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allied
academies
Journal of Gastroenterology and Digestive Diseases | Volume 3
May 25-26, 2018 | New York, USA
World Liver Conference 2018
A
berrant receptor tyrosine kinase (RTK) signaling is
essential during liver cancer evolution and resistance to
therapies. Using mouse genetics, we recently demonstrated
that a subtle increase of wild-type RTK levels leads to
cancer in sensitive tissues, illustrating how the shift towards
cancerogenesis can stem from a slight perturbation of
signaling dosage. In particular, when the Met RTK is slightly
enhanced in liver, mice (namely Alb-R26
Met
) spontaneously
develop hepatocellular carcinoma (HCC), which belong to
the so called “proliferative progenitors” subclass (
Fan et al.
Hepatology 2017 Nov;66(5):1644-1661
). To uncover new
genes that cooperate with RTKs during tumor initiation, we
combined the clinically-relevant
Alb-R26
Met
mice with the
Sleeping Beauty (SB)
transposon (
T2/ONC)
mutagenesis
system. Whereas neither
Alb-R26
Met
nor T2/onc-Alb-R26SB/+
mice developed tumors at 30 weeks of age,
T2/onc-Alb-
R26SB/
Met
mice (with enhanced Met in liver in addition to
active SB-driven mutagenesis) developed multiple liver
tumors, each carrying distinct genomic insertions. Analysis
of 251 independent tumors led to the identification of 285
putative cancer-related genes: some of them correspond to
knownproto-oncogenesortumorsuppressors,thusvalidating
the overall strategy we employed for cancer gene discovery;
other genes have not previously linked to cancer. Integrative
analysis with human data revealed that a large proportion of
identified genes are also altered in HCC patients. Moreover,
we compared our screen outcomes with those performed
in other tumor-sensitizing contexts and found 71 genes that
emerged specifically in our RTK-sensitized background.
In
vivo
assays established the functional relevance of several
new putative tumor suppressors. Overall, our screen strategy
identifies new functional mechanisms destabilizing liver
homeostasis and illustrates how a subtle increase in wild-
type RTK levels provides a permissive context for several
types of cooperative mechanisms leading to liver tumor
initiation.
A subtle increase in wild-type RTK levels provides a permissive context allowing multiple signaling
cooperators to initiate liver cancer
Y Fan
1
, S K Bazai
1
, F Daian
1
, S Richelme
1
, M Arechederra
1
, A Yim
1
, R Dono
1
, B Habermann
1
, D Largaespada
2
and
F Maina
1
1
Aix-Marseille University-CNRS-Developmental Biology Institute of Marseille (IBDM), Marseille (France)
2
Masonic Cancer Center, University of Minnesota, USA