CRISPR-inhibition screen for lncRNAs linked to melanoma growth and metastasis.

Unlabelled: Melanoma being one of the most common and deadliest skin cancers, has been rising since the past decade. Patients at advanced stages of the disease have very poor prognoses, as opposed to at the earlier stages. Nowadays the standard-of-care of advanced melanoma is resection followed by immune checkpoint inhibition based immunotherapy.

AMBRA1 levels predict resistance to MAPK inhibitors in melanoma.

Intrinsic and acquired resistance to mitogen-activated protein kinase inhibitors (MAPKi) in melanoma remains a major therapeutic challenge. Here, we show that the clinical development of resistance to MAPKi is associated with reduced tumor expression of the melanoma suppressor Autophagy and Beclin 1 Regulator 1 (AMBRA1) and that lower expression levels of AMBRA1 predict a poor response to MAPKi treatment. Functional analyses show that loss of AMBRA1 induces phenotype switching and orchestrates an extracellular signal-regulated kinase (ERK)-independent resistance mechanism by activating focal adhesion kinase 1 (FAK1).

Super-enhancer-driven expression of BAHCC1 promotes melanoma cell proliferation and genome stability.

Super-enhancers (SEs) are stretches of enhancers ensuring a high level of expression of key genes associated with cell function. The identification of cancer-specific SE-driven genes is a powerful means for the development of innovative therapeutic strategies. Here, we identify a MITF/SOX10/TFIIH-dependent SE promoting the expression of BAHCC1 in a broad panel of melanoma cells.

Epigenetic Mechanisms Underlying Melanoma Resistance to Immune and Targeted Therapies.

Melanoma is an aggressive skin cancer reliant on early detection for high likelihood of successful treatment. Solar UV exposure transforms melanocytes into highly mutated tumor cells that metastasize to the liver, lungs, and brain. Even upon resection of the primary tumor, almost thirty percent of patients succumb to melanoma within twenty years.

CDK7 and MITF repress a transcription program involved in survival and drug tolerance in melanoma.

Melanoma cell phenotype switching between differentiated melanocytic and undifferentiated mesenchymal-like states drives metastasis and drug resistance. CDK7 is the serine/threonine kinase of the basal transcription factor TFIIH. We show that dedifferentiation of melanocytic-type melanoma cells into mesenchymal-like cells and acquisition of tolerance to targeted therapies is achieved through chronic inhibition of CDK7.

An early Sox2-dependent gene expression programme required for hippocampal dentate gyrus development.

The hippocampus is a brain area central for cognition. Mutations in the human SOX2 transcription factor cause neurodevelopmental defects, leading to intellectual disability and seizures, together with hippocampal dysplasia. We generated an allelic series of Sox2 conditional mutations in mouse, deleting Sox2 at different developmental stages.

Is TFIIH the new Achilles heel of cancer cells?

TFIIH is a 10-subunit complex involved in transcription and DNA repair. It contains several enzymatic activities including a ATP-dependent DNA translocase in XPB and a cyclin-dependent kinase in CDK7. Recently the discovery of several XPB and CDK7 inhibitors with specific impact on the transcriptional addiction of many tumors pinpointed these activities as potential target in cancer chemotherapy.