The low affinity neurotrophin receptor CD271 regulates phenotype switching in melanoma

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.

Novel immune signatures associated with dysplastic naevi and primary cutaneous melanoma in human skin

“…Given that DN clustered in an intermediary position in the PCA plot (Figure B), we investigated the underlying molecular behaviour and changes in pathway activation in the three melanocytic lesions. An unbiased analysis of molecular gene signatures implicated in oncogenesis and melanoma was curated from the literature and the Broad Institute, as listed in Table . Progressive increases in cell proliferation pathways from CMN to DN to MM, with statistically significant and prominent fold changes in MM (Figure A), were observed.…”

BORIS/CTCFL promotes a switch from a proliferative towards an invasive phenotype in melanoma cell lines

“…Multiple transcription factors, signalling pathways and EMT-related genes are important to establish the transitions. Many of these factors are likely involved at different stages of phenotype switching, marked by a transcriptional profile between the proliferative and invasive state (5,60), and contribute to partial or intermediate phenotype switching (10,16,61). Our observation that BORIS expression has no effect on MITF, ZEB1 or ZEB2 expression, suggest that the MM057 melanoma cells have already undergone a partial switch.…”

“…Gene expression profiling of melanoma cell lines and tumor samples has revealed the different transcriptional states that underlie the proliferative and invasive phenotypes of melanoma cells (3)(4)(5)(6)(7). While proliferative cells tend to express high levels of developmental and lineage specification genes such as MITF, MLANA, and DCT as well as SOX10 and PAX3 (1,4,6), cells with an invasive transcriptional state are marked by expression of amongst others, ZEB1, SNAI1, AXL, NGFR, SPARC, WNT5A and genes involved in TGF-β signaling (4,(6)(7)(8)(9)(10). Currently, various transcriptional regulators have been implicated as drivers of the transition towards an invasive phenotype, including BRN2, AP-1, TEAD, NFATC2, and NFIB (4,(11)(12)(13)(14).…”

Harnessing autophagy to overcome mitogen‐activated protein kinase kinase inhibitor‐induced resistance in metastatic melanoma

“…However, results also suggest that CD271 may have opposing effects on autophagy in unstressed cells, such as CD271 + cells from treatment‐naïve cell lines that appear to require autophagy for survival vs. CD271 + cells undergoing drug‐induced stress, where CD271 appears to reduce cytotoxic autophagy. The role of CD271 as a component of diverse and/or opposing signalling networks is supported by recent studies characterizing CD271 as a regulator of the ‘phenotype switch’, and seems increasing likely given the large number of CD271‐interacting partners, as well as the ability of CD271 to function as a homodimer, or to elicit signalling in the absence of ligand binding …”