PhD Project: Single-cell isoform atlases of breast and prostate cancers

Supervisor: Professor Alex Swarbrick

The advent of single cell and spatial transcriptomics has revolutionised our understanding of tumour microenvironments(1). However, the use of short read sequencing has limited our understanding of transcriptional complexity to simply counting gene expression.

Substantial evidence suggests that critical changes in cellular behaviour, potential and evolution are driven through changes to genome and transcriptome structure and organization that are not visible using conventional short-read methods, such as alternative splicing and promoter usage, somatic evolution and gene fusions.

To address this gap, we have formed an exciting new collaboration with Dr. Aziz Al-Khafaji, head of molecular R&D at the Broad Institute of MIT and Harvard, one of the world's leading genomics facilities. In this project, we will use high powered and advanced long read sequencing technologies (2) and apply them to single cell and spatial libraries generated from human breast (3) and prostate(4)  cancer specimens.

You will work within a multidisciplinary team of scientists and clinicians at Garvan to interpret and understand data coming off the Broad Institute’s sequencing and computational pipelines.Together, we will discover new insights into disease progression and drug resistance and validate these in clinical and experimental models.

The training you receive will place you at the leading edge of molecular cancer research. 

This role suits an individual with an interest or, ideally, expertise and formal training in computational biology.  An interest in performing some experimental work to validate findings is desired.

1.     J. Chen, L. Larsson, A. Swarbrick, J. Lundeberg, Spatial landscapes of cancers: insights and opportunities. Nat. Rev. Clin. Oncol. 21, 660–674 (2024).

2.     A. M. Al’Khafaji, J. T. Smith, K. V. Garimella, M. Babadi, V. Popic, M. Sade-Feldman, M. Gatzen, S. Sarkizova, M. A. Schwartz, E. M. Blaum, A. Day, M. Costello, T. Bowers, S. Gabriel, E. Banks, A. A. Philippakis, G. M. Boland, P. C. Blainey, N. Hacohen, High-throughput RNA isoform sequencing using programmed cDNA concatenation. Nat. Biotechnol. 42, 582–586 (2024).

3.     S. Z. Wu, G. Al-Eryani, D. L. Roden, S. Junankar, K. Harvey, A. Andersson, A. Thennavan, C. Wang, J. R. Torpy, N. Bartonicek, T. Wang, L. Larsson, D. Kaczorowski, N. I. Weisenfeld, C. R. Uytingco, J. G. Chew, Z. W. Bent, C.-L. Chan, V. Gnanasambandapillai, C.-A. Dutertre, L. Gluch, M. N. Hui, J. Beith, A. Parker, E. Robbins, D. Segara, C. Cooper, C. Mak, B. Chan, S. Warrier, F. Ginhoux, E. Millar, J. E. Powell, S. R. Williams, X. S. Liu, S. O’Toole, E. Lim, J. Lundeberg, C. M. Perou, A. Swarbrick, A single-cell and spatially resolved atlas of human breast cancers. Nat. Genet. 53, 1334–1347 (2021).

4.         E. Apostolov, D. L. Roden, H. Holliday, A. Cazet, K. Harvey, H. Zhang, S. Z. Wu, S. van der Leij, L. A. Selth, N. Bartonicek, G. Al-Eryani, M. He, J. Lundeberg, J. Reeves, J. G. Kench, A. J. Potter, P. D. Stricker, A. M. Joshua, L. G. Horvath, A. Swarbrick, Profiling of epithelial functional states and fibroblast phenotypes in hormone therapy-naive localised prostate cancer, bioRxiv (2024). https://doi.org/10.1101/2024.10.23.619925.