Extended Data Fig. 10: LXR activation suppresses intestinal tumorigenesis.

(a) Scheme of the experiment showing Apc^Min/+ mice fed with either standard or GW3965 diet post-weaning until approximately 16 weeks of age when mice were sacrificed and evaluated for tumour development. (b) Quantification of tumour numbers and size in the SI of Apc^Min/+ mice fed with standard or GW3965 diet. (c) Representative H&E stained SI Swiss rolls of Apc^Min/+ mice fed with either the standard or GW3965 diet. Areas of tumour are outlined by black dotted lines. (d) Scheme of the experiment showing WT mice fed with standard or GW3965 diet and injected with AOM followed by 3 cycles of DSS. Mice were sacrificed at day 70. (e) Representative H&E stained colon Swiss rolls and quantification of histological lesions of mice undergoing AOM-DSS tumorigenesis and fed with either the standard or GW3965 diet. Areas of tumour are outlined by black dotted lines. (f) Representative H&E stained colon Swiss rolls and quantification of histological lesions of Cyp27a1^−/− and littermate control mice undergoing AOM-DSS tumorigenesis and fed with either the standard or GW3965 diet. Areas of tumour are outlined by black dotted lines. (g) Representative images of immunofluorescence staining of CYP27A1 (green), vimentin (red) and nuclei (Hoechst) in human colonic tissue. (h) Representative pictures and quantification of CYP27A1 immunohistochemical staining in human tissue microarray with healthy and CRC tumour samples. (i) qPCR analysis of expression of EGFR ligands in the colonic tumour biopsies at the end (day 70) of AOM-DSS experiment. (j-k) WT mice fed with standard or GW3965 diet were injected with AOM followed by 3 cycles of DSS and samples were collected after each DSS cycle at indicated time points. Quantification of grossly visible tumours during the course of tumour development (j). Mice fed with either the standard or GW3965 diet (for 22, 43 or 70 days), but not challenged with AOM-DSS were used as day0 samples. (k) Representative H&E images of mice colon fed with standard or GW3965 diet and undergoing AOM-DSS tumorigenesis at day 22 and day 43 post-AOM injection. (l) H&E stained colonic Swiss rolls and spatial transcriptomics (ST) representation of unsupervised clustering of colonic tissue from WT mice fed with STD or GW3965-diet at day 0, day 22 or day 43 of AOM-DSS. Data are representative of one (l) or 2–4 (a-f, and i) independent experiments with 6–13 mice per condition (each dot represents one mouse). For d0, 22 and 43 of AOM-DSS tumour kinetics (j-k), one experiment with 3-4 mice/time point were used, and for d70 two experiments with 11–13 mice were used (as shown in Fig. 4a). In (h) each dot represents one spot in the CRC tumour tissue microarray. Data are shown as mean ± s.e.m. (b, i), median and quartiles (h) or staggered replicates with lines connecting the mean (j). Significance was assessed by unpaired two-sided t test in (b, h, i, j). Part of the schematics in panels a and d were adapted from ref. ¹⁹, CC-BY 4.0.

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