Assessing the impact of epigenetic inhibitors on reversion of the chromatin landscape from metastatic to non-metastatic organoids
Colorectal cancer, a leading cause of cancer-related mortality due to distant metastases, is driven by activating mutations in the Wnt and MAPK pathways. Understanding the interplay between these crucial pathways during metastatic progression is essential for developing effective treatments. Here we developed an immunocompetent mouse model of metastatic colorectal cancer using in vivo orthotopic passaging. We demonstrate that highly metastatic tumor cells show increased accessibility of AP-1 TF motifs and less accessibility at TCF/LEF, suggesting higher MAPK and less WNT activity, respectively. Overall design: We have developed an immuno-competent mouse model of metastatic colorectal cancer by sequentially passaging small intestinal organoids with mutations in Apc, Kras, Tp53 and Smad4 in vivo. Organoids from either Passage 1 (P1, m4) or Passage 5 (P5, m484) were orthotopically injected into the colon of C57BL/6N mice. 5 weeks post orthotopic injection colon tumors were harvested, digested into single cells and live Epcam+ cells sorted. P1 tumors: n=4; P5 tumors: n=4