Podoplanin drives dedifferentiation and amoeboid invasion of melanoma.

Melanoma 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.

Schwann cell plasticity-roles in tissue homeostasis, regeneration, and disease.

How tissues are maintained over a lifetime and repaired following injury are fundamental questions in biology with a disruption to these processes underlying pathologies such as cancer and degenerative disorders. It is becoming increasingly clear that each tissue has a distinct mechanism to maintain homeostasis and respond to injury utilizing different types of stem/progenitor cell populations depending on the insult and/or with a contribution from more differentiated cells that are able to dedifferentiate to aid tissue regeneration. Peripheral nerves are highly quiescent yet show remarkable regenerative capabilities. Remarkably, there is no evidence for a classical stem cell population, rather all cell-types within the nerve are able to proliferate to produce new nerve tissue. Co-ordinating the regeneration of this tissue are Schwann cells (SCs), the main glial cells of the peripheral nervous system. SCs exist in architecturally stable structures that can persist for the lifetime of an animal, however, they are not postmitotic, in that following injury they are reprogrammed at high efficiency to a progenitor-like state, with these cells acting to orchestrate the nerve regeneration process. During nerve regeneration, SCs show little plasticity, maintaining their identity in the repaired tissue. However, once free of the nerve environment they appear to exhibit increased plasticity with reported roles in the repair of other tissues. In this review, we will discuss the mechanisms underlying the homeostasis and regeneration of peripheral nerves and how reprogrammed progenitor-like SCs have broader roles in the repair of other tissues with implications for pathologies such as cancer.