Notch Signaling in Stem Cells and Tumors
U934/UMR3215 – Genetics and Developmental Biology
Silvia Fre
Chef d'équipe
[email protected]
Tel: +33 1 56 24 69 36
How cells coordinate their action to build epithelial
tissues during development, tissue morphogenesis and
remodeling is a fundamental question that remains only
superficially understood. We study the signals
controlling adult stem cell homeostasis, with the final
goal of gaining mechanistic insights into organ
morphogenesis, and also into the critical steps of
malignant transformation. Our research is particularly
focused on three epithelial tissues, the intestine, the
mammary gland and the prostate, and in tumors derived
from them. In these epithelia, the Notch signaling
pathway has a central role in tissue development and
stem cell homeostasis. Our studies will yield insights into
the molecular control of adult stem cell maintenance, as
well as into the mechanisms by which Notch signaling
controls the fate of specific cell populations in both
normal and pathological conditions.
Our goal
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 1
Notch Signaling in Stem Cells and Tumors
U934/UMR3215 – Genetics and Developmental Biology
Figure 1: A section of a mouse colon
showing crypts derived from Notchexpressing stem cells in green and
mucus-producing secretory cells in red.
Blue illustrates nuclei.
A deep comprehension of the cellular hierarchies
originating from tissue-specific stem cells and the
factors that regulate their behaviour will have a major
impact in exploring therapeutic avenues for cancer.
Given the very well documented involvement of Notch
signaling in the maintenance and differentiation of
stem and progenitor cells in a broad organ spectrum,
the in vivo identification of Notch lineages provides an
essential tool to discover critical early progenitors both
for organ homeostasis and cancer development. Our
group seeks to examine the behaviour of normal stem
cells in the mouse intestine and the mammary gland,
with the goal of gaining insights into the cellular
hierarchy of the highly heterogeneous tumor cell
populations. We have chosen to focus our research on
these two epithelial tissues because they are very
dynamic and contain highly active stem cells, to ensure
extremely rapid and continuous cell renewal in the
case of the intestinal epithelium and to guarantee
remarkable tissue remodeling upon hormonal
stimulation for the mammary gland. Our studies on one
hand, use Notch as a tool to study stem/progenitor
cells homeostasis in vivo, and on the other, aim at
revealing if Notch signals can change the fate of
normal and cancer stem cells in our model systems, a
possibility with important therapeutic implications,
given that colon and breast cancer are among the most
common tumors.
Our questions:
Figure 2: Section of a mammary bud from
a mouse embryo showing Notch1expressing cells in green, myoepithelial
1) Can we use Notch as a marker of specific
stem/progenitor cells as well as “stem-cell like” tumor
cell populations? We are addressing this question
through the systematic identification and functional
characterization of Notch-expressing lineages in vivo in
normal and tumor cells of the mouse intestinal and
mammary epithelia.
2) How are stem cell division and migration
dynamically coordinated within a crypt and during
mammary tubulogenesis? In order to visualize stem cell
behaviour and response to injury by time-lapse
imaging, we use 3D organoids ex vivo (“miniguts” for
the intestine and “miniglands” for the mammary gland)
derived from normal or malignant Notch-expressing
cells.
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 2
Notch Signaling in Stem Cells and Tumors
U934/UMR3215 – Genetics and Developmental Biology
cells in cyan and luminal cells in red.
3) Are Notch signals required for stem cell survival in
normal tissues and in tumors? We aim at establishing,
by in vivo genetic ablation and gain of function studies,
the functional role of Notch signaling in maintaining
stem/progenitor cells and in the transformation of the
intestinal and mammary epithelia.
4) Can niche signals affect the establishment of a stem
cell pool during intestinal development? Our group
investigates how the mesenchyme influences Notchexpressing intestinal stem cells both temporally, during
embryonic gut development, and topologically, as
regional differences are established along the anteroposterior axis.
Our Tools: novel knock-in transgenic mice
Figure 3: Example of a “minigut” derived
from a single crypt cultured for 7 days
after tamoxifen induction. Double
fluorescence illustrates the complete
switch from Tomato to GFP membranebound signal upon Cre recombination in
Notch1-derived lineages.
