Lineage-Restricted Regulation of SCD and Fatty Acid Saturation by MITF Controls Melanoma Phenotypic Plasticity

Vivas-García, Yurena; Falletta, Paola; Liebing, Jana; Louphrasitthiphol, Pakavarin; Feng, Yongmei; Chauhan, Jagat; Scott, David A.; Glodde, Nicole; Chocarro-Calvo, Ana; Bonham, Sarah; Osterman, Andrei L.; Fischer, Román; Ronai, Ze’ev; García-Jiménez, Custodia; Hölzel, Michael; Goding, Colin R.

doi:10.1016/j.molcel.2019.10.014

Cited by 105 publications

(123 citation statements)

References 116 publications

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“…As we have identified ATF4 as the responsible transcription factor for PTGS2 induction downstream of NRF2, it is likely that an interaction between ATF4 and MITF regulates PTGS2 in melanoma cells. In support of this theory, it was previously reported that MITF increases the ratio between monounsaturated and saturated fatty acids, which can negatively impact ATF4 [45]. As ATF4 also suppresses MITF levels [8], both are connected by a mutually negative regulatory loop.…”

Section: Discussionmentioning

confidence: 70%

The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression

et al. 2020

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The transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H2O2 or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma.

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Section: Discussionmentioning

confidence: 70%

The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression

et al. 2020

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“…Primary tumors may acquire functional mutations during tumor development that initiate the invasion‐metastatic cascade whereby cancer cells adopt an epithelial‐to‐mesenchymal (EMT) phenotype to disseminate from primary lesions into circulation (Lu & Kang, ; Vivas‐García et al , ). Once cancer cells leave the primary tumor and embark on this journey, they must undoubtedly adapt their metabolism to overcome the stresses and dangers they face in circulation.…”

Section: Introductionmentioning

confidence: 99%

Nutrient metabolism and cancer in the in vivo context: a metabolic game of give and take

et al. 2020

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Nutrients are indispensable resources that provide the macromolecular building blocks and energy requirements for sustaining cell growth and survival. Cancer cells require several key nutrients to fulfill their changing metabolic needs as they progress through stages of development. Moreover, both cell-intrinsic and microenvironment-influenced factors determine nutrient dependencies throughout cancer progression-for which a comprehensive characterization remains incomplete. In addition to the widely studied role of genetic alterations driving cancer metabolism, nutrient use in cancer tissue may be affected by several factors including the following: (i) diet, the primary source of bodily nutrients which influences circulating metabolite levels; (ii) tissue of origin, which can influence the tumor's reliance on specific nutrients to support cell metabolism and growth; (iii) local microenvironment, which dictates the accessibility of nutrients to tumor cells; (iv) tumor heterogeneity, which promotes metabolic plasticity and adaptation to nutrient demands; and (v) functional demand, which intensifies metabolic reprogramming to fuel the phenotypic changes required for invasion, growth, or survival. Here, we discuss the influence of these factors on nutrient metabolism and dependence during various steps of tumor development and progression.

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“…Unlike other fatty acids, sapienate is only found in humans and is a major component of human sebum 78 . Intriguingly, a recent study indicated that SCD expression is positively regulated by MITF 79 . Therefore, one potential mechanism of increased dependency on FADS2-mediated fatty acid desaturation in MITF low /AXL high LD-rich melanoma cell lines could be via MITF.…”

Section: Discussionmentioning

confidence: 99%

FADS2-mediated fatty acid desaturation and cholesterol esterification are signatures of metabolic reprogramming during melanoma progression

Lee

Chen

Collard

et al. 2020

Preprint

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Identifying metabolic alterations in disease progression has been challenged by difficulties in tracking metabolites at sub-cellular level. Here, by high-resolution stimulated Raman scattering and pump-probe imaging and spectral phasor analysis of melanoma cells grouped by MITF/AXL expression pattern and of human patient tissues paired by primary and metastatic status, we identify a metabolic switch from a pigment-containing phenotype in low-grade melanoma to a lipid-rich phenotype in metastatic melanoma. The lipids found in MITFlow/AXLhigh melanoma cells contain high levels of cholesteryl ester (CE) and unsaturated fatty acid species. Elevated fatty acid uptake activity in MITFlow/AXLhigh melanoma contributes to the lipid-rich phenotype, and inhibiting fatty acid uptake suppresses cell migration. Importantly, monounsaturated sapienate is identified as an essential fatty acid that effectively promotes cancer migration. Blocking either FADS2-mediated lipid desaturation or SOAT-mediated cholesterol esterification effectively suppresses the migration capacity of melanoma in vitro and in vivo, indicating the therapeutic potential of targeting these metabolic pathways in metastatic melanoma. Collectively, our results reveal metabolic reprogramming during melanoma progression, and highlight metabolic signatures that could serve as targets for metastatic melanoma treatment and diagnosis.

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Lineage-Restricted Regulation of SCD and Fatty Acid Saturation by MITF Controls Melanoma Phenotypic Plasticity

Cited by 105 publications

References 116 publications

The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression

The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression

Nutrient metabolism and cancer in the in vivo context: a metabolic game of give and take

FADS2-mediated fatty acid desaturation and cholesterol esterification are signatures of metabolic reprogramming during melanoma progression

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