The roles of the transcriptional regulators YAP and TAZ in the progression of human cutaneous squamous cell carcinoma

  • Alex Howard

Student thesis: Doctoral ThesisPhD


Non-melanoma skin cancers (NMSCs) are among the most frequently diagnosed human cancers worldwide. Of all NMSCs, cutaneous squamous cell carcinoma (cSCC) accounts for the vast majority of NMSC-related deaths due to a high metastatic burden when compared to less aggressive and more frequent basal cell carcinoma (BCC). The greatest risk factor for development of cSCC is chronic UV exposure, which means that incidence of cSCC is rising year-on-year worldwide as a consequence of several socioeconomic factors including global warming and sun-seeker holidaying. The standard of care (SOC) for cSCC in situ is surgical removal, with very limited targeted therapeutic options for advanced and metastatic cSCC. Yes-associated protein (YAP1) and associated paralogue WWTR1 (TAZ) are transcriptional co-regulators and effectors of the Hippo signalling pathway. YAP/TAZ have been implicated in many cancer types, including cSCC, and have been shown to be crucial for cSCC tumour initiation and progression in mouse skin models. However, to-date the independent roles of YAP and TAZ as functionally distinct transcriptional regulators are unknown during the process of human cSCC progression.
To this end, in this study I used an isogenic ‘progression series’ cSCC cell line model derived from a single patient at sequential stages of disease to study the distinct and non-redundant roles of YAP and TAZ. The progression series cell lines consist of a premalignant dysplastic lesion (PM1), invasive carcinoma (MET1) and recurrence following treatment (MET2), and lymph node metastasis (MET4). The progression series was used to generate stable YAP- and TAZ-targeted inducible shRNA-expressing sublines, which were then used to characterise the roles of YAP and TAZ in cSCC progression using 2D/3D cell-based assays and bioinformatics. Furthermore, the roles of YAP and TAZ were investigated in a more clinically relevant skin organotypic invasion model, as well as a novel high-throughput zebrafish xenograft metastasis assay.
It was found that there is plasticity in the roles of YAP and TAZ throughout cSCC progression, where early invasive carcinoma cells (MET1) highly depend on YAP for 2D/3D growth, invasion and metastases, and this progresses to a mixed dependence on YAP and TAZ for distinct phenotypes in MET2 cells. Metastatic cSCC (MET4) cells seemingly lose dependency on YAP and TAZ for growth, however single-paralogue knockdowns are sufficient to reduce cell invasion and metastasis. Furthermore, the loss of dependence on YAP and TAZ in MET4 cells was revealed to be a likely result of reciprocal compensation, where dual YAP/TAZ inhibition significantly perturbed growth. Together, previously undefined roles of YAP and TAZ throughout cSCC progression have been uncovered in this study; additionally, careful characterisation of the cSCC progression series gives insight into molecular marker expression/localisation that can possibly predict YAP and/or TAZ inhibition sensitivity or resistance in models of human cSCC.
Date of Award24 May 2023
Original languageEnglish
Awarding Institution
  • University of Bath
SupervisorGernot Walko (Supervisor), Robert Kelsh (Supervisor) & Charareh Pourzand (Supervisor)


  • cSCC
  • YAP
  • TAZ

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