Cell Adhesion Molecules in Plasticity and Metastasis

Abstract

Prior to metastasis, modern therapeutics and surgical intervention can provide a favorable long-term survival for patients diagnosed with many types of cancers. However, prognosis is poor for patients with metastasized disease. Melanoma is the deadliest form of skin cancer, yet in situ and localized, thin melanomas can be biopsied with little to no postsurgical follow-up. However, patients with metastatic melanoma require significant clinical involvement and have a 5-year survival of only 34% to 52%, largely dependent on the site of colonization. Melanoma metastasis is a multi-step process requiring dynamic changes in cell surface proteins regulating adhesiveness to the extracellular matrix (ECM), stroma, and other cancer cells in varied tumor microenvironments. Here we will highlight recent literature to underscore how cell adhesion molecules (CAM) contribute to melanoma disease progression and metastasis.

Figure 1:. Phenotypic characterization of select CAMs in melanoma plasticity.

Schematic representation of the dynamic spectrum and heterogeneity that underlies melanoma progression and metastatic potential. The left side of the figure depicts two melanoma cells with a high proliferative capacity and low invasive potential. Select CAMs known to contribute to this state are highlighted as well as transcription factors associated with high proliferation/low invasiveness. The melanoma cell on the right is portrayed with select CAMs and transcription factors associated with a highly invasive, slow cycling phenotype.

Figure 2:. Differential CAM function in melanoma progression.

Graphical representation of select CAM associated functions in melanoma progression. From top left, clockwise: ECM association: The metastatic potential of melanoma can be dictated by ECM concentration and complexity. Both less dense, low complexity and dense, high complexity ECM can inhibit melanoma invasiveness. Whereas an optimal ECM complexity and density can serve to facilitate invasiveness. Tropism: CAMs contribute to the metastatic tropism of melanoma. Melanoma derived, integrin containing exosomes can prepare the metastatic niche for subsequent colonization. Additionally, CAMs directly interact with organ specific cell types; the gap junction mediated pro-tumor signaling loop between melanoma and astrocytes highlights the role of connexins in CNS tropism. Immune Surveillance: CAMs can stimulate and inhibit cytotoxic response and can be prognostic determinants for immunotherapy efficacy. For instance, immune checkpoint inhibitor treatment is more efficacious when melanoma derived E-cadherin associates with cytotoxic Tcells. CAR Tcells have been engineered to target melanoma with overrepresented integrin αβ expression. Expression of certain CAMs can inhibit innate immune surveillance/response. As an example, the IgSF CEACAM1 has been shown to inhibit the cytotoxic function of NK cells. Tumor Heterogeneity: Heterogeneous CAM expression is associated with increased fitness and therapy resistance. A spectrum depicting highly proliferative/poorly invasive melanoma cells (cluster on right) to highly invasive/slow cycling cells (left) are depicted.