Despite colorectal cancer (CRC) remaining a prominent cause of cancer death worldwide, there is little known about how the surrounding connective tissue “stroma” encourages poorer prognosis. While many studies have attempted to interrogate the molecular cross-talk between the tumour and its stroma, the most important tumour-promoting interactions remain ill-defined. We are yet to adequately exploit these pathways for the prevention and treatment of cancer. Tumour development is often likened to the “organ that never develops”, as common developmental programs appear to be shared with tumourigenesis. We therefore postulated that by interrogating all the differentially expressed genes in the stroma during colonic development and tumourigenesis, compared to the normal homeostatic colon, we might identify the common, and thus the most biologically relevant, factors associated with CRC progression – the ‘Activated Stromal Signature’ of CRC. This list was obtained via RNA sequencing (RNAseq) and refined via prognostic relevance and immunohistochemical validation. These top stromal candidates will be investigated predominantly by organoid culture and orthotopic murine CRC models. We expect to not only identify a network of factors involved in CRC progression, but to suggest novel targets for the prevention and treatment of CRC.