Understanding how loss of ARID2, a chromatin remodelling gene, promotes chromosomal instability and lung cancer evolution
Primary supervisor: Lovorka Stojic, Queen Mary University of London
Secondary supervisor: Nnenna Kanu, UCL
Project
Nearly 25% of all cancers exhibit mutations in SWI/SNF chromatin remodelling genes [1]. SWI/SNF chromatin remodelling complexes function as tumour-suppressors, regulating gene expression, chromatin architecture and genome stability. SWI/SNF activity is crucial in preventing chromosomal instability (CIN) [3], a hallmark of cancer associated with therapeutic resistance, immune evasion and metastasis [4]. The ARID2 protein is an important subunit of the PBAF (Polybromo-associated BAF) chromatin remodelling complex [2], one of the three mammalian SWI/SNF remodelling complexes. ARID2 is mutated in various cancers and its loss drives CIN and cancer evolution. However, the ARID2 function in these processes remains elusive.
Our preliminary findings suggest that ARID2 has a transcription-independent role in preventing CIN. Here, we propose to investigate the mechanism by which loss of ARID2 contributes to CIN and the development of lung cancer. We are uniquely positioned to address this question due to our tools and novel preliminary data. This multidisciplinary research project will combine expertise in cell and chromatin biology with imaging and evolutionary biology of lung cancer to accomplish the following aims:
Aim 1: Characterise the origin of chromosome segregation errors in ARID2-depleted cells.
- we will model ARID2 deficiency using genome editing methods in non-cancerous diploid cell lines, including normal lung epithelial cells.
- we will characterise mitotic defects in ARID2-depleted cells using state-of-the-art microscopy and live-cell imaging.
Aim 2: Dissect the underlying mechanism by which ARID2 loss leads to CIN.
- by combining functional genomics and cellular assays, we will i) determine whether ARID2 associates with (peri)centromeric chromatin, ii) confirm ARID2 interaction with kinetochore proteins; and iii) investigate the effects of ARID2 loss on centromere/kinetochore integrity and aneuploidy.
Aim 3: Explore how ARID2 loss promotes CIN early in lung cancer evolution.
- we will map the progression of ARID2 downregulation from normal tissues to lung adenocarcinoma using clinical samples from the lung TRAcking Cancer Evolution Through Therapy (Rx) (TRACERx) study [5], and examine the correlation between measures of CIN and ARID2 expression in TRACERx dataset.
Given the prevalence of SWI/SNF dysregulation in cancer, understanding how ARID2 loss drives CIN and contributes to the tumor-suppresive role of the SWI/SNF chromatin remodelling complex will open-up new therapeutic approaches for cancer patients.
Candidate background
The candidate must demonstrate enthusiasm for cancer and chromatin biology. Previous wet lab experience, particularly in CRISPR, molecular biology and imaging are highly desirable. This project would also suit candidates with an interest in epigenetics.
Potential Research Placements
- Sarah McClelland, Barts Cancer Institute, Queen Mary University London
- Nnenna Kanu, Francis Crick Institute/ Cancer Institute, UCL
- Nicholas McGranahan, Cancer Institute, UCL
References
- Kadoch, C. et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet 45, 592-601 (2013).
- Brownlee, P.M., Chambers, A.L., Cloney, R., Bianchi, A. & Downs, J.A. BAF180 promotes cohesion and prevents genome instability and aneuploidy. Cell Rep 6, 973-981 (2014).
- Tijhuis, A.E., Johnson, S.C. & McClelland, S.E. The emerging links between chromosomal instability (CIN), metastasis, inflammation and tumour immunity. Mol Cytogenet 12, 17 (2019).
- Pan, D. et al. A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science 359, 770-775 (2018).
- Martinez-Ruiz, C. et al. Genomic-transcriptomic evolution in lung cancer and metastasis. Nature 616, 543-552 (2023).