Retrotransposable elements in glioblastoma pathogenesis and immunogenicity

Project background and description

The human genome is not the static blueprint it was once thought to be. Nearly half of it consists of transposable elements (TEs) — mobile genetic sequences that have integrated into our DNA over millions of years of evolution. The vast majority are fragments of retrotransposable elements (RTEs), including long and short interspersed nuclear elements (LINEs and SINEs, respectively) and endogenous retroviruses (HERVs), the remnants of ancient retroviral infections [2]. While most HERV sequences are silenced through epigenetic mechanisms, a growing body of evidence demonstrates that they become reactivated in cancer, with profound consequences for tumour biology [1].

Glioblastoma multiforme (GBM) remains one of the most lethal human malignancies [2]. A defining feature of GBM is the presence of glioblastoma stem cells (GSCs), a self-renewing population that drives tumour heterogeneity, treatment resistance, and recurrence.

Understanding the molecular underpinnings of GSC identity is therefore a priority for the field. GBM is also characterised by its profound epigenetic dysregulation, which can transcriptionally activate normally silenced RTEs. Aberrantly reactivated RTEs, and members of the most recently integrated HERV subfamily, HERVK(HML-2), have been linked with the maintenance of the GSC niche and the creation of potentially immunogenic GMB-specific antigens for recognition by the adaptive immune response [3-5]. These early findings provide a compelling context in which to investigate RTE reactivation and its functional consequence in GMB.

This PhD project will address several key questions, including the landscape of RTE expression across GBM subtypes and how it may correlate with epigenetic state and patient outcomes; how RTE-encoded proteins or cis-regulation of host genes contribute directly to GBM oncogenesis, proliferation or immunogenicity; and whether genetic or pharmacological manipulation of RTEs, for instance through epigenetic drugs or immune targeting, can be leveraged to altered the disease profile or outcome.

The project will unite two laboratories with complementary expertise. Prof. Sheila Singh (King's College London) is a clinician-scientist and leading authority on GBM stem cell biology, with an extensive biobank of patient-derived GSC lines and orthotopic xenograft models, and a track record of translating mechanistic discoveries toward immunotherapy.

Prof. George Kassiotis (Francis Crick Institute) leads an internationally recognised programme in retroviral immunology and HERV biology, with specific expertise in HERV transcriptomics, locus-specific analysis, and the immunological consequences of endogenous retroviral reactivation in cancer. The student will be embedded in both laboratories and will benefit from an integrated environment spanning molecular retrovirology, cancer stem cell biology and neuro-oncology.

Upon completion, this project is expected to generate mechanistic and functional accounts of RTE biology in GBM, integrating perspectives from HERV immunology, epigenetics and clinical neuro-oncology. By establishing whether RTE reactivation impacts the oncogenic process or modulates immunogenicity, the project will identify novel therapeutic vulnerabilities in a disease that has remained relatively resistant to progress for two decades.

Candidate background

This project would suit candidates with a background in cancer biology, including in mouse models, and an interest in genetics/genomics.

Lab-specific question

Which of the most important unanswered questions relating to the biology of transposable elements, particularly in the context of cancer, would you investigate and how?

Funding Notes

Successful applicants will be awarded a non-taxable annual stipend of £27,715 plus payment of university tuition fees. Students of all nationalities are eligible to apply.