Cancer Research in Switzerland - Krebsliga Schweiz

100
Constam Daniel | Role of activin signalling in
melanoma metastasis (KFS 02487­08­2009)
Duration: 01.02.2010 – 01.02.2013
Malignant melanomas arise from the transformation of
pigment cells. These aggressive tumours are characterized
by a poor prognosis, since the available treatments at best
afford transient improvement. Cell proliferation and the
synthesis of UV­absorbing melanin in pigment cells are
governed by specific nuclear proteins that are themselves
regulated by extracellular factors. Thus, other skin cells
can supply themselves with pigment according to their
needs. However, in the course of tumour progression,
melanomas frequently “learn” how to produce these or
similar signals by themselves. One of these signalling molecules
is activin. To elucidate the role of activin during
melanoma growth and metastasis, we are comparing the
behaviour and tumourigenic potential of cell lines from a
human melanoma that spontaneously progressed from an
activin­negative to an activin­producing state, and we are
manipulating activin signalling to determine which of its
target genes may influence tumour progression.
Project coordinator
Prof. Dr Daniel Constam
Institut suisse de recherche expérimentale
sur le cancer (ISREC)
Faculté des sciences de la vie
EPF de Lausanne (EPFL)
SV­ISREC­UPCDA SV 2837
Bâtiment SV, Station 19
Chemin des Boveresses 155
CH­1015 Lausanne
Phone +41 (0)21 693 07 41
daniel.constam@epfl.ch
Dotto Gian­Paolo | Tumor suppressing function of
calcineurin/NFAT in keratinocytes
(OCS 02361­02.2009)
Duration: 1.10.2009 – 30.09.2012
Squamous cell carcinomas have a very high incidence in
the human population, encompassing skin, oral and esophageal
cancer, squamous (bronchial) lung carcinoma
and carcinoma of the cervix and other parts of the urogenital
system. A distinguishing feature of these tumours
is their high level of heterogeneity, with self­renewing cell
populations admixed with cells at different stages of differentiation.
Important mechanisms involved in restraining cells with
oncogenic potential are the induction of cellular senescence
and/or differentiation. Counteracting these failsafe
mechanisms are conditions of perturbed tissue homeostasis,
such as those resulting from wound healing or inflammation.
The immune system is also thought to play a major
role in preventing or limiting tumour spread. Calcineurin
is the only known serine/threonine phosphatase under
calcium/calmodulin control and key regulator of the immune
system. In the clinics, treatment of patients with
calcineurin­inhibitory drugs like cyclosporin A and FK506
to prevent graft rejection dramatically increases the risk of
cutaneous squamous cell carcinoma (SCC), which are a
major cause of death after organ transplants. The main
goal of this project is to test whether, in parallel with its
function in the immune system, calcineurin/NFAT signalling
plays an intrinsic role in keratinocyte/SCC tumour
suppression. Clinically, we will validate the findings by
analysis of a large cohort of cutaneous SCCs at various
stages of malignancy in the general patient population
versus patients under treatment with calcineurin inhibitors.
Project coordinator
Prof. Dr Gian­Paolo Dotto
Département de biochimie
Faculté de biologie et de médecine
Université de Lausanne
Chemin de Boveresses 155
CH­1066 Epalinges
Phone +41 (0)21 692 57 20
Fax +41 (0)21 692 57 05
paolo.dotto@unil.ch
Dufour Jean­François | Hepatocarcinogenic roles
of mTOR, raptor and rapamycins in absence of
Pten (KFS 02541­02­201)
Duration: 01.08.2010 – 01.08.2013
Hepatocellular carcinoma is a tumour of worldwide significance:
a) it is the fifth most common tumour; b) it is the
third leading cause of cancer­related death; and c) its incidence
has doubled in the last 2 decades. The PI(3)K/
AKT/mTOR pathway is activated in about half of the cases
of hepatocellular carcinoma. mTOR forms two enzymatic
complexes with other proteins: The mTOR complex 1 is
downstream of AKT and regulates protein synthesis; the
mTOR complex 2 is upstream of AKT and activates AKT.
Clinical trials testing drugs inhibiting the mTOR complex 1
as antitumoural agents are underway. Concerns exist:
1) that inhibition of mTOR in a liver with down­regulated
PTEN may lead to hepatocyte attrition and recruitment of
progenitor cells; and 2) that rapamycins have effects additional
to the well characterized inhibition of mTORC1.
We will compare mice with genetic ablation of the mTOR
complex 1 (lacking raptor) with mice without mTOR as
well as with mice treated with an mTOR inhibitor. A better
appreciation for the elusive role of these 2 complexes
in the development of hepatocellular carcinoma will be
partly elucidated by this research.
Project coordinator
Prof. Dr. Jean­François Dufour
Institut für klinische Pharmakologie
Universität Bern
Murtenstrasse 35
CH­3010 Bern
Phone +41 (0)31 632 09 00
Fax +41 (0)31 632 49 97
jf.dufour@ikp.unibe.ch