Understanding how loss of chromatin remodelling factor ARID2 promotes chromosomal instability during lung cancer evolution

Primary supervisor: Lovorka Stojic, Queen Mary University of London

Secondary supervisor: Nnenna Kanu, UCL

Project

Lung cancer is the deadliest cancer worldwide and non-small cell lung cancer (NSCLC) comprises 85% of cases (1) with predicted five-year survival rate of 15.9% (2). The lung TRACERx (TRAcking Cancer Evolution through therapy (Rx), a study using multi-region genome sequencing to determine the timing of somatic events relative to distinct genomic instability processes has transformed our understanding of NSCLC. The TRACERx study has a huge potential to uncover new mechanisms of cancer evolution by analysing the intratumour heterogeneity in lung tumours and tracking its evolutionary trajectory from diagnosis through to relapse.

Chromatin remodelling is known to play a key role in multiple physiological and pathological conditions. SWI/ SNF is a large multi-subunit chromatin remodelling complex that uses the energy of ATP hydrolysis to regulate gene expression. Approximately, 20% of all human cancers have alterations in the SWI/SNF complex (3), an occurrence that is only exceeded by mutations in TP53. ARID2, a subunit of the PBAF (Polybromo-associated BAF) chromatin remodelling complex and a tumour suppresor, has been implicated in transcriptional regulation, cell cycle, embryonic development and DNA damage repair. Current data suggest that 20% of lung cancer patients show ARID2 protein loss (4), which can occur through ARID2 mutations and unknown non-genetic mechanisms. Mutations in SWI/ SNF complex including ARID2 were associated with genome instability in lung cancer suggesting that SWI/ SNF may play an important role in the maintenance of genome stability in lung cancer (5).

The objective of this project is to test whether ARID2 in addition of being a DNA binding protein, can also act as a non-canonical RNA binding protein and contributes to chromosomal instability (CIN) during lung cancer evolution. While a rough framework of ARID2 downregulation in lung cancer has been established (4), the dynamics of ARID2 expression from preinvasive to invasive NSCLC lesions as well as mechanism how loss of ARID2 leads to CIN is not yet fully understood. This aim will be achieved by combining cell and RNA biology, high-throughput approaches, live cell imaging and computational approaches by exploiting in vitro lung cell culture models and clinical samples. Since tumour suppressor gene losses are commonly truncal events in cancer evolution, TRACERx lung study can provide new insights in understanding how ARID2 is downregulated during lung cancer development. Since defects in genome stability functions arise as a consequence of SWI/ SNF loss and can lead to therapeutically exploitable vulnerabilities, identifying new synthetic lethality interactions in the background of ARID2 deficiency could led to new promising therapeutic strategy for lung cancer patients.

The specific aims of the project are:

1. to define the dynamics of ARID2 downregulation during lung cancer evolution;
2. to determine the mechanism how loss of ARID2 leads to CIN in lung cancer cell lines;
3. to identify new synthetic lethality interactions in ARID2-depleted lung cancer cell lines.

Ultimately by understanding the role of ARID2 in NSCLC evolutionary dynamics will provide molecular insights how chromatin regulators interact with RNA and DNA to maintain genome stability during lung cancer evolution, which in the future can lead to new strategies to combat this devastating disease.

Candidate background

The project would be suitable for a candidate with a background in cell and molecular biology and/ or computational expertise, and an interest in using interdisciplinary approaches in cancer research.

Potential Research Placements

1. Faraz Mardakheh, Barts Cancer Institute, Queen Mary University London
2. Nicholas McGranahan, UCL Cancer Institute
3. Nnenna Kanu & Charles Swanton, Francis Crick Institute/ UCL Cancer Institute

References

1. Siegel, R. et al. (2013) Cancer statistics, 2013. CA Cancer J Clin 63 (1), 11-30.
2. Ettinger, D.S. et al. (2010) Non-small cell lung cancer. J Natl Compr Canc Netw 8 (7), 740-801.
3. Kadoch, C. et al. (2013) Proteomic and bioinformatic analysis of mammalian SWI/ SNF complexes identifies extensive roles in human malignancy. Nat Genet 45 (6), 592-601.
4. Moreno, T. et al. (2021) ARID2 deficiency promotes tumor progression and is associated with higher sensitivity to chemotherapy in lung cancer. Oncogene 40 (16), 2923-2935.
5. Huang, H.T. et al. (2015) Loss of function of SWI/ SNF chromatin remodeling genes leads to genome instability of human lung cancer. Oncol Rep 33 (1), 283-91.