New Functional Signatures for Understanding Melanoma Biology from Tumor Cell Lineage-Specific Analysis

Abstract

SUMMARY Molecular signatures specific to particular tumor types are required to design treatments for resistant tumors. However, it remains unclear whether tumors and corresponding cell lines used for drug development share such signatures. We developed similarity core analysis (SCA), a universal and unsupervised computational framework for extracting core molecular features common to tumors and cell lines. We applied SCA to mRNA/miRNA expression data from various sources, comparing melanoma cell lines and metastases. The signature obtained was associated with phenotypic characteristics in vitro, and the core genes CAPN3 and TRIM63 were implicated in melanoma cell migration/invasion. About 90% of the melanoma signature genes belong to an intrinsic network of transcription factors governing neural development (TFAP2A, DLX2, ALX1, MITF, PAX3, SOX10, LEF1, and GAS7) and miRNAs (211-5p, 221-3p, and 10a-5p). The SCA signature effectively discriminated between two subpopulations of melanoma patients differing in overall survival, and classified MEKi/BRAFi-resistant and -sensitive melanoma cell lines.

A gene expression study of dorso-ventrally restricted pigment pattern in adult fins ofNeolamprologus meeli, an African cichlid species

“…There is no evidence yet for such a mechanism in fish, but a recent computational study in human has predicted TFs, including Ap2a and Mitf, and small regulatory RNAs, such as mir-221, as shared upstream regulators of igsf11 and pmel in specific melanocyte lineages (Rambow et al, 2015). Here, we have already tested mitfa expression in our candidate gene survey and did not detect elevated expression in the dorsal black and white stripes In addition, mitfa showed positive expression correlation with pmel but not with igsf11 (Fig.…”

Progress in melanoma modelling in vitro

“…Malignant transformation, primarily driven by genetic mutations in cells, is also accompanied by specific changes in cellular and extracellular mechanical properties, such as stiffness and adhesion . While new computational approaches have detected similarity between tumor and cell lines, mechanobiological signalling in 2D culture systems still fails to mimic solid tumors. In particular, the mechanical regulation influencing tumor growth in vivo and some characteristics, such as for instance hypoxia inside the tumor mass, cannot be reproduced in 2D cultures.…”

ATG5 Mediates a Positive Feedback Loop between Wnt Signaling and Autophagy in Melanoma

“…Knockdown of ATG5 decreased melanoma cell survival in these mouse models (7), and in other settings related to cellular or environmental stress (8). The relevance of dissecting autophagy in the context of lysosomal-associated functions is further emphasized by the discovery of lineage markers that selectively deregulate lysosomal pathways in melanoma cells (9–11), as well as by pharmacological responses in the context of lysosomotropic agents (12–14). Yet, the extent to which oncogenic cascades impinge on the regulation and execution of autophagy in melanoma remain unclear.…”