Decoding molecular programs in melanoma brain metastases

Abstract

The systemic dissemination of tumor cells and the spatiotemporal development of organ- metastases are associated with loss of therapeutic control and decreased overall survival (OS). The emergence of solitary or multiple brain metastases is frequently observed in melanoma patients and responsible for disease progression and dismal prognosis. Here, we used whole transcriptome and methylome profiling as well as targeted sequencing (TargetSeq) of intraoperative/snap frozen or archived melanoma brain metastases to unravel molecular subgroups and subclonal heterogeneity. We discovered that E-cadherin (Ecad)/BRAFV600E/K, CD271/NRASQ61L/R/K, and tumor infiltrated lymphocytes (TIL)-status molecularly subdivided tumors into proliferative/pigmented and invasive/stem-like irrespective of the intracranial location. Moreover, we identified 46 differentially methylated regions in promoters of 14 genes, subdividing MBM into BRAFmut and NRASmut subgroups. We observed that therapy-resistant, migratory CD271+/Ecadneg subclones derived from Ecad+tumors in an epithelial-mesenchymal transition (EMT)-like process and fostered intracranial progression. Hence, CD271high MBM present a therapy-resistant, progressive subset of tumors that are refractory to conventional therapeutic strategies. The knockdown of CD271 or SOX4 in in vitro established, MBM-derived cell lines decreased cell migration, proliferation, and number of suspension cells that were shed by cell lines of progressive tumors. In summary, we propose that an Ecad-to-CD271 switch of MBM is a rate-limiting process that potentially determines intracranial progression in melanoma patients. The therapeutic control of this process may prevent intracranial progression, increasing patient’s overall survival.

Melanoma cells appropriate pericyte:endothelial cell crosstalk during perivascular invasion in the brain

“…For example, melanoma cells have been shown to re-instate neural crest-specific transcription factors that may provide an adaptive, survival advantage in the brain microenvironment 16,37–39 . Notably, while one recent study has found that AXL and EMT-like melanoma cells are enriched in melanoma brain metastases, another recent study found that brain metastases were instead enriched in neuronal-lineage genes and melanocytic state markers such as MITF and SOX10 40,41 . Most likely, melanoma phenotypic plasticity produces a spectrum of different lineage states that interact cooperatively to maintain tumor survival, persistence, and invasion as they compete for various niches in the brain microenvironment (i.e., perivascular positioning).…”