Colorectal cancer cells actively reprogram the connective tissue around them, creating either a growth-friendly or growth-restricting environment depending on the tumour’s genetic fingerprint. Why this matters: Doctors have long known that some colorectal cancers are more aggressive than others, but they have struggled to explain why. This project targets a specific gap—the molecular conversation between cancer cells and the stromal cells that surround them. Two stromal markers, GREM1 and PDGFRA, point in opposite directions: high GREM1 signals a poor prognosis, high PDGFRA a better one. The researchers have shown that different cancer mutations push stromal cells toward one marker or the other, and that the stroma then talks back, altering the cancer cells themselves. Potential impact: If the team can map the gene-regulatory networks that control this stromal switch, they could identify drug targets that flip the stroma from a tumour-promoting to a tumour-suppressing state. This is fundamental science—no immediate clinical tool will emerge. But understanding how a cancer remodels its neighbourhood, and how that neighbourhood feeds back on the cancer, could eventually lead to therapies that treat colorectal cancer by modulating the stroma rather than killing tumour cells directly.
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Colorectal cancer (CRC) is a complex and heterogeneous disease with variable prognosis, but overall high mortality. Some variation has been explained by different molecular phenotypes, specifically linking activated stromal microenvironment with a poor prognosis. Stromal biomarkers of poor prognosis include GREM1, while stromal PDGFRA is associated with better outcome. Using intestinal stromal cells (iSTC) derived from a human iPSC-derived colon model and screening six co-cultured CRC cell-lines, with varying mutational profiles, has shown that specific CRC mutational profiles are associated with induction of either GREM1-hi/PDGFRA-lo or GREM1-lo/PDGFRA-hi stromal cells. There is reciprocity in that co-cultured epithelial CRC cell-lines are altered in response to iSTC. GREM1-hi and PDGFRA-hi stromal subsets differentially express colonic stroma-related transcription factors. Hypothesis Specific CRC genotypes differentially induce gene-regulatory networks (GRNs) in stromal cells leading to PDGFRA-hi or GREM1-hi populations, influencing cancer cell growth. Plan To enable efficient interrogation of GREM1-hi and PDGFRA-hi populations dual-reporter iPSCs will be generated (which then give rise to colonic stromal populations). Population GRNs will be characterised after flow-sorting. Relationship between a variety of CRC genotypes and PDGFRA-hi/GREM1-hi cells will be assessed through co-culture and allow correlation of specific cancer transcriptional patterns with stromal GRNs. Top hit pathways for each will be investigated through small molecules. Findings on stromal induction and epithelial reciprocity will be validated using in vivo-like colonic organoids. Outcome This project will allow new insights into how CRC reprogrammes its microenvironment, and microenvironment reciprocity determining CRC growth. This could lead to new ways of treating CRC through modulating stroma.
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