Alterations in cellular phenotypic diversity underlie colorectal cancer predisposition, development and progression

Colorectal cancer (CRC) progression is characterised by an increase in cellular plasticity and phenotypic heterogeneity, which exacerbates during metastasis and associates with poor patient survival. How cells acquire the ability to shift between states and how this drives cancer progression has remained unclear.
I will present our recent work on BRAF-mutant CRC, a subtype that typically arises via the serrated pathway and associates with poor prognosis. Our findings support a model in which tumor cell plasticity fosters self-organized stem and niche cell interactions. We propose that formation of a tumor-intrinsic niche is a key step in metastatic competence, offering novel therapeutic opportunities.
Additionally, I will present our insights into how LKB1 deficiency, linked to the hereditary Peutz-Jeghers polyposis syndrome (PJS), alters the phenotypical landscape of the intestinal epithelium to mediate an increased cancer risk. By leveraging human PJS-derived intestinal organoids from polyp and non-polyp tissues, we reconstruct clonal relationships and mutational trajectories and shed light on how epithelial genotypic and phenotypic alterations drive cancer risk in PJS.
Finally, I will introduce a novel strategy for targeted degradation of membrane proteins using heterobifunctional antibodies (SureTACs) that promote the recruitment of transmembrane E3 ligases to specific membrane targets, followed by lysosomal degradation. I will present this approach’s efficacy in an immune-oncology CRC model, highlighting its key advantages including tissue specificity and the ability to target otherwise intractable proteins.