Cellular and molecular mechanisms of breast cancer metastasis
Metastasis is a rare event, in which most cancer cells cannot progress through major bottlenecks associated with invasion, intravasation, extravasation, seeding and colonization to produce a malignant macrometastatic tumour. In our laboratory, we use single cell technologies to investigate which kinds of cancer cells can metastasize and what unique properties enable them to do so. In this model, cancer cells are heterogeneous in genotype (nuclei) and phenotype (cytoplasm), and metastasis-initiating cells possess a distinct combination of both (Figure from Lawson, Kessenbrock et al., Nat Cell Biol, 2018). Dashed arrow indicates that cancer cells within micrometastases can die. Death rates within micrometastases can balance proliferation rates, and thereby prevent progression to macrometastasis by the failure to produce net positive growth.
Intratumor heterogeneity and metastasis
Tumours comprise a heterogeneous population of cells, which is regulated by both intrinsic and extrinsic factors. Tumour cells vary in biomarker expression, epigenetic landscape, hypoxic state, metabolic state, stage of differentiation, invasive potential and genotype due to genomic instability (Figure from Lawson, Kessenbrock et al., Nat Cell Biol, 2018). The tumour microenvironment can also be heterogeneous, in which different types of fibroblasts, pro-tumour and anti-tumour immune infiltrate, vascular and lymphatic vessel density and extracellular matrix (ECM) composition affect tumour cell heterogeneity and function. In our laboratory, we use single cell genomics technologies to study intratumour heterogeneity and its role in cancer metastasis.
We use single nucleus and single cell RNA sequencing methods to investigate transcriptional heterogeneity and identify drivers of metastatic progression.
We use single nucleus multiomics (ATAC+RNA) technology to investigate epigenetic drivers of metastasis.
We use spatial transcriptomics technologies to localize cell types and cell states within tissues based on their RNA expression patterns.
We use Co-detection by indexing (CODEX) to resolve cell types and cell states within tissues based on their protein expression patterns.