Purpose: Treatment of BRAF V600E -mutant melanomas with MAPK inhibitors (MAPKi) results in significant tumor regression, but acquired resistance is pervasive. To understand nonmutational mechanisms underlying the adaptation to MAPKi and to identify novel vulnerabilities of melanomas treated with MAPKi, we focused on the initial response phase during treatment with MAPKi.Experimental Design: By screening proteins expressed on the cell surface of melanoma cells, we identified the fatty acid transporter CD36 as the most consistently upregulated protein upon short-term treatment with MAPKi. We further investigated the effects of MAPKi on fatty acid metabolism using in vitro and in vivo models and analyzing patients' pre-and ontreatment tumor specimens.Results: Melanoma cells treated with MAPKi displayed increased levels of CD36 and of PPARa-mediated and carnitine palmitoyltransferase 1A (CPT1A)-dependent fatty acid oxidation (FAO). While CD36 is a useful marker of melanoma cells during adaptation and drug-tolerant phases, the upregulation of CD36 is not functionally involved in FAO changes that characterize MAPKi-treated cells. Increased FAO is required for BRAF V600E -mutant melanoma cells to survive under the MAPKi-induced metabolic stress prior to acquiring drug resistance. The upfront and concomitant inhibition of FAO, glycolysis, and MAPK synergistically inhibits tumor cell growth in vitro and in vivo.Conclusions: Thus, we identified a clinically relevant therapeutic approach that has the potential to improve initial responses and to delay acquired drug resistance of BRAF V600E -mutant melanoma.
Recent studies have revealed the importance of long noncoding RNAs (lncRNAs) as tissue-specific regulators of gene expression. There is ample evidence that distinct types of vasculature undergo tight transcriptional control to preserve their structure, identity, and functions. We determine a comprehensive map of lineage-specific lncRNAs in human dermal lymphatic and blood vascular endothelial cells (LECs and BECs), combining RNA-Seq and CAGE-Seq. Subsequent antisense oligonucleotide-knockdown transcriptomic profiling of two LEC- and two BEC-specific lncRNAs identifies LETR1 as a critical gatekeeper of the global LEC transcriptome. Deep RNA-DNA, RNA-protein interaction studies, and phenotype rescue analyses reveal that LETR1 is a nuclear trans-acting lncRNA modulating, via key epigenetic factors, the expression of essential target genes, including KLF4 and SEMA3C, governing the growth and migratory ability of LECs. Together, our study provides several lines of evidence supporting the intriguing concept that every cell type expresses precise lncRNA signatures to control lineage-specific regulatory programs.
Recent studies have revealed the importance of long noncoding RNAs (lncRNAs) as tissue-specific regulators of gene expression. There is ample evidence that distinct types of vasculature undergo tight transcriptional control to preserve their structure, identity, and functions. We determined, for the first time, the global lineage-specific lncRNAome of human dermal blood and lymphatic endothelial cells (BECs and LECs), combining RNA-Seq and CAGE-Seq. A subsequent genome-wide antisense oligonucleotide-knockdown screen of a robust set of BEC-and LEC-specific lncRNAs identified LESR2 as a critical gatekeeper of the global LEC transcriptome. Deep RNA-DNA, RNA-protein, and phenotype rescue analyses revealed that LESR2 acts as a nuclear trans-acting lncRNA modulating, via key epigenetic factors, the expression of essential target genes, including KLF4 and SEMA3C, governing the growth and migratory ability of LECs. Together, our study provides new evidence supporting the intriguing concept that every cell type expresses precise lncRNA signatures to control lineage-specific regulatory programs.The blood and lymphatic vascular systems are essential for the efficient transport of oxygen, nutrients, signaling molecules, and leukocytes to and from peripheral tissues, the removal of waste products, and the preservation of fluid homeostasis. Increased activation or impaired function of these vascular networks represent a hallmark of many pathological conditions, including cancer progression, chronic inflammatory diseases, and diseases leading to blindness 1-3 .During development, the blood vascular system arises from endothelial cell progenitors that differentiate from mesodermal cells, mostly through the expression of the transcription factor (TF) ETV2. Activation of the VEGFA/VEGFR2 signaling and expression of blood vascular endothelial cell (BEC) markers, such as NRP1 and EphrinB2, further differentiate these precursor cells into BECs, which then form the hierarchical network of blood vessels 4 . In contrast, lymphatic vasculogenesis starts after the establishment of the blood circulatory system. Thereafter, a distinct subpopulation of endothelial cells lining the cardinal vein starts differentiating by expressing the TF PROX1, the master regulator of lymphatic endothelial cell (LEC) identity, via the TFs SOX18 and COUPTFII. Once exiting the veins, LECs starts expressing other lymphatic-specific markers, such as podoplanin, VEGFR3, and NRP2, and they migrate, in a VEGFC-dependent manner, to form the primary lymph sacs from which the lymphatic vascular system further develops following sprouting, branching, proliferation, and remodeling processes 5 . However, a nonvenous origin of LECs has also been described in the skin, mesenteries, and heart 6-8 . In adulthood, while the blood and lymphatic vasculature are generally quiescent, they can be readily activated in pathological conditions such as wound healing, inflammation, and cancer by disturbance of the natural balance of pro-and anti-(lymph)angiogenic factors 1,9 . Therefor...
<p>Table S5, related to Figure S5C</p>
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