Associate Professor

Alex Swarbrick

Multidimensional single cell analysis of the tumour microenvironment

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.