Cancer Research in Switzerland - Krebsliga Schweiz

Basic biomedical research
Presentation of approved research projects in 2009/2010
Aguet Michel | Role of BCL9/BCL9L in regulating
Wnt-mediated epithelial-mesenchymal transition,
stem cell traits and drug sensitivity in Wnt-activated
human cancers (KFS 02674­08­2010)
Duration: 01.09.2010 – 01.09.2012
A major problem of anti­cancer therapies is tumour relapse,
typically associated with resistance to therapy. Recent
observations suggest that tumour cells with stem
cell­like properties, including notably reduced susceptibility
to common chemotherapeutic agents, are often at the
origin of relapses. Our group recently reported that in a
mouse model of colon cancer, inactivation of BCL9 proteins
suppresses malignancy traits, including stem cell
markers. Our current studies focus on validating the relevance
of these observations for human colon cancer. Specifically,
we will address to what extent inhibition of BCL9
results in attenuated stem cell properties and, most importantly,
whether susceptibility to therapy might thereby
get enhanced. The project should therefore contribute to
establishing BCL9 proteins as targets for a novel therapy
aimed at restoring responsiveness to therapy, and to justifying
the search for small compound BCL9 inhibitors.
Project coordinator
Prof. Dr Michel Aguet
Institut suisse de recherche expérimentale
sur le cancer (ISREC)
NCCR Molecular Oncology
Faculté sciences de la vie
EPF de Lausanne (EPFL)
c/o Département de pathologie
Rue du Bugnon 25
CH­1011 Lausanne
Phone +41 (0)21 314 72 17
michel.aguet@epfl.ch
Basler Konrad | Characterization of the role of histone
binding by the WnT signaling components Pygo2 in
murine models of breast cancer and colon cancer
(KFS 02443­08­2009)
Duration: 01.01.2010 – 01.01.2013
Colon and breast cancer are two of the most common
types of tumours. Dysregulation of the Wnt signalling
cascade is known to underlie their formation. The goal of
this project is to better understand the role played by Pygopus,
a key component of the Wnt signalling pathway. It
is now well accepted that “decoding” the marks found on
histones is an essential part of the process that determines
if expression of a gene is turned on or off. Histones are the
proteins that together with DNA form chromatin – the basis
of our genome. We want to find out if Pygopus can act
as a histone code reader and in this way contributes to the
activation of the genetic program triggered by the Wnt
signal. The insights gained from this study will provide important
insights into how the Wnt signalling cascade contributes
to colon and breast cancer progression and will
open new avenues for the treatment of these cancers.
Project coordinator
Prof. Dr. Konrad Basler
Institut für molekulare Biologie
Universität Zürich
Winterthurerstrasse 190
CH­8057 Zürich
Phone +41 (0)44 635 31 10
basler@molbio.uzh.ch
Becher Burkhard | Cellular and molecular characterization
of IL-12-mediated tumor suppression
(KFS 02441­08­2009)
Duration: 01.05.2010 – 01.05.2012
Immune cells (white blood cells) and their secreted signalling
molecules play a critical role in tumour control and
elimination. In a variety of tumour models, the signalling
molecule interleukin­12 (IL­12) has been shown to repress
tumour growth. Yet, IL­12 injection into the blood of human
patients led to severe adverse effects, and therefore
the development of IL­12 therapies has been halted. To
this day, the molecular and cellular events of IL­12 have
been ill­understood. By defining the mechanistic underpinnings
of how IL­12 works, we shed light on how tumour
cells and immune cells interact in general, and in
particular we will enhance the therapeutic targeting of
malignancies in humans. The tumouricidal activity of IL­12
was widely held to be mediated by two specific subsets of
white blood cells, the natural killer cells and the T lymphocytes.
However, we found that tumour suppression is mediated
independently of these two subsets. Instead, we
were able to demonstrate that IL­12 initiates powerful
local anti­tumour immunity by stimulating a subset of
lymphoid tissue inducer (LTi) cells. These cells seem to alter
the blood vessels within the tumour mass in a way that
allows immune cells to enter the tumour and actively fight
it. Lastly, our findings also demonstrate that IL­12 should
be injected directly into the tumour, thereby limiting the
adverse effects observed after injection into the blood
stream.
Project coordinator
Prof. Dr. Burkhard Becher
Institut für experimentelle Immunologie
Universität Zürich
Y44­J92 (Office), J38/42 (Lab)
Winterthurerstrasse 190
CH­8057 Zürich
Phone +41 (0)44 635 37 03
Fax +41 (0)44 635 68 83
burkhard.becher@neuroimm.uzh.ch
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