WNT11-FZD7-DAAM1 signalling supports tumour initiating abilities and melanoma amoeboid invasion

Melanoma is a highly aggressive tumour that can metastasize very early in disease progression. Notably, melanoma can disseminate using amoeboid invasive strategies. We show here that high Myosin II activity, high levels of ki-67 and high tumour-initiating abilities are characteristic of invasive amoeboid melanoma cells. Mechanistically, we find that WNT11-FZD7-DAAM1 activates Rho-ROCK1/2-Myosin II and plays a crucial role in regulating tumour-initiating potential, local invasion and distant metastasis formation. Importantly, amoeboid melanoma cells express both proliferative and invasive gene signatures. As such, invasive fronts of human and mouse melanomas are enriched in amoeboid cells that are also ki-67 positive. This pattern is further enhanced in metastatic lesions. We propose eradication of amoeboid melanoma cells after surgical removal as a therapeutic strategy.

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Policy information about availability of computer code Data collection Phase contrast images were acquired with Zeiss Axio Vert.A inverted microscope and confocal images with Zeiss LSM 510 Meta confocal and Zeiss LSM 710 confocal microscopes and Zen 2.1 SP1 (black) software (Carl Zeiss). BD LSRFortessa™ system (BD Biosciences) and FlowJo 10.6 software were used to collect flow cytometry data. RT-PCR data was obtained using QuantStudio 7 Flex Real-Time PCR System and QuantStudio 1.3 Software (Applied Biosystems). Whole tissue sections were scanned and images obtained using NanoZoomer S210 slide scanner (Hamamatsu) and QuPath 0.1.2 software. Representative TMA pictures according to mean H-score were imaged using iScope microscope (IS.1159EPLi, Euromex) and ImageFocus 4.0 (Euromex) software.
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October 2018
Data Policy information about availability of data All manuscripts must include a data availability statement. This statement should provide the following information, where applicable: -Accession codes, unique identifiers, or web links for publicly available datasets -A list of figures that have associated raw data -A description of any restrictions on data availability Gene expression datasets re-analysed in this study are available from NCBI GEO under accession numbers: GSE23764, GSE8401, GSE7553 and GSE46517. Uncropped immunoblot scans for representative images displayed in the figures are shown in Source data. All other relevant data supporting the findings of this study are available within the article and its supplementary information and from the corresponding author on reasonable request.

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