Cancer Research in Switzerland - Krebsliga Schweiz

108
Radtke Freddy | The role of Notch and TSLPR signaling
during skin cancer (KLS 02387­02­2009)
Duration: 01.08.2009 – 01.08.2012
Our studies previously showed that loss of Notch signalling
in the skin results in a severe form of inflammation
characterized as atopic dermatitis­like disease (AD, also
known as eczema) due to excessive production of thymic
stromal lymphopoietin (TSLP) by Notch deficient keratinocytes.
TSLP is a secreted cytokine that is deeply implicated
in the pathogenesis of AD and asthma in mouse
and human. We genetically removed the TSLPR to prove
that TSLP signalling is indeed causative of the development
of AD in mice having lost Notch1 and Notch2 in the
skin. These mice were rescued from developing AD; however,
unexpectedly they developed rapidly growing invasive
skin tumours, suggesting that TSLP induces a type of
inflammation that protects pre­malignant lesions from
progressing into tumours. We are currently trying to identify
the cellular and molecular mechanisms of the TSLPmediated
protective inflammation. This should lead to
novel insights into how the immune system tries to fight
against cancer.
Project coordinator
Prof. Dr Freddy Radtke
UPRAD
Institut suisse de recherche expérimentale
sur le cancer (ISREC)
Faculté des sciences de la vie
EPF de Lausanne (EPFL)
Station 19
CH­1015 Lausanne
Phone +41 (0)21 693 07 71
freddy.radtke@epfl.ch
Renner Christoph | Inhibition of tumor growth by
targeting cancer-associated fibroblasts
(KFS 02500­08­2009)
Duration: 01.01.2010 – 01.01.2013
Tumours are composed of tumour cells and a variable degree
of stroma, which includes extra­cellular matrix and fibroblasts.
These tumour fibroblasts support tumour growth
and are characterized by the expression of fibroblast activation
protein (FAP). FAP is a dipeptidyl peptidase known
to cleave extra­cellular matrix (such as collagen), which in
turn leads to enhanced metastasis formation.
We postulate that FAP­blocking molecules can inhibit this
process and stop tumour metastasis. Therefore, we developed
mouse­human cross­reactive FAP­specific antibodies
that downregulate FAP expression, and we will analyze
them in mouse models for their potential to impact on
metastasis formation using new imaging approaches. It is
our final goal to transfer this approach into a clinical setting
for the benefit of patients with advanced malignant
diseases.
Project coordinator
Prof. Dr. Christoph Renner
Klinik und Poliklinik für Onkologie
Medizinbereich Innere Medizin – Onkologie
UniversitätsSpital Zürich
Rämistrasse 100
CH­8091 Zürich
Phone +41 (0)44 255 21 54
christoph.renner@usz.ch
Ruiz i Altaba Ariel | Role and prevalence of hedgehog
signalling in human colorectal cancer
(KFS 02359­02­2009)
Duration: 01.07.2010 – 01.07.2013
Despite huge efforts to improve treatments, metastatic
cancers are still linked to a high rate of mortality. This is
the case for colon cancer, which accounts for about 10 %
of all cancer deaths worldwide, with 25 % of the cases being
out of any surgical therapy because of metastasis. The
transition step from primary tumour to metastatic state
therefore appears to be critical in the development of the
disease and should be considered as a priority target for
future therapies.
In this imperative perspective, we propose to study, in a
collaborative effort involving surgeons of the University
hospital Geneva (HUG), the molecular mechanisms underlying
this metastatic transition step. Our data suggest
that the development of colorectal cancer requires the
activity of the sonic hedgehog (SHH)­Gli pathway, a cell
signalling pathway that we have previously identified as
being deregulated in other cancers, namely, brain, skin
and prostate cancers.
From these data, (SHH)­Gli pathway should play an essential
role in the tight regulation of colon cancer stem
cells from which the tumour arises, as well as in later
phases of the disease, like the metastatic transition. To
validate these working hypotheses, we propose to compare
the tumourigenic properties of colon carcinoma cells
obtained from patient biopsies at different stages of the
disease by using mice xenograft models. These experiments
are expected to bring new insights into the molecular
mechanisms underlying the biology of intestinal tumourigenesis
and should allow for the identification and
development of specific (SHH)­Gli pathway antagonists
to treat colorectal tumours and their cancer stem cells
more efficiently.
Project coordinator
Prof. Dr Ariel Ruiz i Altaba
Département de génétique médicale et
de développement
Faculté de médecine
Université de Genève
1, rue Michel­Servet
CH­1211 Genève 4
Phone +41 (0)22 379 54 46
Fax +41 (0)22 379 59 62
ariel.ruizaltaba@unige.ch