University of Birmingham

Professor Jo Parish

Title: Understanding oncogenic human papillomavirus persistence and immune modulation in tonsil epithelia

• Principle Investigator: Jo Parish
• Co-Investigators: Jack Ferguson and Sascha Ott (University of Warwick)
• MRC project grant
• 30^th November 2023 to 31^st October 2026
• £696,694

Human papillomaviruses (HPV) are the cause of cancers of anal and genital regions of the body (including the uterine cervix), and cancers of the head and neck, specifically in the tonsils and base of tongue, collectively known as the oropharynx. The primary site of oropharyngeal HPV infection is the tonsil, a lymphoid organ that serves to detect invading pathogens and prevent respiratory and gastrointestinal infection. Establishment of persistent high-risk HPV infection in the tonsil must therefore require strong suppression of local immune cell activation.

Using state-of-the-art primary cell-based models of HPV infection at the tonsil, and cutting-edge genomics methods, we will investigate how HPV suppresses host immune detection. We will then use our expertise in primary cell culture to combine primary keratinocytes with donor-matched lymphoidal tissue to establish in vitro tonsil organ-like cultures that will be used to study immune cell activation and migration in response to HPV infection through single cell sequencing and digital pathology. The results of this project will uncover novel mechanisms of HPV persistence in the tonsil. This is important as there is a critical need to understand how oncogenic HPV can persist and induce carcinogenesis within the immune-rich oropharynx to enable the development of novel (immuno-) therapies to combat HPV-driven cancers.

Professor Aga Gambus

Title: The role of DONSON in DNA replication initiation

• Principle Investigator: Aga Gambus
• Co-Investigator: Marco Saponaro
• BBSRC project grant
• 1^st December 2023 to 30^th November 2026
• £742,477

Our bodies are built of trillions of cells. Over time, our cells age and become damaged, so a subset of cells in our bodies keep growing and dividing, creating their own replacements. Before each cell division, every cell must first duplicate its DNA - all of it, just once and without mistakes. Mistakes during DNA replication that are not timely repaired can lead to mutations and genetic changes that in turn can lead to problems with cell proliferation, aging and development of cancer. Most of the cancer-driving mutations are results of random mistakes during the process of DNA replication. Moreover, hereditary mutations in components of the DNA replication machinery cause a set of disorders characterised by small stature and small brain due to inability to create enough cells to develop a normally sized human being.

The data we generated in preparation of this proposal suggest that a protein DONSON, which does not exist in yeast, may be a functional equivalent of one of the yeast key origin activators, Sld2, for which such an equivalent in higher eukaryotes is missing. DONSON, when mutated, leads to Meier-Gorlin syndrome - a dwarfism disorder caused by faulty DNA replication initiation; conversely, its overexpression is linked with development of several cancer types. DONSON has been shown to be important for sustaining DNA replication, but its molecular function has not been determined and there is no described role for DONSON in origin activation. Here we propose to investigate the function of DONSON during DNA replication initiation in two higher eukaryotic model systems: cell-free extract prepared from African Clawed frog's eggs and immortalised human cell lines.

We will use biochemical approaches in egg extract to understand where DONSON temporally fits within the origin activation process. We will also determine which part of DONSON is important for its function and how it is regulated. All these will establish if DONSON can act as a key activator of replication origins.

Dr Clare Davies

Title: Understanding the mechanisms of chemoresistance governed by PRMT5 and splicing in breast cancer stem cells

• Principle Investigator: Clare Davies
• Co-Investigator: Roland Arnold
• Breast Cancer Now project grant
• 1^st April 2024 to 30^th March 2027
• £249,806

Breast cancer originates from a specialised type of tumour cell that are called breast cancer stem cells (BCSCs) due to similarities with normal stem cells. Although each tumour contains only a small number of these cells, they are very important as they are responsible for cancer establishment, progression, metastasis and resistance to therapy. Understanding the biology of these cells is imperative to completely eradicate cancer.

For some breast cancer patients, chemotherapies are the only therapeutic option. These drug work by damaging DNA to such an extent that the cancer cell cannot survive. Cancer stem cells from other types of cancers are more drug resistant than the rest of the tumour cells because they can rapidly activate pathways that repair the DNA damage induced by the chemotherapy. We have now shown that this is also the case for BCSCs.

In this project we will build on our recent discoveries using various cancer models to determine if PRMT5, an enzyme that modifies proteins, regulates splicing of DNA repair genes in BCSCs isolated from a highly aggressive subtype of breast cancer called triple negative. This is important as PRMT5 inhibitors are in phase I clinical trials as a new cancer therapy. Together, these experiments will provide new mechanisms by which BCSC evade therapies and new approaches in which to harness the power of PRMT5 inhibitors, ultimately lead to a better patient experience and long-term outcome.