Circular RNAs Linking Viral Infection and Mechanotransduction in Kaposi Sarcoma

About the Project

Title: Circular RNAs Linking Viral Infection and Mechanotransduction in Kaposi Sarcoma

Synopsis: How do circular RNAs (circRNAs) regulate Kaposi sarcoma herpesvirus (KSHV) and biomechanical signalling that drives Kaposi sarcoma, and can targeting these pathways reveal new therapeutic strategies? This project will determine how circRNAs control viral persistence and mechanotransduction via Hippo pathway, revealing new targetable mechanisms linking infection, RNA regulation, and tumorigenesis.

Details: Kaposi sarcoma (KS) is a chronic vascular cancer driven by persistent infection with KSHV. Although viral oncogenes are essential for tumour initiation, disease progression depends on host–pathogen interactions that reprogramme endothelial cell behaviour, inflammatory signalling, and tissue architecture & mechanics. However, the molecular regulators linking viral infection to biomechanical changes in KS are elusive. Mechanosensation and cellular responses have recently been implicated in promoting broad antiviral mechanisms1, but implications for KSHV remain unknown.

CircRNAs are a novel class of regulatory RNAs produced by back-splicing of pre-mRNAs. CircRNAs are highly stable and regulate gene expression by acting as microRNA or RNA-binding protein sponges, scaffolding proteins, or by modulating transcriptional and signalling networks. Both host and viral circRNAs are increasingly recognised as regulators of infection and immune evasion2,3. Despite these discoveries, the role of circRNAs in KSHV infection and cancers remain largely unexplored.

A defining feature of KS is extensive vascular remodelling and altered tissue mechanics. KSHV infection induces endothelial cell reprogramming, angiogenesis, and cytoskeletal remodelling, suggesting biomechanical signalling contributes to disease progression. The Hippo pathway, through transcriptional regulators YAP and TAZ, acts as a central mechanotransduction pathway converting mechanical cues from the extracellular matrix and cytoskeleton into transcriptional programmes controlling proliferation, homeostasis, and stemness4. Dysregulation of Hippo signalling is increasingly implicated in cancer5, but its regulation during KSHV infection remains poorly defined.

This project will investigate how circRNAs link viral infection to biomechanical signalling in KS. By integrating RNA biology, virology, and mechanobiology, the project aims to uncover how circRNAs influence KSHV persistence and tumour-promoting signalling pathways.

First, using microfluidic systems to model physiological shear stress, the circRNA landscape will be defined in endothelial cells using RNA-seq to quantify host- and virus-derived circRNAs induced during infection alongside mRNAs. KSHV-regulated circRNAs will be compared with those from other herpesviruses to identify conserved functional candidates. Selected circRNAs will be validated using biochemical assays and analysed for regulatory networks involving microRNAs and signalling pathways.

Second, the functional roles of candidate circRNAs will be investigated using RNA-targeting approaches including CRISPR-based RNA perturbation, RNA interference, and antisense oligonucleotides. These experiments will assess effects on viral lifecycle, cell proliferation, and host antiviral responses.

Third, the project will determine how circRNAs regulate mechanotransduction pathways contributing to tumour development, including mechanical stress gradients and fibrotic extracellular matrix environments. Using engineered extracellular matrices, microfluidics, high-content imaging, and biomechanical assays, the study will assess how circRNA affects endothelial cell mechanics, cellular function, and Hippo pathway activation. YAP/TAZ localisation, transcriptional activity, and downstream functional consequences will be analysed. Therapeutically targeting this pathway5 may enable reversal of pathogenic phenotypes.

PPIE activities will be embedded in the studentship through the recently established Edinburgh Sarcoma Network, PPI advocates and ongoing engagement with Sarcoma UK.

This interdisciplinary project combines RNA biology, viral pathogenesis, cancer mechanobiology, imaging, and bioinformatics to uncover a new regulatory layer in virus-driven cancer. By linking circRNA regulation to mechanotransductive signalling during infection, the work may reveal new mechanisms by which chronic viral infections drive non-communicable diseases such as cancer.

Potential impacts: Identifying circRNAs that regulate KSHV infection and Hippo signalling may reveal biomarkers and therapeutic targets for Kaposi sarcoma. Targeting pathogenic circRNAs or mechanotransduction pathways, including Hippo signalling, could disrupt virus-driven tumour progression and offer new therapeutic strategies for infection-associated cancers, thereby provide new treatment strategies for infection-associated cancers.

Training and skills development: The student will receive interdisciplinary training across cancer biology, virology, RNA biology, and mechanobiology through the complementary expertise of the Hansen and Tagawa laboratories. The Hansen lab investigates how Hippo pathway signalling drives cancer development in hard-to-treat malignancies and evaluates novel therapeutics targeting this pathway. The group has extensive expertise in high-content imaging, endothelial biology, and mechanotransduction, including advanced microfluidic systems that model physiological fluid forces experienced by cells.

The Tagawa lab brings strong expertise in herpesvirus, bioinformatics, and multi-omics, particularly circRNA quantification and network modelling. The group was among the first to identify virus-encoded circRNAs and their roles in viral–host interactions. Together, the supervisory team provides complementary expertise, enabling the student to develop skills in advanced imaging, mechanobiology, RNA biology, viral infection, and computational analysis. Clinical guidance from Dr Oswald will ensure translational relevance and engagement with the Scottish Sarcoma Network and patient advocates.

The student will be based primarily at the Institute for Regeneration and Repair (IRR), a modern research institute with state-of-the-art imaging facilities, expert technical support, and regular training workshops in imaging, bioinformatics, and quantitative data analysis. Research stays at IQB3 will provide additional exposure to complementary research environments and access to core facilities through the Discovery Research Platform including flow cytometry and proteomics. PPIE training will also be delivered.

The student will benefit from an inclusive and supportive research environment with regular supervision, mentorship, and opportunities to participate in seminars, student-led symposia, outreach & PPI activities, and cohort training, fostering scientific independence, communication, and leadership skills.

Recruitment requirements: The main criteria are a real motivation and drive to conduct an interdisciplinary PhD, to maximise this opportunity for personal & professional growth and to deliver the project. Additionally, a willingness and capacity to learn new technologies and work collaboratively in addressing challenging research questions at the forefront of current knowledge to drive fundamental knowledge gain and translational impact are needed.

Additional non-essential desired experiences are expertise in mammalian tissue culture, bioinformatics, molecular biology and imaging. Candidates will furthermore benefit from hands-on experiences in virology, RNA biology, or immunology. An interest in interactions with patient groups and the public is desirable.

Funding Notes

Students will receive a stipend at UKRI levels, plus £30K in travel and research funds across all three years of the fellowship.

All University fees will be covered.