Deciphering melanoma brain metastases: Role of cellular plasticity and metastatic origin

The treatment of brain metastases in malignant melanoma remains one of the major clinical challenges despite immuno-oncological and targeted therapies. Here, we revealed that successful colonization of the brain by melanoma cells is primarily determined by two complementary factors: (i) intrinsic phenotypic plasticity along the proliferative-invasive axis, and (ii) the metastatic origin of the cells. By combining defined 3D hydrogel models with ex vivo mouse brain slices, we mimicked key mechanical and biochemical features of the cerebral microenvironment, including stiffness, nonlinear mechanical behavior and extracellular matrix composition. Melanoma cell lines representing proliferative and invasive states exhibited distinct, matrix-dependent responses in proliferation, cluster formation, spreading, and migration. Cell spreading was restricted to bioactive matrices and was strongly dependent on hyaluronic acid-mediated signaling, Functional inhibition experiments further supported a contributory role of CD44-mediated interactions in regulating melanoma cell spreading. In ex vivo brain slices, region-specific invasion patterns were observed, consistent with context-dependent plasticity. Our findings demonstrate that melanoma adaptation to brain-like microenvironments arises from the interaction between phenotypic programs and extracellular matrix-dependent signaling. These results provide a framework for the development of biomimetic models to further investigate brain metastasis biology and matrix-driven adaptation mechanisms in melanoma.