1. Molecular Target Identification and Therapeutic Development in Cutaneous Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent type of human cancer, and its incidence continues to increase despite widespread prevention strategies aimed at reducing sun exposure. The genetic architecture of cSCC is complex, characterized by a high mutational burden, mutational heterogeneity, copy number alterations, and recurrent mutations in key tumor suppressor genes. Despite mutational heterogeneity, a relatively small number of master regulators are associated with specific cancer hallmarks. While the tumor suppressor p53 is frequently mutated in cancer, its family member p63 is commonly overexpressed in squamous cell carcinomas. Missero’s research group has shown that p63 is essential for the growth and maintenance of cutaneous tumors, acting as a central driver of oncogenic proliferation. Through genomic and transcriptional analyses, we demonstrate that p63 activates a regulatory network that promotes proliferative signaling and reinforces its own activity through feed-forward mechanisms. Disruption of p63 function leads to loss of these oncogenic programs, resulting in cell cycle arrest and reduced tumor-forming capacity. However, this arrest can be bypassed through modulation of intrinsic checkpoints, revealing a critical balance between p63-driven growth and tumor suppressive barriers. The future goal of these studies is to identify synthetic lethality mechanisms to develop therapeutic strategies aimed at directly or indirectly targeting the p63 pathway.

2. Targeted Therapeutic Approaches for a Genodermatosis Associated with Epidermal Fragility and Skin Erosions.

Heterozygous dominant mutations in the TP63 gene cause a spectrum of ectodermal dysplasia syndromes. Among these, AEC syndrome (Ankyloblepharon-Ectodermal defects-Cleft lip/palate), also known as Hay-Wells syndrome, is a rare genetic disorder characterized by severe and chronic skin erosions during the neonatal and pediatric periods. These lesions are persistent, prone to bleeding, and highly susceptible to infection, making clinical management particularly challenging.

Our group has investigated the pathogenic mechanisms underlying AEC syndrome using genetically engineered mouse models and patient-derived keratinocytes. We identified primary defects in cell–cell adhesion among keratinocytes, as well as in the attachment between the epidermis and the underlying dermis. At the molecular level, we demonstrated that pathogenic TP63 mutations lead to nuclear accumulation of the mutant protein in aggregated form. These aggregates interfere with the function of wild-type p63 and sequester key regulatory factors, thereby exacerbating cellular dysfunction and impairing regenerative capacity.

To counteract these defects, her team is currently working on the identification of therapeutic approaches for AEC syndrome using two independent strategies:

a) developing a genome editing approach to correct the mutant p63 gene in patient-derived cells;

b) evaluating the long-term efficacy and safety of promising chemical compounds recently identified by the lab that are capable of inhibiting aggregation of the mutant protein. The proposed strategies may form the basis for future targeted therapies aimed at improving the quality of life for patients affected by this severe genodermatosis.