The low affinity neurotrophin receptor CD271 regulates phenotype switching in melanoma

Gaetana Restivo,Gregor Kiowski,Mario Bonalli,Mitchell P Levesque,Mitchell P Levesque,Phil F Cheng,Phil F Cheng,Ernst Reichmann,Thomas Biedermann,Thomas Biedermann,Reinhard Dummer,Reinhard Dummer,Johanna Diener,Lukas Sommer

doi:10.1038/s41467-017-01573-6

Abstract

Cutaneous melanoma represents the most fatal skin cancer due to its high metastatic capacity. According to the “phenotype switching” model, the aggressive nature of melanoma cells results from their intrinsic potential to dynamically switch from a high-proliferative/low-invasive to a low-proliferative/high-invasive state. Here we identify the low affinity neurotrophin receptor CD271 as a key effector of phenotype switching in melanoma. CD271 plays a dual role in this process by decreasing proliferation, while simultaneously promoting invasiveness. Dynamic modification of CD271 expression allows tumor cells to grow at low levels of CD271, to reduce growth and invade when CD271 expression is high, and to re-expand at a distant site upon decrease of CD271 expression. Mechanistically, the cleaved intracellular domain of CD271 controls proliferation, while the interaction of CD271 with the neurotrophin receptor Trk-A modulates cell adhesiveness through dynamic regulation of a set of cholesterol synthesis genes relevant for patient survival.

Highlights

Cutaneous melanoma represents the most fatal skin cancer due to its high metastatic capacity
We identify the low affinity neurotrophin receptor CD271 to play a dual role as a mediator of phenotype switching, suppressing melanoma cell proliferation while concomitantly promoting metastasis formation in vivo
Phenotype switching in melanoma involves distinct pathways able to control proliferation vs. invasiveness by independent mechanisms, this needs to be further addressed in future work

Summary

Introduction

Cutaneous melanoma represents the most fatal skin cancer due to its high metastatic capacity. In melanoma only ZEB1 and TWIST1 seem to be implicated in disease progression and metastasis, while ZEB2 expression is to the contrary lost during these processes[6] Another crucial player in phenotype switching in melanoma is the melanocyte-specifying microphthalmia-associated transcription factor (MITF), which controls a variety of target genes involved among others, in melanocyte differentiation[7]. High expression of MITF in melanoma cells confers high sensitivity to MAPK pathway inhibition, while MITFlow cells are intrinsically more resistant to those treatments[13,14] These states appear to be regulated by ZEB1: At least in some melanoma cell lines, ZEB1 overexpression induces resistance to BRAF/MEK inhibitors associated with a conversion of a MITFhigh into a MITFlow phenotype and with high expression of the nerve growth factor receptor CD271 ( termed NGFR, p75NTR) in resistant cells[15,16]. The function of CD271 in phenotype switching remains to be determined

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Conclusion