Melanoma miRNA trafficking controls tumour primary niche formation

Shani Dror, Laureen Sander, Hila Schwartz, Danna Sheinboim, Aviv Barzilai, Yuval Dishon, Sebastien Apcher, Tamar Golan, Shoshana Greenberger, Iris Barshack, Hagar Malcov, Alona Zilberberg, Lotan Levin, Michelle Nessling, Yael Friedmann, Vivien Igras, Ohad Barzilay, Hananya Vaknine, Ronen Brenner, Assaf ZingerAvi Schroeder, Pinchas Gonen, Mehdi Khaled, Neta Erez, Jörg D. Hoheisel, Carmit Levy

Research output: Contribution to journalArticlepeer-review

169 Scopus citations

Abstract

Melanoma originates in the epidermis and becomes metastatic after invasion into the dermis. Prior interactions between melanoma cells and dermis are poorly studied. Here, we show that melanoma cells directly affect the formation of the dermal tumour niche by microRNA trafficking before invasion. Melanocytes, cells of melanoma origin, are specialized in releasing pigment vesicles, termed melanosomes. In melanoma in situ, we found melanosome markers in distal fibroblasts before melanoma invasion. The melanosomes carry microRNAs into primary fibroblasts triggering changes, including increased proliferation, migration and pro-inflammatory gene expression, all known features of cancer-associated fibroblasts (CAFs). Specifically, melanosomal microRNA-211 directly targets IGF2R and leads to MAPK signalling activation, which reciprocally encourages melanoma growth. Melanosome release inhibitor prevented CAF formation. Since the first interaction of melanoma cells with blood vessels occurs in the dermis, our data suggest an opportunity to block melanoma invasion by preventing the formation of the dermal tumour niche.

Original languageEnglish (US)
Pages (from-to)1006-1017
Number of pages12
JournalNature Cell Biology
Volume18
Issue number9
DOIs
StatePublished - Sep 1 2016

ASJC Scopus subject areas

  • Cell Biology

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