Van Raamsdonk, C. D. | bioRxiv Science

bioRxiv2023

BAP1 deficient human and mouse uveal melanomas up-regulate a shared EMT pathway

Monosomy 3 is a negative indicator for uveal melanoma (UM). A key tumor suppressor on chromosome 3 is the deubiquitinase BAP1, which usually has a second hit in cases with monosomy 3. Here, we investigated the role of Bap1 loss in the GNAQQ209L mouse UM model. We found that heterozygous Bap1 mutations increased the proportion of lung lesions reaching an unusually large size and permitted the growth of liver lesions. Comparison of RNAseq data from mouse and human UM identified a set of 270 genes differentially expressed in the same direction when BAP1 is mutant. The most significant pathway in this gene set was Epithelial to Mesenchymal Transition (EMT). The expression of five apical junction complex genes known to be down-regulated in association with EMT was very significantly correlated with survival in human UM patients. Activation of EMT through Bap1 deficiency could increase melanoma plasticity and adaptation to new microenvironments.

cancer biology↗

bioRxiv2021

Crosstalk with keratinocytes causes GNAQ oncogene specificity in melanoma

Different melanoma subtypes exhibit specific and non-overlapping sets of oncogene and tumor suppressor mutations, despite a common cell of origin in melanocytes. For example, activation of the Gq/11 signaling pathway is a characteristic initiating event in primary melanomas that arise in the dermis, uveal tract or central nervous system. It is rare in melanomas arising in the epidermis. Here, we present evidence that in the mouse, crosstalk with the epidermal microenvironment actively impairs the survival of melanocytes expressing the GNAQQ209L oncogene, providing a new model for oncogene specificity in cancer. The presence of epidermal cells inhibited cell division and fragmented dendrites of melanocytes expressing GNAQQ209L in culture, while they promoted the growth of normal melanocytes. Differential gene expression analysis of FACS sorted epidermal melanocytes showed that cells expressing GNAQQ209L exhibit an oxidative stress and apoptosis signature previously linked to vitiligo. Furthermore, PLCB4, the direct downstream effector of Gq/11 signaling, is frequently mutated in cutaneous melanoma alongside P53 and NF1. Our results suggest that a deficiency of PLCB4 promotes cutaneous melanomagenesis by reducing GNAQ driven signaling. Hence, our studies reveal the flip side of the GNAQ/PLCB4 signaling pathway, which was hitherto unsuspected. In the future, understanding how epidermal crosstalk restrains the GNAQQ209L oncogene could suggest novel melanoma therapies.

cancer biology↗