Sara Gallini

Over 25% of cells in normal sun-exposed human skin carry mutations in genes associated with basal and squamous cell carcinomas, the most widespread skin cancers worldwide. Remarkably, this mosaic of mutant and non-oncogenic, wild-type cells in skin epidermis remains clinically normal, maintaining its physiological functions. Despite this apparent stability, cells with different cancerous mutations compete with wild-type cells for growth and survival in the tissue, even in homeostasis, and these dynamics can be influenced by extrinsic factors such as injuries. As a protective armor from the external environment, the skin is constantly exposed to high frequency of injuries. Full-thickness injuries to skin harboring pre-cancerous mutations, such as those in Ras oncogenes, have been shown to promote tumorigenesis. However, this cooperation had mainly been studied in mouse models where the targeted stem cell compartment homogenously expresses Ras mutations, which represents only a small minority of real-life events. It remained unknown how injury affects the physiologically relevant situation of the genetically mosaic epidermis, where healthy cells coexist with Ras mutant cells. We surprisingly discovered that the injury-repair process switches the competitive dynamics between Ras mutant and wild-type cells: wild-type cells selectively increase their proliferation, thereby suppressing the expansion of Ras mutant cells and preventing tumorigenesis (Gallini S. et al., 2023). Mechanistically, this switch is due to differential responses to the injury-induced EGFR-ERK1/2 signaling pathway. This finding suggests that acute injury might actually preventrather than promote tumorigenesis, thereby completely changing our way we think about cancer initiation. Next, our goal is to define the molecular mechanisms used by epidermal stem cells and other skin cell types to reciprocally influence their cellular behaviors to maintain or break tissue homeostasis in uninjured and injured skin. These discoveries will open the door to potential targeted therapeutic strategies harnessing the power of our tissues to preserve overall architecture and homeostasis even when neighboring cells harbor oncogenic mutations.