A European Integrated Project supported through the Sixth Framework Programme

for Research and Technological Development.

Context
Since 1998, a new concept has emerged, based on the
notion that a receptor unoccupied by its ligand is not
necessarily inactive. Rather, such a receptor can mediate two
different signalling pathways, depending on whether or not
it is bound by its ligand. In the absence of ligand, signalling
leads to an active process that results in cell death through
apoptosis. The survival of a cell expressing such a receptor
can therefore be seen as dependent on the presence of
the ligand, hence the concept of “dependence receptors”
(DR). The fact that the different DRs trigger apoptosis in
the absence of ligand suggests that they may all act as
regulators of tumorigenesis. In addition, expression of DRs
is lost or decreased in many tumours, suggesting that they
act as tumour suppressors and that their loss represents a
selective advantage for tumoral cells. HERMIONE proposes
DR
Ligand
Proliferation
Signal = survival
Tumor death
DRs regulate tumor initiation and progression
Objectives
Dependence Receptors (DR) constitute a newly described
family of functionally-related receptors. The mechanisms that
trigger cell death in the absence of ligand are largely unknown,
but typically require cleavage by specific caspases. Recent
reviews have been published to propose the mechanisms
for cell death induction by these receptors, as well as their
potential function in the regulation of tumorigenesis.
HERMIONE focuses attention on four DRs (DCC, UNC5H,
KAI1 and RET) and proposes that all these receptors act
that unravelling the link between different DRs (DCC, UNC5H,
KAI1 and RET), downstream molecules and apoptosis will
lead to the identification of new potential targets for anti-
cancer drugs. HERMIONE will provide a better understanding
of the signalling pathways acting downstream of DRs,
observe the association of mutations with the onset and
progression of tumours (grade, prognosis) and generate
murine models in which the apoptotic signalling of the DR is
turned off to study the Implication of DRs in tumorigenesis in
vivo. Through this, HERMIONE will generate knowledge on
DR signalling pathways involved in the apoptosis of tumoral
cells (colorectal, breast, thyroid and prostate cancers) and
use the general concept of DRs to discover and perform
pre-clinical testing of novel anti-cancer drugs.
Metastasis
Signal = survival
Tumor death
as tumour suppressors via their proapoptotic activity and
that unravelling the link between different DRs, downstream
molecules and apoptosis will lead to the identification of new
potential targets for anti-cancer drugs.
Thus, the global aim of HERMIONE is to generate knowledge
on DR signalling pathways involved in the apoptosis of tumoral
cells (colorectal, breast, thyroid and prostate cancers) and
use the general concept of dependence receptors to discover
and perform pre-clinical testing of novel anti-cancer drugs.
Workplan

WP1
Signalling by dependence receptors

Exploitation & dissemination

Management
WP2 WP3

WP5

WP6
Dependence receptors
Murine models
and their ligands
of tumoral development
in human tumors

WP4
Dependence receptors
as therapeutic targets

Results
Over the 36 months of the project, Hermione has extended
the knowledge on how DRs trigger apoptosis and highlighted
ways to translate this knowledge in term of therapies. Specific
analysis of putative interactors (observed by two-hybrid and
split-ubiquitin assay) or effectors (observed by siRNA screen)
has been done to show their implication in death signalling via
dependence receptor pathways. Some of these interactors
(for example AIP from the RET pathway) have in turn been
shown to be implicated during tumour progression in the
human pathology. Interestingly mutations in AIP have been
identified in pituitary tumors. Finally the proof of concept that
targeting the ligand of DRs (done so far on the ligand netrin-1)
can induce tumor growth inhibition in different mice models
has been done. A screen for small compound that inhibit
netrin-1/receptors interaction has been done on a small library
and may give the hint to innovative drug compounds.

Inhibition of the lung metastasis

formation in mice by disruption
of the netrin-1 autocrine loop by
siRNA (up) or by the candidate drug
DCC-5Fbn (down) after 9 days
of treatment (measure with the
NightOwLB II system).
Consortium
The HERMIONE consortium gathers leading academics in the fields of DR, death signalling and
cancer genetics, a biotechnology SME specialised in the production of reagents and a consulting
firm specialised in communication and dissemination activities/ project management.

Acknowledgment
The HERMIONE project is supported by the European
Commission through the Sixth Research Framework
Programme for Research and Technological Development
(FP6, 2002-2006).
The HERMIONE project addresses the thematic area “Life
sciences, genomics and biotechnology for health”. The project
started on 1st November 2007 and will last 36 months.

Contact:
Project Coordinator: Dr Patrick Mehlen
Apoptosis Cancer and Development Laboratory
CNRS UMR 5238 Centre Léon Bérard Lyon, FRANCE
mehlen@lyon.fnclcc.fr

With the support of ALMA Consulting Group

www.hermione-project.eu Dr. Raffaella Catena: rcatena@almacg.com