Phenotypic and metabolic heterogeneity within tumors is a major barrier to effective cancer therapy. Yet how metabolism is implicated in specific phenotypes, and whether lineage-restricted mechanisms control key metabolic vulnerabilities remains poorly understood. In melanoma, down-regulation of the lineage addiction oncogene Microphthalmia-associated Transcription Factor (MITF) is a hallmark of the proliferative-to-invasive phenotype switch, though how MITF promotes proliferation and suppresses invasion is poorly defined. Here we show that MITF is a lineage restricted activator of the key lipogenic enzyme stearoyl-CoA desaturase (SCD), and that SCD is required for MITF High melanoma cell proliferation. By contrast MITF Low cells are insensitive to SCD inhibition. Significantly, the MITF-SCD axis suppresses metastasis, inflammatory signaling, and an ATF4mediated feedback-loop that maintains dedifferentiation. Our results reveal that MITF is a lineagespecific regulator of metabolic reprogramming, whereby fatty acid composition is a driver of melanoma phenotype-switching, and highlight that cell phenotype dictates response to drugs targeting lipid metabolism.

NOTE: This protocol has not been validated with clinical samples. To facilitate collaborations with interested parties to jointly advance the fight against the current coronavirus pandemic, wehave set up a public forum on www.LAMP-Seq.org.

the global spread of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in over 109 million confirmed cases, and approximately 2.4 million deaths have been attributed to Coronavirus Disease 2019 (COVID-19) 1 . Current containment strategies based on 'test-trace-isolate' face major issues: (1) many infected individuals do not show any symptoms and, therefore, remain untested 2 ; (2) supply chain issues limit testing capacity; and(3) the successive (rather than parallel) testing of contact individuals causes a substantial lag in identifying infection chains, resulting in undetected spread due to delayed diagnosis. By contrast, repeated testing of large groups of individuals, regardless of symptoms or