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EXPAND Report Summary

Project ID: 616333
Funded under: FP7-IDEAS-ERC
Country: Belgium

Mid-Term Report Summary - EXPAND (Defining the cellular dynamics leading to tissue expansion)

Stem cells (SCs) ensure the development of the different tissues during morphogenesis and tissue homeostasis during adult life. SCs are critical for regenerating tissue after injuries and they play a role in tumor initiation. The aim of this project is to investigate the cellular and molecular mechanisms that regulate tissue expansion and cell fate decision during mammalian development, mechanical tissue expansion and tissue repair focusing on skip epidermis, mammary gland and prostate. To achieve this, we use state-of-the-art genetic mouse models to analyze the proliferation dynamics and fate of individual SCs in their native microenvironment. Our tight collaboration with physicists from Cambridge University allow us to develop mathematical model that describes the behavior of SCs during mammalian development in condition of tissue expansion (postnatal growth, tissue regeneration, forced mediated tissue expansion, tumor initiation). Detailed molecular analysis of distinct SC populations in these three epithelia will allow us to determine the mechanisms and genes involved in tissue expansion under these different conditions.
Defining the cellular and molecular mechanisms underlying tissue growth and expansion during development and how these mechanisms differ from tissue regeneration in adulthood will have important implications for understanding developmental defects and for enhancing tissue regeneration.
In this project, we recently showed that there are two distinct populations of SC and progenitors in mouse tail epidermis during adult homeostasis. We defined the clonal dynamics allowing tumor initiation, and showed that oncogene induces a strong increase in self-renewing division leading to tumor formation, which differs from homeostasis and wound healing (Sánchez-Danés, Nature 2016). In contrast, during wound healing, epidermal progenitors divide more rapidly, but conserve their homeostatic mode of division, leading to their rapid depletion, whereas rapid asymmetric division of SCs give rise to new progenitors that mediated cellular expansion required for tissue repair. Molecular profiling of cells isolated from different skin regions surrounding the wound edge identified molecular signatures associated with proliferation, differentiation and migration (Aragona et al. Nature communications 2017). We are currently exploiting this knowledge to determine when these populations are established, what is their role during skin development and how they behave during mechanical tissue expansion.

We developed new lineage tracing strategies and statistical analysis to multipotency in the mammary gland and prostate. We found that in mammary gland the different cells types are maintained by distinct unipotent SC populations during postnatal development, adult homeostasis, pregnancy and lactation. In contrast, in the prostate both multipotent and unipotent SCs populations mediated postnatal expansion (Wuidart, Genes Dev 2016). The methodology developed here offers a generic framework to assess the fate of SCs in different tissues and organs.
To define the mechanisms regulating multipotency in the mammary gland, we expressed oncogenic Pik3ca, a gene frequently mutated in breast cancer patients, in different unipotent SCs of the adult mammary gland. We showed that oncogenic Pik3ca reactivates multipotency in basal and luminal unipotent SCs. This reactivation of multipotency sets the stage for future intratumoral heterogeneity at the earliest stage of tumor development (Van Keymeulen, Nature 2015). We are now studying how different physio-pathological conditions can induce multipotency in the prostate and the mammary gland and how these mechanisms differ from oncogene induced multipotency and what are the gene networks that orchestrate cell fate decision during development, regeneration and malignancy.

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