Characterising the cellular state transitions mediating colorectal cancer metastasis

Background: To form metastasis, cancer cells undergo rapid phenotypic transitions in order to leave the primary site, survive in circulation, adapt to new microenvironments and regenerate tumours at distant sites. This ability to reversibly switch states and adapt is referred to as cellular plasticity.

The transcriptional and epigenetic heterogeneity of cell states and the cellular and molecular changes that drive cellular plasticity during CRC progression and metastasis remain poorly understood.

Our preliminary analyses of single-cell and spatial transcriptomics data uncover extensive transcriptional heterogeneity and potentially invasive cancer subpopulations in both primary and metastatic cancers.

We demonstrate that cancer cells retain the hierarchical organisation of their tissue of origin, indicating that cellular transitions into invasive phenotypes are likely driven intrinsically.

However, different cancer states are spatially segregated and organised into distinct local environments, pointing to the role of the microenvironment in mediating cell states. Aims: We aim to define the cellular transition states underlying CRC metastasis.

We hypothesise that these transitions are regulated by chromatin remodelling and/or activation of specific transcription factors, however, the microenvironment can sustain, enhance, or restrict them.

Specifically: 1) Characterise the phenotype of invasive cells and the cellular and molecular mechanisms driving transitions into pro-metastatic states at primary tumours and transitions to stem cells at metastatic sites; 2) Dissect the cell-cell communication events that drive cellular transitions; 3) Model cell state transitions in vitro using patient-derived organoids; Methods: We will pursue an interdisciplinary approach by combining single-cell multi-omics and spatial transcriptomics from patient primary and metastatic tumours and corresponding blood samples, as well as patient-derived organoids.

Lineage tracing will enable reconstruction of evolutionary trees and quantitative measurement of plasticity and transition rates.

We will computationally model cell-state transitions using joint transcriptomics/chromatin accessibility measurements and identify epigenetic drivers of transcriptional change.

We will investigate how the spatial organisation of cells into local niches shapes cancer phenotypes and disentangle the microenvironmental cues that promote invasive phenotypes.

Analysis of circulating tumour cells will characterise the phenotype of metastasis-initiating cells and integration with primary and metastatic data will enable modelling of the continuum of cell-state transitions during progression from primary to metastatic cancer.

How the results of this research will be used: We will identify epigenetic or signaling factors that can be targeted to restrict cell transition into invasive phenotypes or promote transition into immunosensitive states, laying the groundwork for development of novel therapeutic approaches to impair metastasis.