AXL receptor tyrosine kinase plays established roles in tumor cell dedifferentiation and disease progression, but AXL regulation is more poorly understood. In their study on page 428, Schieven and colleagues find, using a genome-wide CRISPR-Cas9 screen, that the Elongin BC ubiquitin ligase complex targets AXL for proteosomal degradation. Correspondingly, as opposed to AXL expression, Elongin B/C expression positively correlates with melanoma differentiation status. The cover features a creative continuum of melanoma cell dedifferentiation in terms of AXL (magenta) and Elongin B (white) expression, which are displayed in melanoma cell confocal microscopy images that also feature nuclear (cyan) and Golgi apparatus (green) staining. This article is also Highlighted on page 387.