Notch signaling in Stem Cells and Tumors
KeywordsLineage specification, mouse development, Notch, cancer, stem cells, mammary gland, intestine
How cells coordinate their action to build epithelial tissues during development, tissue morphogenesis and remodeling is a fundamental question that remains only superficially understood. Two tissues that are particularly suited to approach this question are the mouse intestine and the mammary gland, where somatic stem cells ensure continuous cell renewal. We study the signals controlling stem cell homeostasis, with the final goal of gaining mechanistic insights into organ morphogenesis during development, and also adult stem cell maintenance in both normal and pathological conditions.
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.
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 Notch-expressing intestinal stem cells both temporally, during embryonic gut development, and topologically, as regional differences are established along the antero-posterior axis.
Our Tools: novel knock-in transgenic mice