A pro-regenerative environment triggers premalignant to malignant transformation of senescent hepatocytes.

Unfortunately, available liver cancer treatments are associated with modest survival advantage. The biggest factor improving survival is early detection, but the current understanding of early transformation events is limited. Therefore, we set up a model to study these early events and investigated the relationship of premalignant, senescent hepatocytes, a regenerative environment, and the influence of secreted factors on liver tumorigenesis. Oncogene-induced senescence (OIS) was triggered in a subset of mouse hepatocytes, which under normal conditions, are eliminated by immunosurveillance. Inducing liver damage and regeneration was sufficient to trigger immunosurveillance escape of oncogene-induced senescent hepatocytes, resulting in premalignant to malignant transformation and hepatocellular tumor development. TFF3 was found to be overexpressed in oncogene-induced senescent hepatocytes and in hepatocellular carcinoma. TFF3 deficiency strongly attenuated malignant transformation by increasing IGFBP5 expression, which consequently dampened insulin growth factor receptor signaling. Furthermore, analysis of pre-cancerous liver tissue validated TFF3 as an early liver cancer biomarker. Altogether, these findings provide mechanistic insights into early transformation and immunosurveillance escape in liver cancer, revealing TFF3 and IGFBP5 to be important players with opposite roles in tumorigenesis.