Chronic inflammation promotes development and progression of colorectal cancer (CRC). To comprehensively understand the molecular mechanisms underlying the development and progression of inflamed CRC, we perform in vivo screening and identify 142 genes that are frequently mutated in inflammation-associated colon tumors. These genes include senescence and TGFβ-activin signaling genes. We find that TNFα can induce stemness and activate senescence signaling by enhancing cell plasticity in colonic epithelial cells, which could act as a selective pressure to mutate senescence-related genes in inflammation-associated colonic tumors. Furthermore, we show the efficacy of the Cdk4/6 inhibitor in vivo for inflammation-associated colonic tumors. Finally, we functionally validate that Arhgap5 and Mecom are tumor suppressor genes, providing possible therapeutic targets for CRC. Thus, we demonstrate the importance of the inactivation of senescence pathways in CRC development and progression in an inflammatory microenvironment, which can help progress toward precision medicine.

慢性炎症促进结直肠癌（CRC）的发生和进展。为了全面了解炎症性结直肠癌发生和进展的分子机制，我们进行了体内筛选并鉴定了炎症相关结肠肿瘤中经常突变的 142 个基因。这些基因包括衰老和 TGFβ-激活素信号基因。我们发现TNFα可以通过增强结肠上皮细胞的细胞可塑性来诱导干性并激活衰老信号传导，这可以作为选择性压力来突变炎症相关结肠肿瘤中的衰老相关基因。此外，我们还展示了 Cdk4/6 抑制剂在体内对炎症相关结肠肿瘤的功效。最后，我们从功能上验证了Arhgap5和Mecom是抑癌基因，为CRC提供了可能的治疗靶点。因此，我们证明了衰老途径失活在炎症微环境中结直肠癌发生和进展中的重要性，这有助于精准医学的进展。