TP53 loss attenuates C1q-associated macrophage remodeling in early adenomatous polyps in a porcine FAP model

Familial adenomatous polyposis (FAP) is a hereditary condition that almost invariably leads to colorectal cancer. While TP53 inactivation is well established as a late event in the adenoma-to-carcinoma sequence, its functional role during the early stage of colorectal polyp development remains unclear.

Three lines of FAP pigs were generated: APC^1311/+ , APC^1311/+ /TP53^+/- , and APC^1311/+ /TP53^-/- . Colonic polyp development was evaluated by colonoscopy at 3 and 9 months of age. Mucosal goblet cell and mucin content were assessed using periodic acid-Schiff/Alcian blue (PAS-AB) staining. Immunohistochemistry for Ki67 and IBA1 was performed to assess epithelial proliferation and macrophage/monocyte-like cell infiltration, respectively. Quantitative PCR was used to measure mRNA expression of macrophage/monocyte - and complement-related genes, including CCL2, FCGR3A, ITGAM, and members of the C1q family.

Macroscopic adenomatous polyp burden and growth dynamics were comparable across genotypes. However, APC^1311/+ /TP53^-/- pigs exhibited significantly reduced epithelial proliferation within polyp crypts, as indicated by decreased Ki67⁺ expression. Furthermore, immunohistochemistry revealed a significant reduction of stromal IBA1⁺ macrophage/monocyte-like cells in polyps from APC^1311/+ /TP53^-/- animals. Consistently, expression levels of CCL2, ITGAM, FCGR3A, and complement components C1QB and C1QC were significantly downregulated.

Loss of TP53 did not accelerate early-stage adenomatous polyp progression in the FAP pig model. However, TP53 deficiency was associated with significant alterations in the polyp microenvironment, particularly characterized by reduced C1q-associated macrophage remodeling and diminished expression of macrophage/monocyte- and complement-related genes. These findings suggest a role for TP53 in modulating the inflammatory tumor microenvironment during colorectal tumorigenesis.