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Oncotarget. 2016 Jan 5;7(1):656-70. doi: 10.18632/oncotarget.6394.

Molecular pathway activation features linked with transition from normal skin to primary and metastatic melanomas in human.

Author information

  • 1Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR.
  • 2Group for Genomic Analysis of Cell Signaling Systems, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
  • 3First Oncology Research and Advisory Center, Moscow, Russia.
  • 4Laboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
  • 5National Research Centre "Kurchatov Institute", Centre for Convergence of Nano-, Bio-, Information and Cognitive Sciences and Technologies, Moscow, Russia.
  • 6Pirogov Russian National Research Medical University, Department of Oncology, Hematology and Radiotherapy, Moscow, Russia.
  • 7Moscow 1st Oncological Hospital, Moscow Russia.
  • 8Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Mosow, Russia.
  • 9Moscow State University, Faculty of Fundamental Medicine, Moscow, Russia.
  • 10Insilico Medicine, Inc, ETC, Johns Hopkins University, Baltimore, MD, USA.
  • 11Novartis Institute for Biomedical Research, Basel, Switzerland.

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.

KEYWORDS:

OncoFinder; intracellular molecular networks; machine learning algorithms; metabolic and signaling pathways; transition from nevus to primary and metastatic melanoma

PMID:
26624979
PMCID:
PMC4808024
DOI:
10.18632/oncotarget.6394
[PubMed - indexed for MEDLINE]
Free PMC Article
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