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. Author manuscript; available in PMC: 2019 Dec 1.
Published in final edited form as: Dev Biol. 2018 Apr 13;444(Suppl 1):S352–S355. doi: 10.1016/j.ydbio.2018.04.008

The Convergent Roles of CD271/p75 in Neural Crest-Derived Melanoma Plasticity

Jennifer C Kasemeier-Kulesa 1, Paul M Kulesa 1,2
PMCID: PMC6186201  NIHMSID: NIHMS968042  PMID: 29660313

Abstract

The embryonic microenvironment is an important source of signals that promote multipotent cells to adopt a specific fate and direct cells along distinct migratory pathways. Yet, the ability of the embryonic microenvironment to retain multipotent progenitors or reprogram de-differentiated cells is less clear. Mistakes in cell differentiation or migration often result in developmental defects and tumorigenesis, including aggressive cancers that share many characteristics with embryonic progenitor cells. This is a striking feature of the vertebrate neural crest, a multipotent and highly migratory cell population first identified by Wilhelm His (His, 1868) with the potential to metamorphose into aggressive melanoma cancer. In this perspective, we address the roles of CD271/p75 in tumor initiation, phenotype switching and reprogramming of metastatic melanoma and discuss the convergence of these roles in melanoma plasticity.

Keywords: neural crest, melanoma, CD271, p75, NGF, microenvironment

Perspective

Trunk neural crest cells migrate in discrete, multicellular streams to contribute to neurons and glia of the peripheral nervous system (PNS) and melanocytes in the skin (LeDouarin and Kalcheim, 1999). Early emerging trunk neural crest cells exit the dorsal neural tube and follow a ventral pathway between the neural tube and somite and later through loosely connected somitic mesoderm (Kulesa and Gammill, 2010). This repeating migratory pattern results in the distribution of trunk neural crest cells into a ventral location to form the sympathetic ganglia (SG) and dorsal location to contribute to the sensory dorsal root ganglia (DRG; Kulesa and Gammill, 2010). Trunk neural crest cells that give rise to melanocytes then exit the dorsal neural tube, travel along a dorsolateral migratory pathway and distribute throughout the ectoderm to differentiate into pigment cells that synthesize melanin. Melanocytes are also derived postnatally from Schwann cell precursors that reside along ventromedial nerve processes (Adameyko et al., 2009; Nitzan et al., 2013). Thus, there is a common pool of trunk neural crest cells that are directed to distinct peripheral locations and build functional tissue architectures along the vertebrate posterior axis.

The trunk neural crest microenvironment is rich in signals that regulate the migration and survival of neural crest cells that contribute to the PNS (Kulesa and Gammill, 2010). Signals within the dorsal aorta initiate the expression of the chemokine ligand CXCL12 (Saito et al., 2012), readout by early exiting neural crest cells that upregulate the CXCR4 receptor after exiting the neural tube (Kasemeier-Kulesa et al., 2010). Later emerging CXCR4-negative cells follow CXCR4-positive leaders to the region near the dorsal aorta and together are sculpted into discrete primary sympathetic ganglia (Kasemeier-Kulesa et al., 2005, 2006, 2010). Further emerging trunk neural crest cells migrate along the ventral pathway but stop in a dorsal position to form the DRG. Within the DRG, cells respond to a number of neurotrophic factors including nerve growth factor (NGF), neurotrophin-3 (NT-3) and brain derived neurotrophic factor (BDNF) (reviewed in Ernsberger, 2009). Thus, the embryonic trunk microenvironment strongly influences the guidance and survival of neural crest cells to assemble the PNS.

In vivo cell tracing, clonal analysis, and quail-chick chimeras have revealed that premigratory neural crest cells are a heterogeneous pool of multipotent neural crest stem cells and lineage-restricted progenitors (Bronner-Fraser and Fraser, 1988, 1989; Raible and Eisen, 1994). The tremendous diversity of trunk neural crest cell derivatives is remarkably influenced by intrinsic signals within the neural tube and extrinsic signals within the many microenvironments through which neural crest cells travel and stop (reviewed in Dupin and Sommer, 2012; Dupin and LeDouarin, 2014; Bronner and Simoes-Costa, 2016; Kalcheim and Kumar, 2017). Single cell cultures (Coelho-Aguiar et al., 2013) and genomic analyses (Simoes-Costa and Bronner, 2015) are further revealing the developmental capacities and transcriptional signatures of embryonic trunk neural crest cells. For example, neural crest cell differentiation into melanocytes involves a feed-forward loop of Sox10 and microphthalmia-associated transcription factor (Mitf) to regulate downstream events that encode melanogenic enzymes that lead to mature, functional melanin producing cells (Simoes-Costa and Bronner, 2015). Mitf is essential for melanocyte stem cell maintenance in the hair follicle bulge and the quiescence and maturity of melanocyte stem cells is regulated by a dynamic interplay between TGF-beta/Mitf signaling (Nishimura et al., 2010).

