Adapt, Recycle, and Move on: Proteostasis and Trafficking Mechanisms in Melanoma

Abstract

Melanoma has emerged as a paradigm of a highly aggressive and plastic cancer, capable to co-opt the tumor stroma in order to adapt to the hostile microenvironment, suppress immunosurveillance mechanisms, and disseminate. In particular, oncogene- and aneuploidy-driven dysregulations of proteostasis in melanoma cells impose a rewiring of central proteostatic processes, such as the heat shock and unfolded protein responses, autophagy, and the endo-lysosomal system, to avoid proteotoxicity. Research over the past decade has indicated that alterations in key nodes of these proteostasis pathways act in conjunction with crucial oncogenic drivers to increase intrinsic adaptations of melanoma cells against proteotoxic stress, modulate the high metabolic demand of these cancer cells and the interface with other stromal cells, through the heightened release of soluble factors or exosomes. Here, we overview and discuss how key proteostasis pathways and vesicular trafficking mechanisms are turned into vital conduits of melanoma progression, by supporting cancer cell’s adaptation to the microenvironment, limiting or modulating the ability to respond to therapy and fueling melanoma dissemination.

An autophagy-driven pathway of ATP secretion supports the aggressive phenotype of BRAFV600E inhibitor-resistant metastatic melanoma cells

“…45 Thus, our study not only extends these pro-tumorigenic effects of eATP to BRAF-inhibitor resistant melanoma cells, but demonstrates the key role of autophagy in exporting ATP extracellularly, thus initiating an autocrine loop fostering melanoma cells' metastastic features. Moreover, these findings are in line with the emerging tumor-promoting roles of hyperactivated lysosomal-dependent vesicular trafficking [46][47][48] and of key autophagy genes, such as ATG7, 49 in melanoma invasion and progression in vivo.…”

Whole-body imaging of lymphovascular niches identifies pre-metastatic roles of midkine

“…Therefore, it is unclear whether (and how) lymphangiogenesis contributes to visceral metastasis. Soluble and vesicle-associated proteins secreted by tumors and/or their stroma have been proposed to condition premetastatic sites in this disease 8, 9, 10, 11, 12, 13, 14 . Still, the identity and prognostic impact of lymphangiogenic mediators remain elusive 2, 14 .…”

Non-Apoptotic Cell Death Signaling Pathways in Melanoma

“…The vesicle nucleation is proceeded by the phosphoinositide 3-kinase (PI3K) complex that includes VPS34/PIK3C3 and Beclin-1. Beclin-1, a BH3-only protein from BCL-2 family of proteins, is phosphorylated by ULK1 and acts as a scaffold facilitating localization of other autophagic proteins [54]. Beclin-1 is also a mechanistic link between autophagy and apoptosis as anti-apoptotic proteins BCL-2 and BCL-X L can interact with Beclin-1 to interrupt both the Beclin-1/VPS34 complex and the interaction with ultraviolet radiation resistance associated gene (UVRAG) [55].…”

“…Processing and conjugation of LC3-I with phosphatidylethanolamine (PE) is catalyzed by ATG4B and ATG7, and leads to the formation of LC3B-II. While LC3-I remains in the cytosol, LC3-II is incorporated into both the outer and the inner membrane of the autophagosome, and therefore LC3-II is largely considered as a marker of autophagy induction [54]. Also, an adaptor protein sequestosome 1 (SQTM1, known as p62), which directs substrates to the autophagosomes, is degraded with its cargo proteins and can be used as a read-out of the autophagic flux [58,59].…”