title: Molecular pathway activation features linked with transition from normal skin to primary and metastatic melanomas in human.
abstract: Melanoma is the most aggressive and dangerous type of skin cancer, but its molecular mechanisms remain largely unclear. For transcriptomic data of 478 primary and metastatic melanoma, nevi and normal skin samples, we performed high-throughput analysis of intracellular molecular networks including 592 signaling and metabolic pathways. We showed that at the molecular pathway level, the formation of nevi largely resembles transition from normal skin to primary melanoma. Using a combination of bioinformatic machine learning algorithms, we identified 44 characteristic signaling and metabolic pathways connected with the formation of nevi, development of primary melanoma, and its metastases. We created a model describing formation and progression of melanoma at the level of molecular pathway activation. We discovered six novel associations between activation of metabolic molecular pathways and progression of melanoma: for allopregnanolone biosynthesis, L-carnitine biosynthesis, zymosterol biosynthesis (inhibited in melanoma), fructose 2, 6-bisphosphate synthesis and dephosphorylation, resolvin D biosynthesis (activated in melanoma), D-myo-inositol hexakisphosphate biosynthesis (activated in primary, inhibited in metastatic melanoma). Finally, we discovered fourteen tightly coordinated functional clusters of molecular pathways. This study helps to decode molecular mechanisms underlying the development of melanoma.
authors.affiliation: Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR.|Group for Genomic Analysis of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
authors.forename: Denis
authors.initials: D
authors.lastname: Shepelin
authors.affiliation: Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR.|First Oncology Research and Advisory Center, Moscow, Russia.
authors.forename: Mikhail
authors.initials: M
authors.lastname: Korzinkin
authors.affiliation: Laboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
authors.forename: Anna
authors.initials: A
authors.lastname: Vanyushina
authors.affiliation: Laboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Aliper
authors.affiliation: First Oncology Research and Advisory Center, Moscow, Russia.|National Research Centre "Kurchatov Institute", Centre for Convergence of Nano-, Bio-, Information and Cognitive Sciences and Technologies, Moscow, Russia.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Borisov
authors.affiliation: National Research Centre "Kurchatov Institute", Centre for Convergence of Nano-, Bio-, Information and Cognitive Sciences and Technologies, Moscow, Russia.
authors.forename: Raif
authors.initials: R
authors.lastname: Vasilov
authors.affiliation: First Oncology Research and Advisory Center, Moscow, Russia.|Pirogov Russian National Research Medical University, Department of Oncology, Hematology and Radiotherapy, Moscow, Russia.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Zhukov
authors.affiliation: Moscow 1st Oncological Hospital, Moscow Russia.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Sokov
authors.affiliation: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Mosow, Russia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Prassolov
authors.affiliation: Moscow State University, Faculty of Fundamental Medicine, Moscow, Russia.
authors.forename: Nurshat
authors.initials: N
authors.lastname: Gaifullin
authors.affiliation: Insilico Medicine, Inc, ETC, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Zhavoronkov
authors.affiliation: Novartis Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Bhupinder
authors.initials: B
authors.lastname: Bhullar
authors.affiliation: Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR.|Laboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.|National Research Centre "Kurchatov Institute", Centre for Convergence of Nano-, Bio-, Information and Cognitive Sciences and Technologies, Moscow, Russia.
authors.forename: Anton
authors.initials: A
authors.lastname: Buzdin
mesh_terms: D000465:Algorithms; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D000069550:Machine Learning; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D009362:Neoplasm Metastasis; D025341:Principal Component Analysis; D015398:Signal Transduction / Q000235:genetics*; D012867:Skin / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D059467:Transcriptome / Q000235:genetics
keywords: OncoFinder; intracellular molecular networks; machine learning algorithms; metabolic and signaling pathways; transition from nevus to primary and metastatic melanoma