Cancer Research - Europa

Keywords | Genomics | cancer metastasis | gene expression | RNA interference | cell-based assays |
TRANSFOG
Translational and functional
onco-genomics: from cancer-oriented
genomic screenings to new diagnostic
tools and improved cancer treatment
Summary
The TRANSFOG project aims at the systematic identifi cation
and functional characterisation of novel cancer genes
with high potential diagnostic and therapeutic value in
breast, colon and lung cancers. The TRANSFOG partners
will bring together world recognised competences and
resources to reach the following, integrated research
objectives:
• identifi cation of novel candidate cancer genes through
cancer- oriented genomic screenings, using tumour tissues
as well as cellular and animal models, to generate
a prioritised panel of genes involved in breast, colon and
lung cancer progression and metastasis;
• full-length cDNA collection of the identifi ed candidates,
and setup of systems for high-throughput in vitro and
in vivo gene delivery;
• collection of retroviral expression plasmids encoding
small interfering RNAs, for systematic downregulation
of candidate genes;
• identifi cation of new molecular targets for cancer
therapy;
• proteomic analysis of signal transduction and proteinprotein
interaction, focussed on the candidate cancer
genes, which will allow better dissection of aberrant
cancer signalling pathways;
• validation of the diagnostic potential of the identifi ed
cancer genes towards the clinical use of diagnostic
molecular signatures;
• generation of a shared informatics platform for data
handling and gene functional annotation. This will signifi
cantly increase European competitiveness, provide
a huge structuring eff ect on the ERA in the fi eld of functional
oncogenomics, and depict several new molecular
targets for anticancer drug discovery and advanced
cancer diagnosis.
Problem
While extensive analysis over the last two decades led to
a deep insight into the control of cell proliferation and survival,
and their alterations during cancer onset, much still remains
EARLY DETECTION, DIAGNOSIS AND PROGNOSIS
to be clarifi ed about the genetic lesions and alterations of
cell signalling that lead to aberrant activation of invasive
growth, cancer progression and metastasis. It should be also
noted that, after completion of genome-sequencing projects
for many organisms, genes with an unknown function represent
over 70 % of all genes. This suggests that current
comprehension of most biological and pathological processes
is still very incomplete, particularly in the case of cancer progression,
where systematic exploration of gene function is
likely to yield a huge amount of information in the next few
years. In this perspective, a crucial issue is the development of
technologies for high-throughput functional analysis. Development
of large-scale functional screens focused on cancer
progression will require a coordinated approach involving
complementary competences and establishment of dedicated
facilities, for which TRANSFOG intends to provide an optimal
organisational and fi nancial framework.
Aim
The fi ve key objectives of the TRANSFOG project are:
• Identifi cation of novel cancer-related genes of high clinicaldiagnostic
potential, with a specifi c focus on progression
and metastasis of colon, breast and lung cancers. This
will be achieved mainly through extensive gene expression
profi ling of tumour/metastasis samples and of
cell-based models of cancer progression. To extend the
exploration range, diff erential proteomics and epigenetic
analysis are also planned. The foreseen outcome is
a ranked list of novel candidate cancer genes emerging
from integration of the screening results, which will
undergo functional characterisation and/or diagnostic
validation.
• Set-up of technologies for systematic cancer gene functional
analysis and for identifi cation of new molecular
targets. Gene functional analysis will be enabled by
assembling collections of full-length cDNAs and of short
interfering RNAs (siRNAs), subcloned in expression plasmids
to assess the consequences of gene gain- or
loss-of-function in cell-based and preclinical models.
• Systematic exploration of oncogenic/antioncogenic signalling
pathways, epigenetic regulatory mechanisms.
Taking advantage of the FL-cDNA and siRNA collections
made available by the project, cellbased experimental
systems to study protein-protein interaction, reporter
gene expression and epigenetic modifi cations will be
exploited for systematic analysis of the candidate genes.
This will result in datasets of protein-protein interaction,
transcriptional and epigenetic regulation allowing a comprehensive
overview of the alterations in signalling and
regulatory networks involved in cancer progression.
157