Leveraging Transcriptional Dynamics to Improve BRAF Inhibitor Responses in Melanoma

Smalley, Inna; Kim, Eun-Jung; Li, Jiannong; Spence, Paige; Wyatt, Clayton; Erolgu, Zeynep; Sondak, Vernon K.; Messina, Jane L.; Babacan, Nalân Akgül; Maria-Engler, Silvya Stuchi; Armas, Lesley de; Williams, Siôn L.; Gatenby, Robert A.; Chen, Y. Ann; Anderson, Alexander R.A.; Smalley, Keiran S.M.

doi:10.2139/ssrn.3409285

Cited by 2 publications

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Circulating Tumour DNA in Melanoma—Clinic Ready?

et al. 2022

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Purpose of Review Liquid biopsies, including circulating tumour DNA (ctDNA), can inform a variety of clinical questions. This review examines the potential role of ctDNA as a clinical tool to inform clinical decision-making from early to late stage cutaneous melanoma. Recent Findings In pre-clinical studies, ctDNA has been shown to detect minimal residual disease and molecular relapse; predict and monitor response to therapy; and identify key resistance mechanisms. Here, we examine the potential utility of ctDNA and discuss its limitations for use in patients with melanoma. We present novel clinical trials, which are testing its value as a tool to augment clinical decision-making. Finally, we discuss the steps that are needed to ensure that ctDNA is used optimally in order to improve outcomes for patients with melanoma. Summary Preclinical studies have shown that ctDNA has huge potential to provide real-time information about disease status in patients with melanoma. It is now time to test it rigorously within clinical trials to assess how it can be optimally used to benefit patients in the clinic.

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Circulating Tumour DNA in Melanoma—Clinic Ready?

et al. 2022

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HDAC8-mediated inhibition of EP300 drives a neural crest-like transcriptional state that increases melanoma brain metastasis

Emmons

Bennett

Riva

et al. 2022

Preprint

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Melanomas are heterogeneous and adopt multiple transcriptional states that can confer an invasive phenotype and resistance to therapy. Little is known about the epigenetic drivers of these cell states, limiting our ability to regulate melanoma heterogeneity and tumor progression. Here we identify stress-induced HDAC8 activity as the driver of a neural crest stem cell (NCSC)-like transcriptional state that increased the formation of melanoma brain metastases (MBM). Exposure of melanocytes and melanoma cells to multiple different stresses led to HDAC8 activation, a switch to a NCSC gene expression signature and the adoption of an amoeboid, invasive phenotype. This cell state enhanced the survival of melanoma cells under shear stress conditions and increased the formation of metastases in the brain. scRNA-seq analyses showed that HDAC8 expression was correlated with the NCSC cell state in clinical MBM specimens. ATAC-Seq and ChIP-Seq analysis showed HDAC8 to alter chromatin structure by increasing H3K27ac and accessibility at c-Jun binding sites without changing global histone acetylation. The increased accessibility of Jun binding sites was paralleled by decreased H3K27ac and accessibility at MITF binding sites and loss of melanoma-lineage gene expression. Mass spectrometry-based acetylomics demonstrated that HDAC8 deacetylated the histone acetyltransferase (HAT) EP300 leading to its enzymatic inactivation. This, in turn, led to an increased binding of EP300 to Jun-transcriptional sites and decreased binding to MITF-transcriptional sites. Increased expression of EP300 decreased invasion and increased the sensitivity of melanoma cells to multiple stresses while inhibition of EP300 function increased invasion and resistance to stress. We identified HDAC8 as a novel mediator of transcriptional co-factor inactivation and chromatin accessibility that increases MBM development.

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Leveraging Transcriptional Dynamics to Improve BRAF Inhibitor Responses in Melanoma

Cited by 2 publications

References 0 publications

Circulating Tumour DNA in Melanoma—Clinic Ready?

Circulating Tumour DNA in Melanoma—Clinic Ready?

HDAC8-mediated inhibition of EP300 drives a neural crest-like transcriptional state that increases melanoma brain metastasis

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