We have recently generated and characterized a novel
collection of unique transgenic mice that give us now
the opportunity to assess Notch expression and
function in vivo in an unprecedented fashion.
Specifically, these mice permit the conditional
expression of a given transgene in the cells where the
promoters of the four Notch receptor paralogues are
endogenously active. In addition, we have also
developed reporter mice, allowing us to visualize cells
with an active Notch pathway and transgenic animals
allowing conditional activation of the four Notch
paralogues. These three groups of novel reagents
define exceptional tools, which allow us to probe the
relationship between Notch-related activity and normal
and cancer stem cells in vivo.
Key publications
Year of publication 2015
María Elena Fernández-Sánchez, Sandrine Barbier,
Joanne Whitehead, Gaëlle Béalle, Aude Michel,
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 3
Notch Signaling in Stem Cells and Tumors
U934/UMR3215 – Genetics and Developmental Biology
Heldmuth Latorre-Ossa, Colette Rey, Laura Fouassier,
Audrey Claperon, Laura Brullé, Elodie Girard, Nicolas
Servant, Thomas Rio-Frio, Hélène Marie, Sylviane
Lesieur, Chantal Housset, Jean-Luc Gennisson,
Mickaël Tanter, Christine Ménager, Silvia Fre, Sylvie
Robine, Emmanuel Farge (2015 Jul 2)
Mechanical induction of the tumorigenic βcatenin pathway by tumour growth
pressure.
Nature : 92-5 : DOI : 10.1038/nature14329
Veronica Rodilla, Alessandro Dasti, Mathilde Huyghe,
Daniel Lafkas, Cécile Laurent, Fabien Reyal, Silvia Fre
(2015 Feb 17)
Luminal progenitors restrict their lineage
potential during mammary gland
development.
PLoS biology : e1002069 : DOI :
10.1371/journal.pbio.1002069
Year of publication 2014
Maia Chanrion, Inna Kuperstein, Cédric Barrière,
Fatima El Marjou, David Cohen, Danijela Vignjevic,
Lev Stimmer, Perrine Paul-Gilloteaux, Ivan Bièche,
Silvina Dos Reis Tavares, Giuseppe-Fulvio Boccia,
Wulfran Cacheux, Didier Meseure, Silvia Fre,
Loredana Martignetti, Patricia Legoix-Né, Elodie
Girard, Luc Fetler, Emmanuel Barillot, Daniel Louvard,
Andreï Zinovyev, Sylvie Robine (2014 Apr 9)
Concomitant Notch activation and p53
deletion trigger epithelial-to-mesenchymal
transition and metastasis in mouse gut.
Nature communications : 5005 : DOI :
10.1038/ncomms6005
Year of publication 2013
Daniel Lafkas, Veronica Rodilla, Mathilde Huyghe,
Larissa Mourao, Hippokratis Kiaris, Silvia Fre (2013
Oct 7)
INSTITUT CURIE, 20 rue d’Ulm, 75248 Paris Cedex 05, France | 4
Notch Signaling in Stem Cells and Tumors
U934/UMR3215 – Genetics and Developmental Biology
Notch3 marks clonogenic mammary luminal
progenitor cells in vivo.
The Journal of cell biology : 47-56 : DOI :
10.1083/jcb.201307046
Year of publication 2011
Silvia Fre, Edouard Hannezo, Sanja Sale, Mathilde
Huyghe, Daniel Lafkas, Holger Kissel, Angeliki Louvi,
Jeffrey Greve, Daniel Louvard, Spyros ArtavanisTsakonas (2011 Jul 5)
Notch lineages and activity in intestinal
stem cells determined by a new set of
knock-in mice.
PloS one : e25785 : DOI :
10.1371/journal.pone.0025785
Year of publication 2009
Silvia Fre, S K Pallavi, Mathilde Huyghe, Marick Laé,
Klaus-Peter Janssen, Sylvie Robine, Spyros ArtavanisTsakonas, Daniel Louvard (2009 Feb 27)
Notch and Wnt signals cooperatively control
cell proliferation and tumorigenesis in the
intestine.
Proceedings of the National Academy of Sciences of
the United States of America : 6309-14 : DOI :
10.1073/pnas.0900427106
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