The underlying drivers of cancer biology vary between cancer types, and even between cancer subtypes. Accordingly, assigning an appropriate biological model to the growth and progression of a given cancer and understanding the mechanics of that model, is critical to deriving effective therapies.
The plastic cancer cell model, first described by Chaffer et al, 2011, establishes that genetically identical cancer cells undergo bi-directional conversions between the highly aggressive tumour-initiating (TIC) state and the non-TIC cell state. In the breast cancer (BRCA) setting, our group has identified subpopulations of cells that readily switch from the non-TIC to TIC state, a process mediated by the transcription factor ZEB-1. We have found that basal type BRCA non-TICs are uniquely endowed with this plastic phenotype due to their ability to maintain the chromatin at the ZEB-1 promoter in a poised state, ready for activation. Together, these data demonstrate that non-TIC populations have the potential to convert toward more aggressive cellular states, thus acquiring metastatic and adaptive potential.
Confirming the existence of the above-described cellular plasticity in clinical samples and unravelling the molecular networks underlying it, will shed light into key aspects of tumour progression, chemoresistance and recurrence. We are currently testing cell plasticity dynamics in patient derived xenografts (PDX's), combining leading-edge genomic techniques (Chip-seq/RNA-seq) with functional assays and in vivo models of tumorigenesis. Excitingly, preliminary data have shown correspondence between TIC and non-TIC populations observed in cell lines and PDX's models. Further analysis will establish the degree to which the epigenetics regulation observed in cell lines applies to clinical samples. Additionally, we are seeking to understand the nature of ZEB-1 mediated non-TIC to TIC plasticity and to determine if pathways independent of ZEB-1 are critical for non-TIC to TIC inter-conversions. By establishing the mechanisms driving non-TIC to TIC cell plasticity we aim to discover novel therapeutic strategies that will prevent the progression of breast cancer to advanced-stage disease and, ultimately, improve patient survival.