Bath Alumni Fund (BB-F1819B-RS01) - Targeting YAP/TAZ in cutaneous squamous cell carcinoma

Project: Research-related funding

Project Details

Description

Nonmelanoma skin cancers (NMSCs), often now also termed keratinocyte cancers, are by far the most frequently diagnosed human cancers, and rates continue to rise by 2–4% each year. Currently, 2–3 million NMSCs and 132,000 melanoma skin cancers are diagnosed worldwide each year (http://www.who.int/uv/faq/skincancer/ en/index1.html). Cutaneous squamous cell carcinoma (cSCC) accounts for the majority of deaths associated with NMSCs. cSCC can be cured by surgical removal if detected early. But if left untreated and the cancer cells spread to other parts of the body, no effective treatment is available. This is serious, resulting in death in 70-89% of patients, with immunocompromised patients being at greatly increased risk (up to 10%) of developing metastatic disease.

The closely related transcriptional co-activator proteins YAP and TAZ(WWTR1) have emerged as important drivers of tumour initiation, progression and metastasis in many different cancers, including cSCC. YAP/TAZ are essential in cSCC, but are largely dispensable for normal tissue homeostasis, pinpointing them as prime candidates for effective treatments. YAP/TAZ lack enzymatic activities, thus anti-YAP/TAZ therapies must target protein-protein interactions. Consequently, the overall aim of this project is to identify and characterise the different transcriptional binding partners that enable YAP/TAZ to execute their various downstream transcriptional programmes to promote cSCC progression.

We will obtain global pictures of the nuclear interaction partners of YAP/TAZ in premalignant human epidermal cells and human cSCC cells using a novel technique called rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) that allows the study of chromatin-bound transcription factor complexes in a rapid and robust manner by combining chromatin immuno-precipitation with mass spectrometry. RIME will inform us about the different functional components that form a complex with chromatin-recruited YAP/TAZ, enabling us to monitor changes in the chromatin-associated YAP/TAZ interactome during cSCC progression, and to identify and characterise cSCC-specific/enriched YAP/TAZ transcriptional binding partners as novel candidate drug targets.
Short title4,862
StatusActive
Effective start/end date12/04/19 → …