Prof Jane Visvader: The breast epithelial differentiation hierarchy and tumour heterogeneity
Location:Seminar Room 1 and 2, Children’s Medical Research Institute (CMRI), 214 Hawkesbury Rd, Westmead
Prof Jane Visvader, Head of the ACRF Cancer Biology and Stem Cell Division, Walter and Eliza Hall Institute of Medical Research
Seminar Title: The breast epithelial differentiation hierarchy and tumour heterogeneity
Host: Roger Reddel
Abstract: Breast cancer is a highly heterogeneous disease at both the molecular and pathological levels. To understand this heterogeneity and the ‘cells of origin’ of breast cancer, it is important to dissect the normal mammary epithelial hierarchy. Despite accumulating evidence for a mammary differentiation hierarchy, the basal compartment comprising stem cells remains poorly characterized. Through the use of a novel cell surface marker Tspan8 together with Lgr5 we have identified a dormant subset of MaSCs that is localized to the proximal region of the gland throughout life but remains highly responsive to stimuli. Moreover, recent single cell gene expression analyses have revealed unexpected complexity within the basal and luminal compartments. Analysis of different stages of development spanning embryogenesis to the pregnancy cycle has provided insights into the earliest ‘lineage priming’ events and a large-scale shift in the gene expression program near the onset of puberty.
In a further layer of investigation, lineage tracing studies combined with 3D confocal imaging has enabled the visualisation of large regions of intact tissue and provided insights into tumour heterogeneity and cellular dynamics at clonal resolution. We have used a combined lineage tracing and 3D imaging strategy to exploit novel transgenic strains harbouring specific gene regulatory regions to direct expression of specific mammary oncogenic lesions to discrete cell types. Through a pipeline that integrates multicolour lineage tracing, 3D imaging, cell sorting and RNA-sequencing of tumour clones, we identified potential cells of origin of cancer and showed that plasticity is a frequent event at a clonal level. This work highlights the inherent plasticity of mammary tumours and suggests that the epithelial-to-mesenchymal transition (EMT) is not a rare event in vivo.