Department of Biology
Friday 3 February 2023, 1.00PM
Speaker(s): Professor Andrew Macdonald, Chair of Tumour Virology, (University of Leeds)
Persistent infection with high-risk human papillomaviruses, such as HPV16 and HPV18, is the cause of ~5% of the global cancer burden, including nearly all carcinomas of the cervix, other anogenital sites and oropharynx. Cervical cancer remains the fourth most common cause of cancer death in women, and this burden disproportionately impacts low- and middle-income countries (LMIC), where the death rate is 18 times higher than in developed nations. Limited vaccine availability in LMIC, vaccine hesitancy in developed countries and the lag between infection and disease ensures that the burden of HPV-associated malignancies remains high. As such, HPV still represents a major burden in many clinical settings. Thus, understanding the mechanisms controlling HPV cancer initiation and progression has potentially significant academic, financial and medical implications for treatment of HPV malignancies.
Understanding which host factors are required for the pathogenicity and transforming activity of the HPV oncoproteins is crucial. Equally important will be to determine if virus type specific manipulation of cellular pathways contributes to observed differences in pathology, eg lymph node metastasis, stromal invasion and tumour associated apoptosis, between HPV16 and HPV18-positive cancers. Transcriptional coactivator with PDZ binding motif (TAZ) and its paralogue Yes-activated protein (YAP1) are master regulators of epithelial homeostasis, whose deregulation fuels the initiation, progression and metastasis of some of the most common human cancers.
Whilst YAP1 knowledge benefits from a rich body of research, we know less about TAZ regulation and function in cancers. This presentation will address key questions about TAZ function, building on our observation that TAZ is strongly upregulated in HPV18-, but not HPV16-transformed cells. Crucially, TAZ is essential for HPV18-driven cervical cancer cell growth and the loss of TAZ is not compensated for by over-expressing YAP1, indicating TAZ specific influences in HPV18-driven cervical cancers. Building upon this, using RNA-Seq analysis identified both known and novel TAZ-specific targets, including genes previously unconnected to carcinogenesis that we show contribute to key hallmarks of cervical cancer.
In summary this presentation provides information on a key host oncogene and potentially a molecular explanation for the poorer prognosis of HPV18-positive cervical cancers.
Location: B/K018, Dianna Bowles Lecture Theatre