Cutaneous melanoma initiates with the abnormal proliferation of malignant epidermal melanocytes. A key step towards the development of an aggressive and metastatic disease is when some malignant cells cross the basement membrane and enter the dermis. The molecular and cellular mechanisms enabling dermal invasion of melanoma cells are largely unknown. This is due to a lack of accurate in vivo model systems that recapitulate this event.
To fill out this gap, we have developed a novel melanoma mouse model, which allows activation of a BrafV600E-driven melanomagenic program in tail epidermal melanocytes and in vivo fate mapping of the melanoma cells. The model takes advantage of an X-linked spontaneous Eda(Ta-6j) mutation (Tabby) which abrogates the formation of hair follicles in the tail, thereby ensuring that melanoma early development remains strictly confined to the epidermis.
Using intravital microscopy, we observed that individual melanoma cells change their morphology before entering the dermis and cross the basement membrane through a limited number of gaps created by "leading" cells. We leveraged single-cell RNA sequencing (10X Genomics) to portray the transcriptional heterogeneity of early melanoma lesions and to monitor the transcriptional changes that accompany dermal invasion. We discovered that this process associates with a partial de-differentiation of melanoma cells and the upregulation of a hypoxia-related gene signature.
All in all, we have established a suitable in vivo model to study the cellular and molecular mechanisms underlying melanoma dermal invasion. This model provides a unique platform for the discovery of novel biomarkers of dermal invasion and therapeutic interventions that intercept the disease before its lethal dissemination to vital organs.
