ABSTRACT
The epithelial to mesenchymal transition (EMT) is a key cellular process underlying cancer progression, with multiple intermediate states whose molecular hallmarks remain poorly characterized. To fill this gap, we explored EMT trajectories in 7,180 tumours of epithelial origin and identified three macro-states with prognostic and therapeutic value, attributable to epithelial, hybrid E/M and mesenchymal phenotypes. We show that the hybrid state is remarkably stable and linked with increased aneuploidy and APOBEC mutagenesis. We further employed spatial transcriptomics and single cell datasets to show that local effects impact EMT transformation through the establishment of distinct interaction patterns with cytotoxic, NK cells and fibroblasts in the tumour microenvironment. Additionally, we provide an extensive catalogue of genomic events underlying distinct evolutionary constraints on EMT transformation. This study sheds light on the aetiology of distinct stages along the EMT trajectory, and highlights broader genomic and environmental hallmarks shaping the mesenchymal transformation of primary tumours.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
We have made the following major modifications to the analysis and manuscript: 1.Built a consensus dataset from multiple cancer and non-transformed cell lines to act as reference for EMT reconstruction 2.Performed tumour purity correction of expression data to account for potential confounding signals from the tumour microenvironment (TME) 3.Re-inferred the EMT pseudotimeline and states pan-cancer and in selected cancer types 4.Analysed several longitudinal EMT datasets to further validate the method 5.Added spatial transcriptomics profiling to better explore the relation between tumour cells in different EMT states and their microenvironment, as well as the relation to hypoxia 6.Added single cell transcriptomics data to get further insights into EMT-TME cell interactions 7.Validated genomic associations using public siRNA screens