Adult neural crest–derived melanocytes retain features of plasticity. When single melanocytes from quail embryos are cultured in the presence of Endothelin-3 (Edn3), cells de-differentiate and activate glial-specific genes, giving rise to clonal progeny that contain glial cells and melanocytes (Dupin et al., 2000). Hair follicle injury by epilation has now revealed this event induces melanocyte stem cell activation in vivo through Edn3/Ednrb signaling (Li et al., 2017). Thus, new advances are identifying the molecules required for the establishment and control of neural crest cell self-renewal and multipotency.

Neural crest stem cells may be isolated from postnatal neural crest-derived tissue by flow cytometry based on the expression of specific receptors. Using antibodies against the cell surface antigens p75 (the low affinity neurotrophin receptor also known as NGFR and CD271), and P0 (a peripheral myelin protein), Morrison and colleagues fractionated E14.5 mouse sciatic nerve by flow cytometry into 5 distinct subpopulations (Morrison et al., 1999). The p75-positive/P0-negative subfraction was highly enriched in cells that were functionally indistinguishable from neural crest stem cells in vitro (Stemple and Anderson, 1992). These cells also generated neurons and glia after microinjection into the anterior somite regions of 3-day old chick embryos (Morrison et al., 1999). Together, these data demonstrated the existence of neural crest stem cells that contribute to melanocytes and neurons during late fetal or postnatal development with implications for diagnosis and treatment of neurocristopathies and neural crest-derived cancers.

Whether tumorigenic cancer stem cells that propagate different subtypes of cells while continuing to proliferate existed in human neural crest-derived melanomas remained unclear. Interestingly, CD271 expression is present in cells within a number of human neural crest-derived tissues and in melanomas (Chesa et al., 1988; Pietra et al., 2009). When CD271-positive cells were isolated from human patient-derived melanomas collected amongst a broad spectrum of sites and stages and implanted into immunodeficient mice, the CD271-positive subset of cells was identified as the tumor initiating population in 9 out of 10 melanomas tested (Boiko et al., 2010). The CD271-positive patient-derived cells were found capable of metastasis in vivo and lacked expression of TYR (a gene that provides instruction for making an enzyme called tyrosinase) and MART-1 (a marker for melanosome formation) in greater than 68% of melanoma patients (Boiko et al., 2010). Together, this helped to establish CD271 as a marker for melanoma stem cell-like properties, but left open the question of the role of CD271 in melanoma disease progression and metastasis.

Recent studies have now examined CD271 expression in the context of melanoma progression and metastasis (Radke et al., 2017; Redmer et al., 2017). By curating the available gene expression databases of human nevi, primary melanoma and melanoma metastases, they found that CD271 expression gradually rises with melanoma progression (Radke et al., 2017). The highest levels of CD271 were discovered in melanomas that metastasized to the brain (Radke et al., 2017). This is not surprising given the evidence that brain biopsies have increased amounts of NGF in tumor adjacent tissue at the invasion front of human melanoma tumors (Marchetti et al., 2003). Comparative analysis of CD271-high versus CD271-low brain tumors revealed 2834 differentially regulated genes, with 99 genes (62 enhanced and 37 reduced) associated with migration, DNA repair and stemness (Radke et al., 2017). When CD271 function was knocked down in vitro in human patient-derived tumor cells (T20/02) placed in a scratch assay, cells reduced migration and expression of candidate regulatory genes (FGF13, CSPG4, HMGA2, AKT3) of melanoma cell migration (Radke et al., 2017). Together, these data suggest another function for CD271 to promote melanoma cell invasion and highlight its potential role in brain metastases.

The capacity of melanoma cells to dynamically switch between proliferative and invasive phenotypes is thought to underlie tumor progression, metastasis formation and therapy resistance in melanoma (Hoek et al., 2008; Vandamme and Berx, 2014; Li et al., 2015). Mitf, a well known melanoma differentiation marker has been used to define proliferative (high expression) versus invasive (low expression) phenotypes and more recently implicated in a dynamic interplay with epithelial-to-mesenchymal genes (Caramel et al., 2013; Denecker et al., 2014), providing mechanistic insights into phenotype switching. More recently, work has now identified CD271 to play a dual role as a mediator of phenotype switching, suppressing melanoma cell proliferation while concomitantly promoting metastasis formation in vivo (Restivo et al., 2017). When CD271 overexpression is controlled in a reversible manner, the gene expression signatures defining proliferative versus invasive cells hardly overlapped with previously established profiles (Restivo et al., 2017). On the basis of their findings, CD271 exerts its function in phenotype switching through heterodimerization of CD271 with the Trk-A receptor, mediating NGF signaling to specifically affect melanoma cell invasiveness but not proliferation. Further, the intracellular domain resulting from CD271 processing suppresses proliferation without altering adhesion and invasiveness of melanoma cells. Thus, with the data that CD271 marks neural crest stem cells (Morrison et al., 1999) and the implication of the CD271 signaling axis underlying phenotype switching of melanoma tumor initiating cells (Restivo et al, 2017), CD271 is at the interface of suppressing tumorigenicity versus differentiation into a benign cell type. Together, this provides an opportunistic avenue for examining the potential reprogramming of metastatic melanoma cells to a less aggressive cell type through the NGF signaling pathway.

