van Rooijen, E. | bioRxiv Science

bioRxiv2020

SATB2 induction of a neural crest mesenchyme-like program drives invasion and drug resistance in melanoma

Recent genomic and scRNA-seq analyses of melanoma identified common transcriptional states correlating with invasion or drug resistance, but failed to find recurrent drivers of metastasis. To test whether transcriptional adaptation can drive melanoma progression, we made use of a zebrafish mitfa:BRAFV600E;tp53-/- model, in which malignant progression is characterized by minimal genetic evolution. We undertook an overexpression-screen of 80 epigenetic/transcriptional regulators and found neural crest-mesenchyme developmental regulator SATB2 to accelerate aggressive melanoma development. Its overexpression induces invadopodia formation and invasion in zebrafish tumors and human melanoma cell lines. SATB2 binds and activates neural crest-regulators, including pdgfab and snai2. The transcriptional program induced by SATB2 overlaps with known MITFlowAXLhlgh and AQP1+NGFR1high drug resistant states and functionally drives enhanced tumor propagation and resistance to Vemurafenib in vivo. Here we show that melanoma transcriptional rewiring by SATB2 to a neural crest mesenchyme-like program can drive invasion and drug resistance in endogenous tumors.

cancer biology↗

bioRxiv2019

Cross-species analysis of melanoma enhancer logic using deep learning

Genomic enhancers form the central nodes of gene regulatory networks by harbouring combinations of transcription factor binding sites. Deciphering the combinatorial code by which these binding sites are assembled within enhancers is indispensable to understand their regulatory involvement in establishing a cells phenotype, especially within biological systems with dysregulated gene regulatory networks, such as melanoma. In order to unravel the enhancer logic of the two most common melanoma cell states, namely the melanocytic and mesenchymal-like state, we combined comparative epigenomics with machine learning. By profiling chromatin accessibility using ATAC-seq on a cohort of 27 melanoma cell lines across six different species, we demonstrate the conservation of the two main melanoma states and their underlying master regulators. To perform an in-depth analysis of the enhancer architecture, we trained a deep neural network, called DeepMEL, to classify melanoma enhancers not only in the human genome, but also in other species. DeepMEL revealed the presence, organisation and positional specificity of important transcription factor binding sites. Together, this extensive analysis of the melanoma enhancer code allowed us to propose the concept of a core regulatory complex binding to melanocytic enhancers, consisting of SOX10, TFAP2A, MITF and RUNX, and to disentangle their individual roles in regulating enhancer accessibility and activity.

genomics↗