Notch signaling in stem cells and tumor

Team's presentation

 In spite of the great advances of developmental biology in the past years, the mechanisms underlying morphogenesis and homeostasis of adult organs remain only superficially understood. Somatic stem cells are critical players during developmental growth and for maintaining adult tissue homeostasis.

 

The main focus of our research is understanding how tissue-specific stem cells engage in differentiation while retaining self-renewal potential and plasticity.

 

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 are studying the signals regulating lineage specification and maintenance in the mouse mammary gland with the final goal of gaining mechanistic insights into organ morphogenesis and into the critical steps of malignant transformation.

 

Our questions

MG confetti
Figure 1: Notch1 Confetti embryonic mammary gland stained for Keratin 5.

   How are lineage specification and morphogenesis coordinated during mammary embryonic development? We combine single cell RNA sequencing (scRNAseq) with live ex vivo imaging and spatial transcriptomics to determine the dynamics of mammary fate commitment and the mechanisms coordinating cell fate acquisition with branching morphogenesis.

 

   How does the stroma regulate epithelial branching morphogenesis during embryonic and pubertal development? To assess the role of stroma in branching morphogenesis, we co-culture  epithelial organoids with stromal cells in both wt and mutant conditions.

 

   What are the first steps of tumor initiation and how do cellular clones evolve in pre-neoplastic and invasive tumor contexts? We use different tumor models and combine scRNAseq data, whole mount immunostaining and intravital imaging to understand how tumors are formed, how specific oncogenes promote tumor development and how cellular clones interact and evolve  during tumor progression and metastasis.

 

  Our goals

  Our group seeks to understand how cell fate is specified in coordination with cell movements, using the paradigm of mammary stem cells, which restrict their lineage potential early in  development but maintain a high cellular plasticity. We believe that a thorough comprehension of cell behavior during normal development, including embryonic phases when mammary stem  cells become lineage committed, will help us to understand how cells respond to morphogenetic cues and eventually will shed light on how tumors are formed. By ex vivo live imaging of  embryonic explants or intravital imaging of pubertal mammary glands, we aim to understand how molecular events are related to branching morphogenesis at the tissue-scale. We are  convinced that a deep comprehension of the cellular hierarchies of tissue-specific stem cells and the factors that regulate their behavior will have a major impact in exploring therapeutic    avenues for cancer.  

 

In vitro branching of mammary organoids
Figure 2: Mammary organoids ineracting by fibroblast
Luminal cells stained in yellow (Keratin 5), Basal cells in blue (Keratin 8).
Original magnification 40X.
MG confetti PyMT
Figure 3: Tumor clones marked by Confetti
(Red, green, yellow and blue).
Keratin 5 is marked in grey.