Therapeutic manipulation of the stromal compartment in colorectal cancer (360G-Wellcome-203966_Z_16_A)

Recently, experts agreed upon 4 consensus molecular subtypes (CMS) for the classification of colorectal cancer (CRC). CMS1 and CMS4 show a stronger stromal component together with poorer overall survival. Current CRC therapy only targets the tumour epithelium. Harnessing the power of the tumour microenvironment and immune system in CRC could represent a new drug paradigm. We will study the role the mesenchymal-epithelial cross-talk in colon homeostasis by focusing on gremlin-1. This secreted Bone Morphogenetic Protein antagonist is expressed exclusively by subepithelial myofibrobalsts in health. This protein maintains the stem cell phenotype at the bottom of the intestinal crypts, and dysregulation facilitates tumour initiation and progression. We will use mice and orthotopic xenograph models to assess the efficacy of BMP inhibition through an anti-GREM1 blocking antibody. Recent data supports the potential of immunotherapies in immunogenic MSI-H and polymerase epsilon (POLE) mutated tumours. We’ll receive blood and tumour samples from a clinical trial testing a combination of ipilumumab and nivolumab in MSI-H and POLE cases. We’ll use lymphocyte quantification, immunohistochemistry analysis and neo-epitope prediction to find determinants of response to these therapies. These studies will help better understanding and therapeutically exploiting the contribution of the mesenchymal and immune compartments to CRC pathogenesis.