Julien Ablain

Cancer genetics has uncovered many tumor-suppressor and oncogenic pathways, but few alterations have revealed mechanisms involved in tumor spreading. Here, we examined the role of the third most significant chromosomal deletion in human melanoma that inactivates the adherens junction gene NECTIN1 in 55% of cases. We found that NECTIN1 loss stimulates melanoma cell migration in vitro and spreading in vivo in both zebrafish and human tumors specifically in response to decreased IGF1 signaling. In human melanoma biopsy specimens, adherens junctions were seen exclusively in areas with low IGF1 levels, but not in NECTIN1-deficient tumors. Our study establishes NECTIN1 as a major determinant of melanoma dissemination and uncovers a genetic control of the response to microenvironmental signals.

Activating mutations in RAS genes are the most common genetic driver of human cancers. Yet, drugging this small GTPase has proven extremely challenging and therapeutic strategies targeting these recurrent alterations have long had limited success. To circumvent this difficulty, research has focused on the molecular dissection of the RAS pathway to gain a more-precise mechanistic understanding of its regulation, with the hope to identify new pharmacological approaches. Here, we review the current knowledge on the (dys)regulation of the RAS pathway, using melanoma as a paradigm. We first present a map of the main proteins involved in the RAS pathway, highlighting recent insights into their molecular roles and diverse mechanisms of regulation. We then overview genetic data pertaining to RAS pathway alterations in melanoma, along with insight into other cancers, that inform the biological function of members of the pathway. Finally, we describe the clinical implications of RAS pathway dysregulation in melanoma, discuss past and current approaches aimed at drugging the RAS pathway, and outline future opportunities for therapeutic development.

Functional evaluation of genetic lesions can discover a role in cancer initiation and progression and help develop novel therapeutic strategies. We previously identified the negative MAPK regulator SPRED1 as a novel tumor suppressor in KIT-driven melanoma. Here, we show that SPRED1 is also frequently deleted in human melanoma driven by mutant BRAF. We found that SPRED1 inactivation in human melanoma cell lines and primary zebrafish melanoma conferred resistance to BRAF^V600E inhibition in vitro and in vivo. Mechanistically, SPRED1 loss promoted melanoma cell proliferation under mutant BRAF inhibition by reactivating MAPK activity. Consistently, biallelic deletion of SPRED1 was observed in a patient whose melanoma acquired resistance to MAPK-targeted therapy. These studies combining work in human cells and in vivo modeling in zebrafish demonstrate a new mechanism of resistance to BRAF^V600E inhibition in melanoma.

Genome-wide association studies (GWAS) have identified ~20 melanoma susceptibility loci, most of which are not functionally characterized. Here we report an approach integrating massively-parallel reporter assays (MPRA) with cell-type-specific epigenome and expression quantitative trait loci (eQTL) to identify susceptibility genes/variants from multiple GWAS loci. From 832 high-LD variants, we identify 39 candidate functional variants from 14 loci displaying allelic transcriptional activity, a subset of which corroborates four colocalizing melanocytecis-eQTL genes. Among these, we further characterize the locus encompassing the HIV-1 restriction gene,MX2(Chr21q22.3), and validate a functional intronic variant, rs398206. rs398206 mediates the binding of the transcription factor, YY1, to increaseMX2levels, consistent with thecis-eQTL ofMX2in primary human melanocytes. Melanocyte-specific expression of humanMX2in a zebrafish model demonstrates accelerated melanoma formation in aBRAF^V600Ebackground. Our integrative approach streamlines GWAS follow-up studies and highlights a pleiotropic function ofMX2in melanoma susceptibility.

Hunting and fishing for cancer genes: Mucosal melanoma is a rare, but deadly, form of melanoma that occurs in sun-protected tissues. Little is known about the genetic alterations that drive the growth of these tumors. Ablain et al. sequenced mucosal melanomas from 43 patients and found that a substantial fraction showed inactivation or loss of SPRED1 , a gene that encodes a negative regulator of RAS–MAPK (mitogen-activated protein kinase) signaling. Using a platform called MAZERATI (Modeling Approach in Zebrafish for Rapid Tumor Initiation), they discovered that SPRED1 loss may help explain the poor response of melanoma patients to drugs that inhibit the KIT tyrosine kinase. The results suggest that a combination of KIT inhibitors and drugs that inhibit MAPK signaling may be more effective. Science , this issue p. 1055

Visualizing the beginnings of melanoma: In cancer biology, a tumor begins from a single cell within a group of precancerous cells that share genetic mutations. Kaufman et al. used a zebrafish melanoma model to visualize cancer initiation (see the Perspective by Boumahdi and Blanpain). They used a fluorescent reporter that specifically lit up neural crest progenitors that are only present during embryogenesis or during adult melanoma tumor formation. The appearance of this tumor correlated with a set of gene regulatory elements, called super-enhancers, whose identification and manipulation may prove beneficial in detecting and preventing melanoma initiation. Science , this issue p. 10.1126/science.aad2197 ; see also p. 453