Abstract
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/p75NTR) 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 of 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 tumor growth 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.
Highlights
Melanoma represents one of the most aggressive types of cancer due to its high proliferative and metastatic potential[1]
In this systems biology study, using clinical melanoma samples, fluorescent-activated cell sorting (FACS) in combination with global transcriptome profiling, we report distinct signaling pathways connected to CD271 expression in melanoma and melanocytes
We demonstrate that depending on the state of the tissue homeostasis elevated levels of the neurotrophin receptor, CD271, can serve as a cell proliferative/survival switch for melanoma-initiating cells or as a differentiation switch for developing melanocytes
Summary
Melanoma represents one of the most aggressive types of cancer due to its high proliferative and metastatic potential[1]. Unraveling heterogeneity of CD271 signaling to discover new subpopulations of cells within the tumor has been fundamental to many advances in cancer biology, including identification of tumor-initiating subsets and cells resisting immune-therapeutic regimens[9,18,19,20] In this systems biology study, using clinical melanoma samples, fluorescent-activated cell sorting (FACS) in combination with global transcriptome profiling, we report distinct signaling pathways connected to CD271 expression in melanoma and melanocytes. CD271+ cells derived from human melanoma patients in comparison to CD271− counterparts and CD271+ cells derived from normal melanocytic lineages elucidate a contrasting network response during normal development and malignant transformation
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