Solid cancers are a complex ‘ecosystem’ of diverse cell types, whose heterotypic interactions play central roles in defining the aetiology of disease and its response to therapy. We used a multi-dimensional single cell genomics approach to characterise the tumour microenvironment in a unique cohort of early breast cancers.
Malignant cells showed remarkable intra-tumoural heterogeneity for canonical breast cancer features, such as intrinsic subtype, hormone receptor expression and transcriptional drivers. By integrating with the Nanostring DSP platform for spatial RNA profiling, we identify signatures to distinguish malignant cell clusters from benign and morphologically normal epithelial cells.
Cancer Associated Fibroblasts (CAFs) were found in at least two states: a myofibroblast-like subset and an inflammatory-mediator subset. Distinct transcription factor networks regulated these polarised states. We show distinct functions for these subsets.
We applied CITE-Seq to measure >150 cell surface immune markers and checkpoint proteins simultaneous to RNA-Sequencing. We resolve the tumour-immune milieu with high precision and generate new transcriptional signatures of breast tumour-infiltrating leukocytes.
To track lymphocyte clonal dynamics through space and time, we developed a novel method to permit simultaneous full-length lymphocyte receptor- and short-read RNA-sequencing at single cell resolution. We observe clonal expansion and trafficking of CD4+ and CD8+ T lymphocytes between the lymph nodes, blood and tumor of patients.
This data provides by far the most extensive insights into the cellular landscape of breast cancer and will reveal new biomarkers and opportunities for stromal- and immune-based therapy.
Associate Prof Alex Swarbrick
Laboratory Head, Garvin Institute of Medical Research
Alex graduated with a Bsc (Hons I) in Molecular and Cellular Biology from UNSW in 1995. After obtaining his PhD in 2003 he undertook postdoctoral training with Nobel laureate J. Michael Bishop at the University of California, San Francisco, supported by a CJ Martin Travelling Fellowship from the NHMRC.
In 2008 Alex established the Tumour Progression Laboratory in the Garvan Institute and in 2012 was appointed co-Head of the Breast Translational Oncology Program in the newly commissioned Kinghorn Cancer Centre. Alex is an Associate Professor at UNSW and an NHMRC Senior Research Fellow.
His lab uses single cell ‘omics analysis of clinical tissue cohorts and patient-avatar models to discover novel treatment strategies for solid cancers, including breast, prostate, melanoma and neuroblastoma.
Alex is the convenor of the Lorne Cancer Conference, Australia’s pre-eminent multi-disciplinary cancer research conference & the Australian Translational Breast & Prostate Cancer Symposium. He serves on the Cancer Research Committee of the Cancer Council NSW.