Podoplanin drives dedifferentiation and amoeboid invasion of melanoma

Charlotte M De Winde,Samantha L George,Eva Crosas-Molist,Yukti Hari-Gupta,Abbey B Arp,Agnesska C Benjamin,Lindsey J Millward,Spyridon Makris,Alexander Carver,Valerio Imperatore,Víctor G Martínez,Victoria Sanz-Moreno,Sophie E Acton

doi:10.1016/j.isci.2021.102976

Charlotte M De Winde, Samantha L George + Show 11 more

Open Access

https://doi.org/10.1016/j.isci.2021.102976

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Abstract

SummaryMelanoma is an aggressive skin cancer developing from melanocytes, frequently resulting in metastatic disease. Melanoma cells utilize amoeboid migration as mode of local invasion. Amoeboid invasion is characterized by rounded cell morphology and high actomyosin contractility driven by Rho GTPase signalling. Migrastatic drugs targeting actin polymerization and contractility are therefore a promising treatment option for metastatic melanoma. To predict amoeboid invasion and metastatic potential, biomarkers functionally linked to contractility pathways are needed. The glycoprotein podoplanin drives actomyosin contractility in lymphoid fibroblasts and is overexpressed in many cancers. We show that podoplanin enhances amoeboid invasion in melanoma. Podoplanin expression in murine melanoma drives rounded cell morphology, increasing motility, and invasion in vivo. Podoplanin expression is increased in a subset of dedifferentiated human melanoma, and in vitro is sufficient to upregulate melanoma-associated marker Pou3f2/Brn2. Together, our data define podoplanin as a functional biomarker for dedifferentiated invasive melanoma and a promising migrastatic therapeutic target.

Highlights

Metastatic melanoma has a very poor prognosis, and there is a need for additional treatment options
SUMMARY Melanoma is an aggressive skin cancer developing from melanocytes, frequently resulting in metastatic disease
Amoeboid invasion is characterized by rounded cell morphology and high actomyosin contractility driven by Rho GTPase signalling

Summary

Introduction

Metastatic melanoma has a very poor prognosis, and there is a need for additional treatment options. Combinations of BRAF inhibitors and immunotherapies targeting PD-1/PD-L1 show encouraging results; some patients develop resistance to treatment (Jenkins and Fisher, 2021). A novel alternative treatment strategy is to directly inhibit metastatic spread with migrastatic drugs, inhibiting actin polymerization and contractility mechanisms (Gandalovicovaet al., 2017). Amoeboid invasive cells exhibit rounded cell morphology and continuous formation of protruding membrane blebs, allowing the cell to squeeze through the extracellular matrix (ECM) (Tozluoglu et al, 2013) and reduce the requirement for proteolytic degradation of ECM (Pandya et al, 2017). Matrix metalloprotease inhibitors are ineffective in blocking amoeboid invasion (Wyckoff et al, 2006)

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