Determinanti della polarità cellulare: ruolo degli stimoli polarizzanti extracellulari nell'attivazione e mantenimento di programmi genetici e funzionali in organismi multicellulari

The contribution of this UO will deal with EMT in the determination of cell fate and of the modality of self-renewal in the mammary stem cell (SC) compartment. This will be approached through the study of the protein Numb, a known determinant of cell fate in developmental systems. The rationale for the proposed approach is the following:

1. EMT is known to be relevant to the conversion of normal SC/progenitors into cancer SCs (see “state of the art” section);

2. Numb is a known cell fate determinant, which we have involved in the determination of cell fate in the mammary SC compartment. In particular, Numb controls the asymmetric mode of division of the SC (see Introduction to Task 2);

3. Numb expression is frequently lost in breast cancer, an event which is causal to breast tumorigenesis;

4. The known molecular functions of Numb are those of antagonizing the Notch pathway and of stabilizing p53. However, we have uncovered a novel role of Numb in EMT (see preliminary results). In particular, Numb is a suppressor of EMT and loss-of-Numb causes the acquisition of a mesenchymal type of motility.

Based on the above, we hypothesize that that Numb is a critical determinant in controlling asymmetric division in breast SCs. Loss of Numb in breast cancers would lead to EMT in the SC compartment, with ensuing conversion of normal SCs to cancer SCs. To validate this theory we will:

1. Identify the molecular machinery controlled by Numb and leading to EMT once Numb expression is lost;

2. Test whether Numb is a regulator of SC asymmetric division, and whether its loss leads to symmetric division through EMT.