CD271 is a molecular switch with divergent roles in melanoma and melanocyte development

Dysregulation of signaling networks controlling self-renewal and migration of developmental cell lineages is closely linked to the proliferative and invasive properties of tumors. Identification of such signaling pathways and their critical regulators is vital for successful design of effective targeted therapies against neoplastic tissue growth. The neurotrophin receptor (CD271/NGFR/p75/NTR) is a key regulator of the melanocytic cell lineage through its ability to mediate cell growth, survival, and differentiation. Using clinical melanoma samples, normal melanocytes and global gene expression profiling we have investigated the role of CD271 in rewiring signal transduction networks of melanoma cells during neoplastic transformation. Our analysis demonstrates that depending on the cell fate, tumor initiation vs normal development, elevated levels of CD271 can serve as a switch between proliferation/survival and differentiation/cell death. Two divergent arms of neurotrophin signaling hold the balance between positive regulators of proliferation, selfrenewal, and survival controlled by E2F, MYC, SREBP1 and AKT3 pathways on the one hand, and differentiation, senescence, and apoptosis controlled by TRAF6/IRAK-dependent activation of AP1 and TP53 mediated processes on the other hand. A molecular network map revealed in this study uncovers CD271 as a context-specific molecular switch between normal development and malignant transformation. https://doi.org/10.1038/s41598-019-42773-y http://orcid.org/0000-0001-9889-5727 Flow cytometry in combination with lineage- and CD271-specific monoclonal antibodies was used to purify distinct CD271+ and CD271- tumor cell subsets from surgically removed, human melanoma tumor tissue specimens. In addition, the same approach was used to purify CD271+ and CD271- cell population from epidermal melanocytes separately isolated from healthy human skin tissue. All CD271+ and CD271- cell populations were then subjected to RNA extraction, transcriptomic profiling, and systems biology analysis.