
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132 Our results could pave the way
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134 new drugs that specifically tar
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136 slides in two different concent
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138 Conclusions A strong network of
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140 tions introduced to ARE motifs
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142 Müller Beatrice U. | The maste
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144 A novel method was developed fo
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146 (SAKK 35-98) the Swiss Group fo
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148 Timmermann Beate | Prospective
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150 recurrence of the disease, we a
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152 Zucca Emanuele | A prospective
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154 Heinimann Karl | KFS 02489-08-2
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156 Riggi Nicolò | BIL KFS 02717-0
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158 activity at the single cell lev
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160 Our research projects aim at un
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162 Körner Meike | In vitro evalua
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164 Nadal David | Is endemic Burkit
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166 (> 50.000/patient). For their a
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168 Zeller Rolf | Functional analys
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170
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172 area of health services researc
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174 The financing of palliative car
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176 National Strategy for Palliativ
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178 Psychosocial research List of c
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180 Within the patient group, level
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182 Further, the results suggest th
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184 It is in this context that the
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186 Recommendation Female spouses o
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188 Psychosocial research Presentat
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190 rates communication skills rema
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Epidemiological research Epidemiolo
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data from cancer registries. In the
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The importance of cancer registries
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Ess Silvia | Patterns of care and s
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Epidemiological research List of ap
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Impact This work will serve as the
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Thürlimann Beat | Management of br
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