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HPV Tumour Biology Team

Team Leader: Dr Tim Fenton

Research summary

Our overall aim is to learn more about the cellular pathways involved in tumour development by studying the molecular mechanisms by which oncogenic viruses cause cancer. Our focus is on the high-risk human papillomaviruses (HPV), which cause nearly all cervical cancers, a large proportion of other anogenital cancers and an increasing number of head and neck cancers (HNSCC). We are also part of the head and neck cancer research team. In addition to learning more about the fundamental mechanisms by which tumour development occurs, we are also identifying cellular genes that become critical for the survival of HPV-transformed cells with the objective of developing targeted therapies for these cancers.

Team Lead: Tim Fenton

My research background is in mitogenic signal transduction pathways and how these become aberrantly activated in cancer. After completing my Ph.D. with Ivan Gout at the UCL branch of the Ludwig Institute for Cancer Research (LICR), I moved to another LICR branch, at the University of California San Diego, for postdoctoral training with Webster Cavenee and Frank Furnari. I returned to the UK to work with Chris Boshoff at UCL Cancer Institute and became interested in an emerging cancer: HPV-associated HNSCC. The team continues to focus on the biology of HPV-associated tumours and our studies have extended to cervical cancer; a shared interest with Prof Kerry Chester, in whose lab I have established the HPV tumour biology team. We hope that our research into the biology of HPV-driven cancers will uncover novel targets for Kerry and her team. Tim Fenton UCL Iris research profile

Team members:

Luke Williams (PhD student) I am in my second year of PhD under the supervison of Prof Kerry Chester, Mr Nicholas Kalavrezos and Dr Tim Fenton.  My background is in oral and maxillofacial surgery and I am qualified in dentistry and medicine.  My research concerns genetic and epigenetic heterogeneity of head and neck cancer and novel targets in HPV-associated tumours.  I am supported by a research endowment from the British Association of Oral and Maxillofacial Surgeons.

Ankur Chakravarthy (PhD student) I am a second year PhD student with a range of research interests connected to the development of HPV-driven tumours. My research is focused on using bioinformatics, molecular biology and genomic editing approaches to understand the transcriptional profiles of HPV-driven tumours and the genetic and epigenetic changes that underlie the establishment of these profiles.

  • Priyam Tyagi (Biosciences MRes student)
  • Greg Jones (CRUK PhD rotation student)

Previous members:

Xiao Xiao Han (MSc student)
Research projects:
1. Through analysing HNSCC sequence data from The Cancer Genome Atlas (TCGA) project, we recently discovered that many of the somatic mutations in cellular genes that cooperate with HPV oncogenes to drive tumour development are likely caused by cytidine deaminases; a family of enzymes involved in the innate immune response to viral infection. We are currently using CRISPR-Cas9 engineering to test whether APOBEC genes are required for HPV-driven transformation in cell-based models.

2. In collaboration with Drs. Alan Ashworth and Chris Lord at the Institute of Cancer Research we have screened an siRNA library targeting the entire human kinome against a panel of HPV+ and HPV- HNSCC and cervical cancer cell lines. We have identified a number of kinases that appear to be specifically required for the growth of the HPV+ cells and we are investigating their potential suitability as therapeutic targets for HPV-associated cancers.

3. We have defined a cross-tissue gene expression signature for HPV-associated cancer and are investigating the functional role that these signature genes play in tumour development and maintenance. We are also employing the CRISPR-Cas9 system to disrupt regulators of this transcriptional programme to understand their role in HPV-driven oncogenesis.

4. We are exploring the genetic and epigenetic heterogeneity of HPV-associated cancers from the head and neck and cervix by multi-region exome sequencing of tumour samples and DNA methylation analysis of both tumour samples and premalignant lesions.

Collaborators:

  •     John Doorbar (University of Cambridge)
  •     Stephen Henderson (Bill Lyons Informatics Centre, UCL Cancer Institute)
  •     Matthias Lechner (UCLH / UCL Cancer Institute)
  •     Chris Lord (Institute of Cancer Research)
  •     Martin Widschwendter (UCLH/UCL Cancer Institute)
  •     Andy Feber (UCL Cancer Institute)

Related publications:

Henderson, S., Fenton, T. 2015 ‘APOBEC3 genes: retroviral restriction factors to cancer drivers’ Trends Mol Med 21(5):274-284

Henderson, S., Chakravarthy, A., Fenton, T.R. 2014 ‘When defense turns into attack: Antiviral cytidine deaminases linked to somatic mutagenesis in HPV-associated cancer’ Mol Cell Oncol 1 (1), e29914. doi:10.4161/mco.29914

Henderson, S., Chakravarthy, A., Su, X., Boshoff, C. Fenton, T.R. 2014 ‘APOBEC-mediated cytosine deamination links PIK3CA helical domain mutations to Human Papillomavirus-driven tumour development.’ Cell Reports 7(6):1833-45.

Lechner M, Frampton G, Fenton T, Feber A, Palmer G, Jay A, Pillay N, Forster M, Cronin MT, Lipson D, Miller VA, Brennan TA, Henderson S, Vaz F, O 8217 Flynn P, Kalavrezos N, Yelenski R, Beck S, Stephens PJ, Boshoff C. 2013 ‘Targeted next-generation sequencing of head and neck squamous cell carcinoma identifies novel genetic alterations in HPV+ and HPV- tumors.’ Genome Med 5(5):49.

Lechner M, Fenton T, West J, Wilson G, Feber A, Henderson S, Thirlwell C, Dibra HK, Jay A, Butcher L, Chakravarthy AR, Gratrix F, Patel N, Vaz F, O'Flynn P, Kalavrezos N, Teschendorff AE, Boshoff C, Beck S. 2013 ‘Identification and functional validation of HPV-mediated hypermethylation in head and neck squamous cell carcinoma.’ Genome Med 5(2):15.

Read, R, D., Fenton, T. R., Gomez G. G., Vandenberg, S. R., Wykosky, J., Babic, I., Yang, H., Iwanami, A., Cavenee, W. K., Mischel, P. S., Furnari, F. B., Thomas, J. B. 2013 ‘A kinome-wide RNAi screen in Drosophila glia reveals that RIO kinases mediate cell proliferation and survival through TORC2-Akt signaling in glioblastoma.’ PLoS Genetics Feb 14; 10.1371/journal.pgen.1003253.

Fenton, T. R., Nathanson, D., Ponte de Albuquerque, C., Kuga, D., Iwanami, A., Dang, J., Yang, H., Kazuhiro, T., Oba-Shinjo, S. M., Uno, M., Inda, M. M., Wykosky, J., Bachoo, R.M., James, C.D., DePinho, R.A., VandenBerg, S. R., Zhou, H., Marie, S. K. N., Mischel, P.S., Cavenee, W.K., Furnari, F.B. 2012 ‘Resistance to EGF receptor inhibitors in glioblastoma mediated by phosphorylation of the PTEN tumour suppressor at tyrosine 240’ Proc Nat Acad Sci USA Aug 28; 109(35):14164-9.