The embryonic neural crest microenvironment of the chick provides an attractive model system to examine melanoma tumor cell reprogramming (Kulesa et al., 2006; Hendrix et al., 2007). We learned that human C8161 metastatic melanoma cells placed into the chick dorsal neural tube followed host neural crest migratory pathways and did not reform tumors (Kulesa et al., 2006). Further, we reported that the amelanotic human C8161 metastatic melanoma cells upregulated MART-1 after exposure to the embryonic neural crest microenvironment (Kulesa et al., 2006). These intriguing results demonstrated that metastatic melanoma cells can respond to developmental cues, and suggested that factors unique to the neural crest embryonic microenvironment may be implemented to reprogram melanoma cells to a more benign melanocytic cell type. Further, this innovative approach allowed us to identify and test potential candidate molecules to control and reprogram metastatic melanoma cells, including the unknown signals that direct MART-1 re-expression.

We methodically determined the age, tissue type and ultimately NGF as the signal driving re-expression of MART-1, using a lentiviral MART-1:GFP reporter to observe dynamic changes in gene expression in co-cultures of human C8161 metastatic melanoma cells with various chick embryonic neural crest microenvironment tissues (Kasemeier-Kulesa et al., 2018). Our results showed that NGF receptors Trk-A and CD271 cooperate to induce MART-1 re-expression. When human C8161 metastatic melanoma cells were exposed to NGF, we found enhanced expression of MART-1, MITF, TYR and the acquisition of a gene signature characteristic of the poorly aggressive human C81-61 melanoma cells, suggesting NGF reprogrammed cells to a differentiated state. Further, MART-1-positive human C8161 metastatic melanoma cells, after exposure to NGF, significantly reduced invasiveness when transplanted into the chick embryonic neural crest microenvironment. Additionally, this MART-1 subpopulation showed a dramatic increase in p75/CD271 expression compared to the wild-type counterpart. Our data suggest that phenotype switching of human metastatic melanoma cells to a less aggressive cell type may be initiated by NGF acting through CD271.

Summary

When Wilhelm His first identified the vertebrate neural crest cells, little did he realize that one day the cell population would become a workhorse model system to study complex questions at the interface of development and cancer. Since then, we have learned that the plasticity, proliferation and invasiveness of multipotent embryonic neural crest cells and neural crest-derived melanoma are regulated by specific signals in the embryonic microenvironment (Fig. 1). In this perspective, we discussed the high expression of CD271/p75 correlates with human melanoma invasiveness (Fig. 1B; Boiko et al., 2010; Radke et al., 2017). The regulation of CD271/p75 expression underlies phenotype switching between human melanoma proliferation and invasion (Fig. 1A; Restivo et al., 2017). CD271/p75-positive human metastatic melanoma cells may be reprogrammed to a benign cell type with ectopic NGF (Fig. 1C; Kasemeier-Kulesa et al., 2018). This is consistent with the above studies (Radke et al., 2017; Restivo et al., 2017) since we speculate that CD271-high expressing C8161 metastatic melanoma cells with low MART-1, MITF, and TYR expression may be preferentially responsive to NGF treatment and the induction of downstream signals leading to a melanocyte-like cell type. Future experiments that determine the percentage of CD271-high versus -low expressing cells within the C8161 population by single cell protein analysis may test this idea. Together, these data support the convergent roles of CD271/p75 in neural crest-derived melanoma plasticity. Thus, targeting CD271 (Ngo et al., 2016) and NGF signaling pathways may represent a therapeutic strategy to explore in the treatment of neural crest-derived cancers. We honor Professor His for his contributions to neural crest biology that have led us on an exciting journey to better understand neural crest stem cell fate and migration decisions, and the dynamic ability to revert between cell types and behaviors.

Figure 1.

Figure 1

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Convergence of the roles of CD271/p75 in melanoma plasticity. (A, Phenotype switching) CD271 as a regulator of phenotype switching in melanoma. (B, Tumor initiating cell marker) CD271 as a marker for tumor initiating cells. (C, Reprogramming potential) NGF-induced MART1 as a marker of melanoma reprogramming of CD271-positive cells to a less aggressive cell type.

Highlights.

  • Trunk neural crest cells are highly migratory and diverse in cell fate

  • The low affinity NGF receptor, CD271/p75 is a marker for melanoma stem cells

  • CD271 promotes melanoma cell invasion and mediates phenotype switching

  • Metastatic melanoma may be reprogrammed by NGF to a benign cell type

  • Targeting CD271/NGF signaling may limit neural crest-derived cancer invasion

Acknowledgments

PMK would like to thank the kind and generous funding from the Stowers Institute for Medical Research and partially supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under Award Number R21NS092001 and Alex's Lemonade Stand Foundation Innovator Award.

Footnotes

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